Cardiorespiratory abnormalities in ICU survivors of COVID-19 with postacute sequelae of SARS-CoV-2 infection are unrelated to invasive mechanical ventilation.

Postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) often leads to exertional intolerance and reduced exercise capacity, particularly in individuals previously admitted to an intensive care unit (ICU). However, the impact of invasive mechanical ventilation (IMV) on PASC-associated cardiorespiratory abnormalities during exercise remains poorly understood. This single-center, cross-sectional study aimed to gather knowledge on this topic. Fifty-two patients with PASC recruited ∼6 mo after ICU discharge were clustered based on their need for IMV (PASC + IMV, n = 27) or noninvasive support therapy (PASC + NIS, n = 25). Patients underwent pulmonary function and cardiopulmonary exercise testing (CPX) and were compared with a reference group (CONTROL, n = 19) comprising individuals of both sexes with similar age, comorbidities, and physical activity levels but without a history of COVID-19 illness. Individuals with PASC, irrespective of support therapy, presented with higher rates of cardiorespiratory abnormalities than CONTROL, especially dysfunctional breathing patterns, dynamic hyperinflation, reduced oxygen uptake and oxygen pulse, and blunted heart rate recovery (all P < 0.05). Only the rate of abnormal oxygen pulse was greater among PASC + IMV group than PASC + NIS group (P = 0.05). Mean estimates for all CPX variables were comparable between PASC + IMV and PASC + NIS groups (all P > 0.05). These findings indicate significant involvement of both central and peripheral factors, leading to exertional intolerance in individuals with PASC previously admitted to the ICU, regardless of their need for IMV.NEW & NOTEWORTHY We found cardiorespiratory abnormalities in ICU survivors of severe-to-critical COVID-19 with PASC to be independent of IMV need. Overall, both group of patients experienced dysfunctional breathing patterns, dynamic hyperinflation, lower oxygen uptake and oxygen pulse, and blunted heart rate responses to CPX. PASC seems to impact exertional tolerance and exercise capacity due to ventilatory inefficiency, impaired aerobic metabolism, and potential systolic and autonomic dysfunction, all of these irrespective of support therapy during ICU stay.

Damage measured by Damage Index for Antiphospholipid Syndrome (DIAPS) in antiphospholipid antibody-positive patients included in the APS ACTION registry.

OBJECTIVES: Our primary objective was to quantify damage burden measured by Damage Index for Antiphospholipid Syndrome (DIAPS) in aPL-positive patients with or without a history of thrombosis in an international cohort (the APS ACTION cohort). Secondly, we aimed to identify clinical and laboratory characteristics associated with damage in aPL-positive patients. METHODS: In this cross-sectional study, we analysed the baseline damage in aPL-positive patients with or without APS classification. We excluded patients with other autoimmune diseases. We analysed the demographic, clinical and laboratory characteristics based on two subgroups: (i) thrombotic APS patients with high vs low damage; and (ii) non-thrombotic aPL-positive patients with vs without damage. RESULTS: Of the 826 aPL-positive patients included in the registry as of April 2020, 586 with no other systemic autoimmune diseases were included in the analysis (412 thrombotic and 174 non-thrombotic). In the thrombotic group, hyperlipidaemia (odds ratio [OR] 1.82; 95% CI 1.05, 3.15; adjusted P = 0.032), obesity (OR 2.14; 95% CI 1.23, 3.71; adjusted P = 0.007), aß2GPI high titres (OR 2.33; 95% CI 1.36, 4.02; adjusted P = 0.002) and corticosteroid use (ever) (OR 3.73; 95% CI 1.80, 7.75; adjusted P < 0.001) were independently associated with high damage at baseline. In the non-thrombotic group, hypertension (OR 4.55; 95% CI 1.82, 11.35; adjusted P = 0.001) and hyperlipidaemia (OR 4.32; 95% CI 1.37, 13.65; adjusted P = 0.013) were independent predictors of damage at baseline; conversely, single aPL positivity was inversely correlated with damage (OR 0.24; 95% CI 0.075, 0.77; adjusted P = 0.016). CONCLUSIONS: DIAPS indicates substantial damage in aPL-positive patients in the APS ACTION cohort. Selected traditional cardiovascular risk factors, steroids use and specific aPL profiles may help to identify patients more prone to present with a higher damage burden.

