Immunogenicity and safety of primary fractional-dose yellow fever vaccine in autoimmune rheumatic diseases.

BACKGROUND: Brazil faced a yellow fever(YF) outbreak in 2016-2018 and vaccination was considered for autoimmune rheumatic disease patients(ARD) with low immunosuppression due to YF high mortality. OBJECTIVE: This study aimed to evaluate, prospectively for the first time, the short-term immunogenicity of the fractional YF vaccine(YFV) immunization in ARD patients with low immunossupression. METHODS AND RESULTS: A total of 318 participants(159 ARD and 159 age- and sex-matched healthy controls) were vaccinated with the fractional-dose(one fifth) of 17DD-YFV. All subjects were evaluated at entry(D0), D5, D10, and D30 post-vaccination for clinical/laboratory and disease activity parameters for ARD patients. Post-vaccination seroconversion rate(83.7%vs.96.6%, p = 0.0006) and geometric mean titers(GMT) of neutralizing antibodies[1143.7 (95%CI 1012.3-1292.2) vs.731 (95%CI 593.6-900.2), p<0.001] were significantly lower in ARD compared to controls. A lower positivity rate of viremia was also identified for ARD patients compared to controls at D5 (53%vs.70%, p = 0.005) and the levels persisted in D10 for patients and reduced for controls(51%vs.19%, p = 0.0001). The viremia was the only variable associated with seroconvertion. No serious adverse events were reported. ARD disease activity parameters remained stable at D30(p>0.05). CONCLUSION: Fractional-dose 17DD-YF vaccine in ARD patients resulted in a high rate of seroconversion rate(>80%) but lower than controls, with a longer but less intense viremia. This vaccine was immunogenic, safe and did not induce flares in ARD under low immunosuppression and may be indicated in YF outbreak situations and for patients who live or travel to endemic areas. TRIAL REGISTRATION: This clinical trial was registered with Clinicaltrials.gov (#NCT03430388).

Poor Prognosis of COVID-19 Acute Respiratory Distress Syndrome in Lupus Erythematosus: Nationwide Cross-Sectional Population Study Of 252 119 Patients.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) has progressed rapidly around the world, reaching a lethality of up to 20% due to acute respiratory distress syndrome (ARDS). This latter condition is a relevant concern for systemic lupus erythematosus (SLE); however, data on this topic are limited to few case series. Our objective was to evaluate in hospitalized patients with SLE and with COVID-19-associated ARDS (confirmed by reverse transcription-polymerase chain reaction) the risk of mortality and combined poor outcomes (death, intensive care unit [ICU] admission, and/or mechanical ventilation [MV] use) and to compare with that of patients without SLE. METHODS: This is a nationwide cross-sectional study of patients with severe acute respiratory syndrome coronavirus 2 nested in the national Influenza Epidemiological Surveillance Information System (Sistema de Informação de Vigilância Epidemiológica da Gripe [SIVEP-gripe]). Mortality rates, frequencies of ICU admissions, and MV use for 319 patients with SLE and 251 800 patients without SLE were calculated as well as relative risks (RRs). A fully adjusted multiple logistic regression was performed to adjust factors, such as age and well-known comorbidities, that might impact worse outcomes. RESULTS: Patients with SLE had an increased risk of death and combined poor outcome compared with patients without SLE (RR = 1.738, 95% confidence interval [CI]: 1.557-1.914, and RR = 1.391, 95% CI: 1.282-1.492, respectively). Among all investigated comorbidities, SLE yielded the higher risk of death and combined poor outcomes (RR = 2.205, 95% CI: 1.780-2.633, and RR = 1.654, 95% CI: 1.410-1.88, respectively). CONCLUSIONS: This study provides novel evidence that patients with SLE hospitalized because of COVID-19 have significantly higher risks of death and poor outcomes compared with patients without comorbidities and patients with other comorbidities.

Cognitive dysfunction and serum levels of brain-derived neurotrophic factor (BDNF) in primary anti-phospholipid syndrome (PAPS).

