Risk factors of significant relapse and appropriate maintenance therapy strategy in SLE-associated immune thrombocytopenia.

Background: Systemic lupus erythematosus-associated immune thrombocytopenia (SLE-ITP) is characterized by relapse. The risk factors of relapse and appropriate maintenance therapy strategy deserve further exploration. Objectives: To determine the risk factors for relapse and appropriate maintenance therapy in significant SLE-ITP patients (a platelet count ⩽30 × 109/l) after the first complete response. Design: Retrospective cohort study using the medical records of 105 patients diagnosed as significant SLE-ITP in Fujian Medical University Union Hospital during December 2012 to March 2021. Patients were followed through a call for observations in January 2022. Methods: Data including demographics, initial clinical feature, induction and maintenance therapy, and outcome at the end of follow-up were analyzed. Risk factors for significant relapse were analyzed using multivariate logistic regression models. The cumulative hazard of significant relapse and the duration of response were estimated, and the differences in outcome between groups were compared using the Cox regression analysis. Results: A total of 65 significant SLE-ITP patients were eligible for the final analysis. Median [interquartile range (IQR)] follow-up duration and median [IQR] duration of response were 62.2 [41.0-79.6] months and 43.4 [20.3-68.7] months, respectively. After the first complete response, 19/65 (29.2%) had a significant relapse. Compared with sustained clinical remission (SCR) + sustained response (SR) group, significant relapse group had a higher proportion of discontinued patients (47.4% versus 8.7%, p = 0.001). Among the 13 discontinued patients, the duration of maintenance therapy of the patients in significant relapse group was significantly shorter than that of the patients in SCR + SR group (months, median [IQR], 43.1 [32.0-62.4] versus 12.0 [5.1-22.0], p = 0.009). Multivariate logistic regression analysis showed that drug withdrawal was an independent risk factor for significant relapse [odds ratio (OR) = 10.4, confidence interval (CI) 95% 2.2-47.8, p = 0.003]. There was no significant difference between glucocorticoids (GCs) + hydroxychloroquine (HCQ) group and GCs + HCQ + immunosuppressive agents (ISAs) group in significant relapse rate (26.7% versus 22.2%, p > 0.05). The two SR curves of GCs + HCQ and GCs + HCQ+ ISA group basically coincided by the Cox regression analysis, demonstrating comparable long-term outcomes (p > 0.05). Conclusion: Drug withdrawal, especially abrupt withdrawal with insufficient duration of maintenance therapy, is an independent risk factor for significant relapse of SLE-ITP. HCQ combined with GCs is expected to be the first choice of the maintenance therapy for SLE-ITP patients.

Immunogenicity of inactivated COVID-19 vaccine in patients with autoimmune inflammatory rheumatic diseases.

Progress has been made in COVID-19 vaccine development, with encouraging safety and efficacy data. The purpose of this study was to investigate the immunogenicity of inactivated COVID-19 vaccine in patients with autoimmune inflammatory rheumatic diseases (AIIRD). Patients with AIIRD (n = 101) were included in this study. All patients received 2 doses of inactivated COVID-19 vaccine. Serum anti-S1/RBD protein IgG was detected 2-16 weeks after the second vaccination. Seropositivity was defined as IgG ≥ 1.00 bound antibody unit S/CO. Immunogenicity of inactivated COVID-19 vaccine was assessed by seropositivity rate and the levels of serum IgG antibody against anti-S1/RBD protein, compared with the general population (n = 46). There was no difference by statistical significance in the seropositivity rate between patients with AIIRD (82.2%) and SLE (86.1%) and the control group (93.5%), p > 0.05. The level of anti-S1/RBD protein IgG antibodies in patients with AIIRD (median [IQR], 8.8 [2.2-17.3]) and SLE (median [IQR], 9.6 [2.4-20.4]) was comparable to that in the control group (median [IQR], 7.2 [3.1-14.2]), p > 0.05. Patients treated with glucocorticoids(GCs) (median dose, [IQR]: 2.5 mg/day [IQR 2.5-5.0]) or hydroxychloroquine(HCQ) or GCs + HCQ without other immunomodulatory medications, had an appropriate immunogenic response(88.1%) with high levels of anti-S1/RBD protein IgG(median [IQR], 12.1 [6.5-20.4]). Neither of patients treated with rituximab had positive serum antibodies, which was statistically significant, compared with the control group (p < 0.01). Compared with the control group, methotrexate(MTX) and iguratimod(IGU) was significantly reduced the level of anti-S1/RBD protein IgG antibodies. Inactivated COVID-19 vaccine had appropriate immunogenicity in patients with AIIRD. Immunogenicity of inactivated COVID-19 vaccine was severely impaired by rituximab, and also suppressed by MTX and IGU, while low doses of GC and HCQ had negligible effect.