Associations Among Antiphospholipid Antibody Types, Isotypes, and Titers: An AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) Study.

Several antiphospholipid antibody (aPL) profiles ("triple" and lupus anticoagulant [LA] positivity) are associated with a higher risk for clinical manifestations of antiphospholipid syndrome (APS). Further risk is correlated with higher levels of anticardiolipin antibody (aCL) and anti-ß2 glycoprotein-I antibody (aß2GPI), and with aPL persistence. Given that the 3 aPL tests detect partially overlapping sets of antibodies, the primary goal of this study was to characterize the associations among aPL tests using AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) core laboratory data. The APS ACTION Registry includes annually followed adult patients with positive aPL based on the Revised Sapporo Classification Criteria. We analyzed baseline and prospective core laboratory data of the registry for associations among aPL tests using the Spearman rank correlation with Bonferroni-adjusted significance level for multiple comparisons. An aPL Load was calculated based on 6 tests (aCL IgG/IgM/IgA and aß2GPI IgG/IgM/IgA); a receiver operating characteristic curve was used to evaluate the diagnostic performance of the aPL Load in predicting LA positivity. In 351 patients simultaneously tested for LA, aCL, and aß2GPI, the frequency of moderate-to-high (≥40 U) titers of aCL and aß2GPI IgG/IgM/IgA was higher in patients who were positive for LA vs those who were negative. An aPL Load was calculated for each patient to assess the overall aPL burden. For every 1-point increase in the aPL Load, the possibility of a positive LA test increased by 32% (odds ratio, 1.32; 95% CI, 1.2-1.5; P < .001). Based on core laboratory data from a large international registry, most aPL enzyme-linked immunosorbent assay ≥40 U and a high calculated aPL Load combining 6 aPL enzyme-linked immunosorbent assays were predictive of a positive LA. These data suggest that the combined quantitative burden of aPL may provide a mechanistic explanation of a positive LA.

Assessing disease activity and damage in antiphospholipid syndrome.

Antiphospholipid syndrome (APS) has been characterized by a variety of vascular and pregnancy manifestations related to an interplay between thrombotic and inflammatory mechanisms, a progressive accrual of irreversible organ damage and increased morbidity and mortality rates, supporting a high need of optimal treatment approach. The lack of standardized outcome measures is a significant barrier in the design of clinical studies in APS. Disease activity (in principle reversible) and its distinction from disease damage (in principle irreversible) needs to be evaluated by validated scores for use in clinical trials but also in daily clinical practice in APS. A disease damage score in APS, the DIAPS score, has been developed and validated in external cohorts. The development of a disease activity score that will provide an accurate and reproducible rating of each disease domain, can help clinicians and researchers to comprehensively assess the activity of disease and the response to treatment, in an attempt to prevent future damage.

Comorbid association of obstructive sleep apnea (OSA) and thrombotic primary antiphospholipid syndrome (tPAPS): A more severe phenotype?

OBJECTIVE: We aimed to evaluate the frequency of obstructive sleep apnea (OSA) in patients with thrombotic primary antiphospholipid syndrome (tPAPS), to investigate the performance of screening tools for OSA in this scenario and to compare clinical/laboratorial differences in tPAPS patients with and without OSA. METHODS: We consecutively enrolled patients with tPAPS to undergo sleep studies using a portable monitor. OSA was defined as apnea-hypopnea index ≥15 events/h. Frequency of OSA in tPAPS was evaluated and compared with age-, gender-, and BMI-matched controls (1:3 ratio) from the Estudo Longitudinal de Saúde do Adulto (ELSA-Brasil). Next, we tested the performance of three different screening tools for assessing OSA in patients with tPAPS. Finally, patients with tPAPS were stratified according to OSA status comparing their clinical and laboratory characteristics (including damage burden measured by Damage Index for Antiphospholipid Syndrome [DIAPS] and biomarkers associated with thrombosis) using standard statistical procedures. RESULTS: Fifty-two patients were included for analysis (females: 82.7%; mean age: 48 ± 14 years; body-mass index: 31.1 ± 6.5 Kg/m2; 25% with moderate-severe OSA). When compared to matched controls from ELSA-Brasil (n = 115), there was no significant differences in the frequencies of OSA (tPAPS: 12/42 [28.6%] vs. controls: 35/115 [30.4%], p = 0.821). Among screening tools, NoSAS had the highest area under ROC curve (AUC 0.806, CI 95% 0.672-0.939, p = 0.001), followed by STOP-Bang (AUC 0.772, CI 95% 0.607-0.938, p = 0.004). Patients with comorbid tPAPS and OSA presented higher levels of von Willebrand factor (vWF) (median 38.9 vs. 32.6, p = 0.038) and DIAPS (median 5 vs. 2, p = 0.020), when compared to those without OSA. OSA remained statistically associated with higher DIAPS, even after controlling for age, disease duration and BMI. CONCLUSION: OSA is common in patients with tPAPS, with rates comparable to a non-referred population. Both NoSAS and STOP-Bang scores seems to be useful for screening OSA in these patients. Patients with tPAPS+OSA had higher damage burden and higher levels of vWF, which might suggest a more severe phenotype of tPAPS in this scenario.