OBJECTIVES: Cognitive dysfunction (CD) is a poorly understood non-stroke central neurological manifestation in anti-phospholipid syndrome (APS). Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays an important role in neural plasticity and could potentially be a biomarker of CD in primary APS (PAPS). The aim of the study is to assess CD in PAPS patients and to evaluate its association with clinical data, anti-phospholipid antibodies and serum BDNF levels. METHODS: This cross-sectional study compared 44 PAPS patients and 20 healthy controls matched for age, gender and education. PAPS patients and controls underwent a standardized cognitive examination. The demographic, clinical and laboratory characteristics of patients were recorded. Serum BDNF was measured by Enzyme Linked Immunosorbent. RESULTS: Fourteen (31.8%) of the 44 patients with PAPS had CD compared with only one (5%) healthy control (P =0.019). PAPS patients presented lower serum BDNF levels when compared with controls (P =0.007). Lower levels of BDNF were associated with CD in PAPS patients (P =0.032). In the univariate analysis, a positive association was found between CD and livedo reticularis, deep vein thrombosis, stroke, seizure, smoking as well as a negative association with Mini Mental State Examination and serum BDNF. According to multivariate analysis, the only independent predictor of CD in PAPS was stroke (OR 137.06; 95% CI: 4.73, 3974.32; P =0.004). CONCLUSIONS: CD is commonly reported in PAPS patients; however, its assessment lacks in standards and objective screening tests. The association between CD and low serum BDNF suggests that this neurotrophin can be a promising biomarker for PAPS cognitive impairment.

Is serum uric acid a predictor of long-term renal outcome in lupus nephritis?

BACKGROUND/OBJECTIVE: Recent studies observed an association between increased serum uric acid (SUA) levels and renal damage in lupus. However, the predictive value of UA for the development of long-term renal dysfunction in lupus nephritis (LN) is still unknown. The aim of this study was to evaluate if SUA may be a predictor of long-term renal outcome in LN. METHODS: Eighty biopsy-proven LN patients > 7 years of follow-up were selected. SUA levels were measured in sera stored at - 70 °C. All patients had serum stored from LN baseline, and 32 also had stored serum from 6 and 12 months after LN. Renal outcome was addressed after 7 years of follow-up to determine if SUA could be a predictor of long-term renal outcome. A good long-term renal outcome in 7 years was defined as a creatinine clearance (CrCl) ≥ 90.0 mL/min/1.73 m2, and poor if CrCl < 90 mL/min/1.73 m2. Patients were divided in two groups according to the renal outcome to assess whether SUA levels at different time points of follow-up could differentiate such groups. An ROC curve was plotted to assess accuracy. RESULTS: SUA levels at baseline and 6 months were not able to differentiate good from poor long-term renal outcomes in LN (respectively p = 0.37, p = 0.28), but at 12 months (p = 0.02), they could clearly differentiate the two groups. ROC curve (12 months) accuracy was 0.76. SUA cutoff was 6.05 mg/dL (sensitivity = 0.67, specificity = 0.89, positive predictive value = 0.85, negative predictive value = 0.73). CONCLUSION: SUA levels < 6.05 mg/dL at 12 months of follow-up is a predictor of good long-term renal outcome in lupus nephritis. KEY POINTS: • Previous studies reported an association between increased serum uric acid level and short-term renal damage in lupus patients. • The predictive value of serum uric acid for the development of long-term renal dysfunction in lupus nephritis was never assessed. • At 12 months of follow-up serum uric acid clearly differentiated good from poor long-term renal outcome in lupus nephritis. • SUA level < 6.05 mg/dL at 12 months of follow-up was a predictor of good long-term renal outcome in lupus nephritis.

Enhanced type I interferon gene signature in primary antiphospholipid syndrome: Association with earlier disease onset and preeclampsia.

OBJECTIVE: Recently, two studies demonstrated that a relevant percentage of primary antiphospholipid syndrome (PAPS) patients had an upregulation of interferon (IFN) genes. However, 20%-28% of these patients had anti-dsDNA, a highly specific systemic lupus erythematosus (SLE) autoantibody. This study aimed to determine the prevalence of the type I IFN signature in the peripheral blood mononuclear cells of PAPS patients without specific SLE autoantibodies and search for its clinical associations. METHODS: Fifty-three PAPS patients (Sydney's criteria) were consecutively selected and age-matched with 50 healthy controls. A third group of nonimmune-mediated thrombophilia patients was also included. The expression of 41 IFN-induced genes was analyzed using real time quantitative PCR. A principal component analysis determined which genes composed the IFN signature, and the z-score was calculated. An ROC curve defined the signature cut-off. RESULTS: Six genes remained in the IFN signature DNAJA1, IFIT5, IFI27, MX1, IFI6, and TYK2. The ROC cutoff was 3.9-fold (AUC = 0.706, S = 0.49, E = 0.86, PPV = 0.79, NPV = 0.61). The type I IFN signature was present in 49% of the patients with PAPS compared with 14.0% of the healthy controls and 17% of the nonimmune-mediated thrombophilia patients (p < .0001). The IFN signature was associated with a younger age at the first antiphospholipid syndrome event (p = .023) and with preeclampsia (p = .032). CONCLUSION: Our results indicate that PAPS patients without lupus-specific antibodies have an enhanced type I IFN gene signature that is not observed in nonimmune-mediated thrombophilia. Also, this overexpression of type I IFN-regulated genes associated with an earlier onset of antiphospholipid syndrome event and preeclampsia.