High titers of antinuclear antibody and the presence of multiple autoantibodies are highly suggestive of systemic lupus erythematosus.

The aim of this study is to evaluate the relationship between antinuclear antibody (ANA) titer and specificity, as well as the relationship between the number of positive-autoantibodies (AAbs) in antinuclear antibodies (ANAs) and specificity for systemic lupus erythematosus (SLE), so as to explore their significance in the diagnosis of SLE. A total of 1297 patients with ANA results was enrolled in this study, including 148 patients with SLE patients. The sensitivity, specificity, sensitive likelihood ratio and specific likelihood ratio of indicators in SLE were determined by receiver-operator characteristic (ROC) curve after measurement of ANA and ANAs by indirect immunofluorescence (IIF) and immunoblotting, respectively. ROC analysis showed that the specificity of ANA titer ≥ 1 +, ≥ 2 + and ≥ 3 + for SLE was estimated to be 81.29%, 90.69% and 96.52% respectively, with a increased titer-specific likelihood ratio (5.16, 9.29 and 19.60, respectively). The specificity of the number of positive-AAbs ≥ 1, ≥ 2 and ≥ 3 in ANAs for SLE was estimated to be 80.42%, 94.95% and 99.3% respectively, with a increased number-specific likelihood ratio (4.8, 15.26 and 72.48, respectively). The estimated sensitivity of the number of positive-AAbs ≥ 3, AnuA and anti-rRNP was higher than that of anti-Sm (p < 0.01) (50.68%, 41.89% and 31.76% vs. 16.89%, respectively), while there was no significant difference in their specificity (99.3%, 99.74% and 99.56% vs. 99.74%, respectively) (p > 0.05). High titers of ANA and the presence of multiple AAbs in ANAs are highly specific for SLE and highly suggestive of SLE. The likelihood of SLE can be assessed by ANA titer and the number of positive-AAbs in ANAs.

Antinuclear antibody-negative systemic lupus erythematosus: How many patients and how to identify?

Objectives: This study aims to the prevalence of antinuclear antibody (ANA)-negative systemic lupus erythematosus (SLE) and their clinical characteristics in a large single-center SLE inception cohort to provide guidance for early diagnosis. Patients and methods: Between December 2012 and March 2021, the medical records of a total of 617 firstly diagnosed SLE patients (83 males, 534 females; median age [IQR]: 33+22.46 years) who fulfilled the selection criteria were retrospectively analyzed. The patients were divided into groups with ANA-negative SLE and ANA-positive SLE, or with prolonged use of glucocorticoids or immunosuppressants (SLE-1) and without (SLE-0). Demographic, clinical characteristics, and laboratory features were collected. Results: The total prevalence of ANA-negative SLE patients was 2.11% (13/617). The prevalence of ANA-negative SLE in SLE-1 (7.46%) was significantly higher than that in SLE-0 (1.48%) (p<0.01). The ANA-negative SLE patients had a higher prevalence of thrombocytopenia (84.62%) than ANA-positive SLE patients (34.27%). As with ANA-positive SLE, ANA-negative SLE also had a high prevalence of low complement (92.31%) and anti-double-stranded deoxyribonucleic acid (anti-dsDNA) positivity (69.23%). The prevalence of medium-high titer anti-cardiolipin antibody (aCL) IgG (50.00%) and anti-ß2 glycoprotein I (anti-ß2GPI) (50.00%) of ANA-negative SLE was significantly higher than that of ANA-positive SLE (11.22% and 14.93%, respectively). Conclusion: The prevalence of ANA-negative SLE is very low, but it exists, particularly under the influence of prolonged use of glucocorticoids or immunosuppressants. Thrombocytopenia, low complement, positive anti-dsDNA, and medium-high titer antiphospholipid antibody (aPL) are the main manifestations of ANA-negative SLE. It is necessary to identify complement, anti-dsDNA, and aPL in ANA-negative patients with rheumatic symptoms, particularly thrombocytopenia.

Influence of Accelerometer Placement and/or Heart Rate on Energy Expenditure Prediction during Uphill Exercise.