2023 ACR/EULAR antiphospholipid syndrome classification criteria.

OBJECTIVE: To develop new antiphospholipid syndrome (APS) classification criteria with high specificity for use in observational studies and trials, jointly supported by the American College of Rheumatology (ACR) and EULAR. METHODS: This international multidisciplinary initiative included four phases: (1) Phase I, criteria generation by surveys and literature review; (2) Phase II, criteria reduction by modified Delphi and nominal group technique exercises; (3) Phase III, criteria definition, further reduction with the guidance of real-world patient scenarios, and weighting via consensus-based multicriteria decision analysis, and threshold identification; and (4) Phase IV, validation using independent adjudicators' consensus as the gold standard. RESULTS: The 2023 ACR/EULAR APS classification criteria include an entry criterion of at least one positive antiphospholipid antibody (aPL) test within 3 years of identification of an aPL-associated clinical criterion, followed by additive weighted criteria (score range 1-7 points each) clustered into six clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and two laboratory domains (lupus anticoagulant functional coagulation assays, and solid-phase enzyme-linked immunosorbent assays for IgG/IgM anticardiolipin and/or IgG/IgM anti-ß2-glycoprotein I antibodies). Patients accumulating at least three points each from the clinical and laboratory domains are classified as having APS. In the validation cohort, the new APS criteria vs the 2006 revised Sapporo classification criteria had a specificity of 99% vs 86%, and a sensitivity of 84% vs 99%. CONCLUSION: These new ACR/EULAR APS classification criteria were developed using rigorous methodology with multidisciplinary international input. Hierarchically clustered, weighted, and risk-stratified criteria reflect the current thinking about APS, providing high specificity and a strong foundation for future APS research.

Effects of a 16-week home-based exercise training programme on health-related quality of life, functional capacity, and persistent symptoms in survivors of severe/critical COVID-19: a randomised controlled trial.

BACKGROUND: Long-lasting effects of COVID-19 may include cardiovascular, respiratory, skeletal muscle, metabolic, psychological disorders and persistent symptoms that can impair health-related quality of life (HRQoL). We investigated the effects of a home-based exercise training (HBET) programme on HRQoL and health-related outcomes in survivors of severe/critical COVID-19. METHODS: This was a single-centre, single-blinded, parallel-group, randomised controlled trial. Fifty survivors of severe/critical COVID-19 (5±1 months after intensive care unit discharge) were randomly allocated (1:1) to either a 3 times a week (~60-80 min/session), semi-supervised, individualised, HBET programme or standard of care (CONTROL). Changes in HRQoL were evaluated through the 36-Item Short-Form Health Survey, and physical component summary was predetermined as the primary outcome. Secondary outcomes included cardiorespiratory fitness, pulmonary function, functional capacity, body composition and persistent symptoms. Assessments were performed at baseline and after 16 weeks of intervention. Statistical analysis followed intention-to-treat principles. RESULTS: After the intervention, HBET showed greater HRQoL score than CONTROL in the physical component summary (estimated mean difference, EMD: 16.8 points; 95% CI 5.8 to 27.9; effect size, ES: 0.74), physical functioning (EMD: 22.5 points, 95% CI 6.1 to 42.9, ES: 0.83), general health (EMD: 17.4 points, 95% CI 1.8 to 33.1, ES: 0.73) and vitality (EMD: 15.1 points, 95% CI 0.2 to 30.1, ES: 0.49) domains. 30-second sit-to-stand (EMD: 2.38 reps, 95% CI 0.01 to 4.76, ES: 0.86), and muscle weakness and myalgia were also improved in HBET compared with CONTROL (p<0.05). No significant differences were seen in the remaining variables. There were no adverse events. CONCLUSION: HBET is an effective and safe intervention to improve physical domains of HRQoL, functional capacity and persistent symptoms in survivors of severe/critical COVID-19. TRIAL REGISTRATION NUMBER: NCT04615052.