Extra-criteria manifestations of antiphospholipid syndrome: Risk assessment and management.

OBJECTIVES: Extra-criteria manifestations of antiphospholipid syndrome (APS) might impact on prognosis and morbidity of the disease. In this study, we aimed to evaluate a population of patients with primary APS (PAPS) whether the extra-criteria manifestations were more frequently found in subjects with higher adjusted Global APS Score (aGAPSS) values when compared to patients with thrombotic and/or obstetric APS ("criteria" manifestations) only. METHODS: Clinical records were analyzed to retrieve extra-criteria manifestation of APS, cardiovascular risk factors and antiphospholipid antibodies profile. The aGAPSS was calculated by adding the points, as follows: 3 for hyperlipidaemia, 1 for arterial hypertension, 5 for anticardiolipin antibodies IgG/IgM, 4 for anti-ß2 glycoprotein I IgG/IgM, and 4 for lupus anticoagulant. RESULTS: This retrospective multicenter study included 89 consecutive PAPS [mean age 43.1 (S.D. ± 12.9), female 67%, 52% arterial and 65% venous]. Twenty-seven patients (30.3%) had a history of livedo, 19 (21.3%) had a history of confirmed thrombocytopenia, 3 (3.4%) had biopsy-proven antiphospholipid antibodies (aPL)-related nephropathy and 3 (3.4%) had a history of valvulopathy. Patients with extra-criteria manifestations presented a mean aGAPSS significantly higher [mean 10.30 (S.D. ± 3.57, range: 4-17) vs mean 8.16 (S.D. ± 3.52;range: 4-16, p = 0.005). When comparing patients with and without extra-criteria manifestations, the first group had significantly higher incidence of anti-ß2GPI antibodies positivity (59% and 33%, respectively, p = 0.015), double aPL positivities (53% and 31%, respectively, p = 0.034), cerebrovascular events history (52% and 24%, respectively, p = 0.007) and arterial hypertension (52% and 24%, respectively, p = 0.007). CONCLUSIONS: Our results suggest that patients with higher aGAPSS, might be at higher risk for developing extra-criteria manifestations of APS and should therefore undergo a thorough laboratory and instrumental evaluation.

Serum uric acid levels are associated with lupus nephritis in patients with normal renal function.

Uric acid has been recognised as a potential marker of endothelial dysfunction and kidney disease but there are scarce data about its importance in systemic lupus erythematosus (SLE) nephritis. This study aimed to evaluate serum uric acid (UA) levels in lupus nephritis (LN), by comparing SLE patients with normal renal function, with and without nephritis. Forty-six female SLE patients were consecutively selected and divided in two groups according to renal activity at the evaluation: presence of a recently diagnosed lupus nephritis (LN+, n = 18) and absence of lupus nephritis (LN-, n = 28). Age-matched healthy women were selected (CONTROL, n = 28). Patients with gout, creatinine clearance lower than 80 ml/min and use of drugs that interfere in UA were excluded. Laboratory and clinical data were analysed by appropriate tests. A multivariate analysis was performed, and a receiver operating characteristic (ROC) curve was plotted, and the area under the curve was calculated to assess the diagnostic strength of UA in LN. The mean age was similar among LN+, LN- and CONTROL groups (32.44 ± 6.09 vs. 30.68 ± 5.36 vs. 30.86 ± 5.00 years, p = 0.52). UA was significantly higher in LN+ compared to LN- (5.54 ± 1.67 vs. 3.65 ± 1.090 mg/dL, p < 0.001) and CONTROL (5.54 ± 1.67 vs. 3.92 ± 0.95 mg/dL p < 0.001). Multivariate analysis confirmed that high UA was an independent variable related to LN (p < 0.001). The cut-off value for UA using the ROC curve was 4.47 mg/dL (AUC 0.86, p = 0.00004, CI 95% 0.75-0.96). Lupus nephritis was associated with higher UA. Hyperuricemia as a predictor of renal damage in SLE needs to be evaluated in further studies.

Difficult clinical situations in the antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is characterized by antiphospholipid antibodies (aPL) associated with thrombosis and/or pregnancy morbidity. However, there is a range of other manifestations associated with APS, called non-criteria manifestations that add significant morbidity to this syndrome and, some of them, represent difficult clinical situations to deal with. Other issues such as refractory treatment also represent challenging situations poorly addressed in the literature. Therefore, the purpose of this article is to review the management of difficult clinical situations in APS and provide information to help the readers in their decision-making process.