Studies using a triaxial accelerometer and heart rate (HR) simultaneously for estimating energy expenditure (EE) during uphill exercise are rare. Exploring the optimal location for placing the accelerometer for predicting EE during uphill exercise is essential. Sixteen healthy male participants (M ± SEM; age 25.00 ± 0.61 years; body weight 74.13 ± 2.51 kg; body height 1.74 ± 0.01 m; body mass index 24.30 ± 0.63 kg/m2) exercised on a treadmill under 12 conditions (4 speeds and 3 gradients) on 3 days. Triaxial accelerometers, an HR recorder, and a metabolic measurement system were simultaneously used. Accelerometer outputs from various anatomical locations (upper arm, chest, lower back, waist, thigh, and instep) showed significant positive correlations with EE (0.819, 0.846, 0.816, 0.820, 0.672, and 0.669, respectively; p < .05). The linear regression equation for changes in HR showed the highest coefficient of determination (r2) of .837 with 87.9% reliability. When the HR signal was included, the r2 value (> .842) and reliability (87.9%) between the accelerometer outputs and EE improved. Accelerometer outputs from the waist position alone provide highly accurate EE values. Using both accelerometer outputs and HR for EE estimation during uphill exercise is feasible and improves the accuracy of EE prediction.

Diagnostic value of serum complement C3 and C4 levels in Chinese patients with systemic lupus erythematosus.

In 2009, hypocomplementemia involving C3, C4, and total hemolytic complement (CH50) was proposed as an immunologic criterion to enhance the sensitivity of systemic lupus erythematosus (SLE) classification criteria. This study evaluated the diagnostic value of low serum complement C3 and C4 levels in Chinese patients with SLE. In total, 2452 patients were enrolled in this study (158 with SLE and 2294 with other diseases). Receiver operating characteristic analysis showed that the optimal C3 and C4 cut-off levels for a diagnosis of SLE were 0.785 g/L (sensitivity, 77.9%; specificity, 81.5%) and 0.145 g/L (sensitivity, 80.1%; specificity, 83.2%), respectively. The prevalence of a low C3 or C4 level alone was similar between patients with SLE and those with other diseases, while the prevalence of simultaneously low C3 and C4 levels was higher in patients with SLE (73.42%). Antinuclear antibody had a high sensitivity (96.64%) and low negative likelihood ratio (0.04). Hypocomplementemia with positive antinuclear antibody had a high positive likelihood ratio. Inclusion of hypocomplementemia as a classification criterion for SLE resulted in a 16.18% increase in the number of patients assigned to the SLE group (from 136 to 158 patients). Hypocomplementemia was highly prevalent in patients with hematological disease (41.94%). These results suggest that hypocomplementemia has important diagnostic value for SLE by improving the sensitivity of the diagnosis of SLE. C3 and C4 should be tested simultaneously because a low C3 or C4 level alone is not a suitable immunological criterion.

Ranolazine improves diastolic function in spontaneously hypertensive rats.

Diastolic dysfunction can lead to heart failure with preserved ejection fraction, for which there is no effective therapeutic. Ranolazine has been reported to reduce diastolic dysfunction, but the specific mechanisms of action are unclear. The effect of ranolazine on diastolic function was examined in spontaneously hypertensive rats (SHRs), where left ventricular relaxation is impaired and stiffness increased. The objective of this study was to determine whether ranolazine improves diastolic function in SHRs and identify the mechanism(s) by which improvement is achieved. Specifically, to test the hypothesis that ranolazine, by inhibiting late sodium current, reduces Ca(2+) overload and promotes ventricular relaxation and reduction in diastolic stiffness, the effects of ranolazine or vehicle on heart function and the response to dobutamine challenge were evaluated in aged male SHRs and Wistar-Kyoto rats by echocardiography and pressure-volume loop analysis. The effects of ranolazine and the more specific sodium channel inhibitor tetrodotoxin were determined on the late sodium current, sarcomere length, and intracellular calcium in isolated cardiomyocytes. Ranolazine reduced the end-diastolic pressure-volume relationship slope and improved diastolic function during dobutamine challenge in the SHR. Ranolazine and tetrodotoxin also enhanced cardiomyocyte relaxation and reduced myoplasmic free Ca(2+) during diastole at high-stimulus rates in the SHR. The density of the late sodium current was elevated in SHRs. In conclusion, ranolazine was effective in reducing diastolic dysfunction in the SHR. Its mechanism of action, at least in part, is consistent with inhibition of the increased late sodium current in the SHR leading to reduced Ca(2+) overload.

Impact of Center-of-Mass Acceleration on the Performance of Ultramarathon Runners.