Controversies in the Management of Antiphospholipid Syndrome.

ABSTRACT: Strategies to prevent thrombosis in antiphospholipid antibody (aPL)-positive patients are of the utmost importance. The risk of thrombosis in patients with aPLs varies, depending on additional venous thrombosis and cardiovascular risk factors, as well as associated comorbidities. Recurrent thrombosis despite treatment with vitamin K antagonists is relatively common in daily practice. In this context, the effectiveness of the new direct oral anticoagulants in antiphospholipid syndrome is debated, as well as that of low-dose aspirin for primary thromboprophylaxis. There is an urgent unmet need to recognize the subgroup of patients that may benefit from low-dose aspirin use. Here we also discuss different points of view on primary and secondary thrombosis preventions in aPL-positive patients, which were presented as a debate during the 2021 PANLAR Congress (Pan-American League of the Association of Rheumatology) and that was organized by GESAF (Argentine Society of Rheumatology APS Study Group). It is the intention of this article to provide a useful discussion to aid treatment decision-making in daily clinical practice.

Oxygen uptake kinetics and chronotropic responses to exercise are impaired in survivors of severe COVID-19.

The post-acute phase of coronavirus disease 2019 (COVID-19) is often marked by several persistent symptoms and exertional intolerance, which compromise survivors' exercise capacity. This was a cross-sectional study aiming to investigate the impact of COVID-19 on oxygen uptake (V̇o2) kinetics and cardiopulmonary function in survivors of severe COVID-19 about 3-6 mo after intensive care unit (ICU) hospitalization. Thirty-five COVID-19 survivors previously admitted to ICU (5 ± 1 mo after hospital discharge) and 18 controls matched for sex, age, comorbidities, and physical activity level with no prior history of SARS-CoV-2 infection were recruited. Subjects were submitted to a maximum-graded cardiopulmonary exercise test (CPX) with an initial 3-min period of a constant, moderate-intensity walk (i.e., below ventilatory threshold, VT). V̇o2 kinetics was remarkably impaired in COVID-19 survivors as evidenced at the on-transient by an 85% (P = 0.008) and 28% (P = 0.001) greater oxygen deficit and mean response time (MRT), respectively. Furthermore, COVID-19 survivors showed an 11% longer (P = 0.046) half-time of recovery of V̇o2 (T1/2V̇o2) at the off-transient. CPX also revealed cardiopulmonary impairments following COVID-19. Peak oxygen uptake (V̇o2peak), percent-predicted V̇o2peak, and V̇o2 at the ventilatory threshold (V̇o2VT) were reduced by 17%, 17%, and 12% in COVID-19 survivors, respectively (all P < 0.05). None of the ventilatory parameters differed between groups (all P > 0.05). In addition, COVID-19 survivors also presented with blunted chronotropic responses (i.e., chronotropic index, maximum heart rate, and heart rate recovery; all P < 0.05). These findings suggest that COVID-19 negatively affects central (chronotropic) and peripheral (metabolic) factors that impair the rate at which V̇o2 is adjusted to changes in energy demands.NEW & NOTEWORTHY Our findings provide novel data regarding the impact of COVID-19 on submaximal and maximal cardiopulmonary responses to exercise. We showed that V̇o2 kinetics is significantly impaired at both the onset (on-transient) and the recovery phase (off-transient) of exercise in these patients. Furthermore, our results suggest that survivors of severe COVID-19 may have a higher metabolic demand at a walking pace. These findings may partly explain the exertional intolerance frequently observed following COVID-19.

Increment of immunogenicity after third dose of a homologous inactivated SARS-CoV-2 vaccine in a large population of patients with autoimmune rheumatic diseases.

OBJECTIVE: To determine the immunogenicity of the third dose of CoronaVac vaccine in a large population of patients with autoimmune rheumatic diseases (ARD) and the factors associated with impaired response. METHODS: Adult patients with ARD and age-balanced/sex-balanced controls (control group, CG) previously vaccinated with two doses of CoronaVac received the third dose at D210 (6 months after the second dose). The presence of anti-SARS-CoV-2 S1/S2 IgG and neutralising antibodies (NAb) was evaluated previously to vaccination (D210) and 30 days later (D240). Patients with controlled disease suspended mycophenolate mofetil (MMF) for 7 days or methotrexate (MTX) for 2 weekly doses after vaccination. RESULTS: ARD (n=597) and CG (n=199) had comparable age (p=0.943). Anti-S1/S2 IgG seropositivity rates significantly increased from D210 (60%) to D240 (93%) (p<0.0001) in patients with ARD. NAb positivity also increased: 38% (D210) vs 81.4% (D240) (p<0.0001). The same pattern was observed for CG, with significantly higher frequencies for both parameters at D240 (p<0.05). Multivariate logistic regression analyses in the ARD group revealed that older age (OR=0.98, 95% CI 0.96 to 1.0, p=0.024), vasculitis diagnosis (OR=0.24, 95% CI 0.11 to 0.53, p<0.001), prednisone ≥5 mg/day (OR=0.46, 95% CI 0.27 to 0.77, p=0.003), MMF (OR=0.30, 95% CI 0.15 to 0.61, p<0.001) and biologics (OR=0.27, 95% CI 0.16 to 0.46, p<0.001) were associated with reduced anti-S1/S2 IgG positivity. Similar analyses demonstrated that prednisone ≥5 mg/day (OR=0.63, 95% CI 0.44 to 0.90, p=0.011), abatacept (OR=0.39, 95% CI 0.20 to 0.74, p=0.004), belimumab (OR=0.29, 95% CI 0.13 to 0.67, p=0.004) and rituximab (OR=0.11, 95% CI 0.04 to 0.30, p<0.001) were negatively associated with NAb positivity. Further evaluation of COVID-19 seronegative ARD at D210 demonstrated prominent increases in positivity rates at D240 for anti-S1/S2 IgG (80.5%) and NAb (59.1%) (p<0.0001). CONCLUSIONS: We provide novel data on a robust response to the third dose of CoronaVac in patients with ARD, even in those with prevaccination COVID-19 seronegative status. Drugs implicated in reducing immunogenicity after the regular two-dose regimen were associated with non-responsiveness after the third dose, except for MTX. Trial registration number NCT04754698.

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

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

CoaguChek® XS versus standard laboratory prothrombin time for anticoagulant monitoring in patients with antiphospholipid syndrome.

INTRODUCTION: The standard of care for thrombotic antiphospholipid syndrome (APS) is anticoagulation with vitamin K antagonists (VKAs). Prothrombin time, and its corresponding international normalized ratio (INR), is the laboratory test routinely performed to assess anticoagulation. Self-management of VKA therapy using point-of-care (POC) devices seems to be an attractive option. PURPOSE/OBJECTIVE: To evaluate the accuracy of a POC device (CoaguChek XS) in APS patients by comparing it with venous laboratory INR. Furthermore, we analyzed whether other clinical and laboratory features could interfere with the CoaguChek XS results. PATIENTS AND METHODS: This is a single-center cross-sectional study with 94 APS patients from a tertiary rheumatology clinic performed from August 2014 to March 2015. The comparison between CoaguChek XS and venous laboratory INR results was evaluated using the coefficient of determination (r) followed by the Bland-Altman test. A paired t-test was also applied. A difference of up to ±0.5 INR unit between the two systems was considered clinically acceptable. RESULTS: The mean CoaguChek-INR was 2.94 ± 1.41 and venous laboratory INR was 2.43±0.86, with a correlation coefficient (r) of 0.95. Categorizing INR values in ranges (INR <2, INR 2-3, INR 3-4, and INR >4), we found that the INR >4 group presented a lower correlation (r = 0.64) compared to the other ranges (p < 0.05). Although both methods were highly correlated, CoaguChek XS showed higher values than the venous laboratory INR, with an increased average of 0.42 ± 0.54. Therefore, we proposed a simple linear regression model to predict the venous laboratory INR values, using results obtained from CoaguChek XS. A difference ≤0.5 INR unit between the two systems was observed in 57.4% of patients, and the aPL profile did not influence the results. CONCLUSION: Although CoaguChek XS and venous laboratory INR demonstrated a good linear correlation in the group of INR ≤4, extra caution should be taken in APS patients, since a reasonable proportion of patients can present differences in INR results that are not acceptable. We do not recommend routine POC in APS patients.