Ultramarathon races are rapidly gaining popularity in several countries, raising interest for the improvement of training programs. The aim of this study was to use a triaxial accelerometer to compare the three-dimensional center-of-mass accelerations of two groups of ultramarathon runners with distinct performances during different running speeds and distances. Ten runners who participated in the 12-h Taipei International Ultramarathon Race underwent laboratory treadmill testing one month later. They were divided into an elite group (EG; n = 5) and a sub-elite group (SG; n = 5). The triaxial center-of-mass acceleration recorded during a level-surface progressive intensity running protocol (3, 6, 8, 9, 10, and 12 km/h; 5 min each) was used for correlation analyses with running distance during the ultramarathon. The EG showed negative correlations between mediolateral (ML) acceleration (r = -0.83 to -0.93, p < 0.05), and between anterior-posterior (AP) acceleration and running distance (r = -0.8953 to -0.9653, p < 0.05), but not for vertical control of the center of mass. This study suggests that runners reduce stride length to minimize mediolateral sway and the effects of braking on the trunk; moreover, cadence must be increased to reduce braking effects and enhance impetus. Consequently, the competition level of ultramarathons can be elevated.

RSD1235 blocks late INa and suppresses early afterdepolarizations and torsades de pointes induced by class III agents.

OBJECTIVE: RSD1235 is a novel antiarrhythmic drug with atria-selective electrophysiological actions on Na(+) and K(+) currents. The mechanism for its protection of ventricular repolarization was assessed by its action on Purkinje fibers, and by block of late sodium current active during repolarization. Further, RSD1235's ability to reverse the pro-arrhythmic actions of the class III agents dofetilide and clofilium was assessed in isolated Purkinje fibers and an in vivo model of torsades de pointes (TdP). METHODS: Action potential and early after-depolarization (EAD) recordings were made from in situ and isolated rabbit Purkinje fibers at 37 degrees C using floating sharp microelectrodes; late I(Na) was recorded using a whole-cell patch clamp technique of Nav1.5 expressed in HEK cells at 22 degrees C; In vivo, anesthetized methoxamine-sensitized rabbits were used to test the ability of RSD1235 to suppress clofilium-induced TdP. RESULTS: RSD1235 (0.5-30 microM) had minor dose-dependent effects on action potential duration (APD) at 50% and 90% repolarization in Purkinje fibers, but pre-treatment significantly attenuated the APD-prolonging effects of dofetilide (300 nM). EADs induced by 300 nM dofetilide were terminated by 30 microM RSD1235 in all experiments (n=7). RSD1235 blocked a late component of Na current (I(Na)), which can produce inward currents contributing to EAD formation. RSD1235 pre-treatment (1 micromol/kg/min) or acute infusions prevented/terminated TdP induced by clofilium in 8 of 9 rabbits, and reduced the duration of TdP episodes from 71 +/- 23 s in control to 17 +/- 7 and 14 +/- 14 s at infusion rates of 0.3 and 1.0 micromol/kg/min, respectively (n = 9, p < 0.001). CONCLUSION: RSD1235 itself has minor actions on repolarization in Purkinje fibers, but can reverse the AP-prolonging actions of class III agents and terminate arrhythmias in a model of TdP. We suggest that these protective actions of RSD1235 may result, at least in part, from its ability to inhibit late I(Na) during action potential repolarization.

The mechanism of atrial antiarrhythmic action of RSD1235.

INTRODUCTION: RSD1235 is a novel drug recently shown to convert AF rapidly and safely in patients.(1) Its mechanism of action has been investigated in a rat model of ischemic arrhythmia, along with changes in action potential (AP) morphology in isolated rat ventricular myocytes and effects on cloned channels. METHODS AND RESULTS: Ischemic arrhythmias were inhibited with an ED50 of 1.5 micromol/kg/min, and repolarization times increased with non-significant effects on PR and QRS durations. AP prolongation was observed in rat myocytes at low doses, with plateau elevation and a reduction in the AP overshoot at higher doses. RSD1235 showed selectivity for voltage-gated K+ channels with IC50 values of 13 microM on hKv1.5 (1 Hz) versus 38 and 30 microM on Kv4.2 and Kv4.3, respectively, and 21 microM on hERG channels. RSD1235 did not block IK1 (IC50 > 1 mM) nor ICa,L (IC50= 220 microM) at 1 Hz in guinea pig ventricular myocytes (n = 4-5). The drug displayed mild (IC50= 43 microM at 1 Hz) open-channel blockade of Nav1.5 with rapid recovery kinetics after rate reduction (10-->1 Hz, 75% recovery with tau= 320 msec). Nav1.5 blocking potency increased with stimulus frequency from an IC50= 40 microM at 0.25 Hz, to an IC50= 9 microM at 20 Hz, and with depolarization increasing from 107 microM at -120 mV to 31 microM at -60 mV (1 Hz). CONCLUSIONS: These data suggest that RSD1235's clinical selectivity and AF conversion efficacy result from block of potassium channels combined with frequency- and voltage-dependent block of INa.