Ocular findings in asymptomatic patients with primary antiphospholipid syndrome.

BACKGROUND: Primary antiphospholipid syndrome (PAPS) is characterized by the presence of antiphospholipid antibodies (aPL), repetitive fetal loss, and arterial/venous thrombosis and no association with other autoimmune rheumatic disease. Ocular involvement can also occur including retinal vascular thrombosis and neuro-ophthalmological manifestations, such as optic neuropathy and amaurosis fugax. Early detection of ocular changes is crucial to minimize functional loss. PURPOSE: To perform a multimodal evaluation, including the use of Optical Coherence Angiotomography (OCTA), in patients with PAPS without ocular complaints and compare with healthy individuals. METHODS: We performed a complete structural and functional ophthalmological evaluation using OCTA and microperimetry exam in patients with PAPS, followed at a tertiary Rheumatology outpatient clinic. RESULTS: We included 104 eyes of 52 subjects [PAPS without ocular complaints (N = 26) and healthy individuals (N = 26)]. Among PAPS patients, 21 were female (80.8%) and 21 (80.8%) were Caucasians. PAPS manifestations were venous (65.4%), arterial thrombosis (34.6%), and obstetrical (34.6%) and all of them had lupus anticoagulant. Ophthalmologic findings were more frequent in PAPS compared to healthy individuals (19.2% vs. 0%, p = 0.05). The most common retinal change was paracentral acute middle maculopathy (PAMM) (3 patients, 5 eyes), followed by drusen (1 patient, 2 eyes) and pachychoroid pigment epitheliopathy (PPE) (1 patient, 1 eye). Hypertension and hyperlipidemia were present in 100% of the PAPS patients with PAMM, while only six patients (26.1%) with PAPS without PAMM presented these two risk factors together (p = 0.03). CONCLUSIONS: We provide novel evidence that approximately 20% of our asymptomatic PAPS patients without ocular symptoms have ophthalmologic findings that require early identification and careful surveillance focusing on minimizing systemic and vascular risk factors.

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.

Immunosuppression use in primary antiphospholipid antibody-positive patients: Descriptive analysis of the AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) Clinical Database and Repository ("Registry").

BACKGROUND/PURPOSE: APS ACTION Registry was created to study the outcomes of patients with persistently positive antiphospholipid antibodies (aPL) with or without other systemic autoimmune disease (SAIDx). Given that immunosuppression (IS) is used for certain aPL manifestations, for example, thrombocytopenia (TP), our primary objective was to describe the indications for IS in aPL-positive patients without other SAIDx. Secondly, we report the type of IS used in patients with selected microvascular or non-thrombotic aPL manifestations. METHODS: An online database is used to collect clinical data. The inclusion criteria are positive aPL based on the laboratory section of the APS Classification Criteria, tested at least twice within one year prior to enrollment. Patients are followed every 12 ± 3 months. For this descriptive retrospective and prospective analysis, we included aPL-positive patients without other SAIDx and excluded those with new SAIDx classification during follow-up. For each patient, we retrieved clinical data at baseline and follow-up including selected aPL manifestations (diffuse alveolar hemorrhage [DAH], antiphospholipid-nephropathy [aPL-N], livedoid vasculopathy [LV]-related skin ulcers, TP, autoimmune hemolytic anemia [AIHA], cardiac valve disease [VD]), and IS medications. RESULTS: Of 899 patients enrolled, 537 were included in this analysis (mean age 45 ± 13 years, female 377 [70%], APS Classification in 438 [82%], and at least one selected microvascular or non-thrombotic aPL manifestation in 141 (26%)). Of 537 patients, 76 (14%) were reported to use IS (ever), and 41/76 (54%) received IS primarily for selected aPL manifestation. In six of 8 (75%) DAH patients, 6/19 (32%) aPL-N, 4/28 (14%) LV, 25/88 (28%) TP, 6/11 (55%) AIHA, and 1/43 (2%) VD, the IS (excluding corticosteroids/hydroxychloroquine) indication was specific for selected aPL manifestation. CONCLUSION: In our international cohort, 14% of aPL-positive patients without other SAIDx were reported to receive IS; the indication was at least one of the selected microvascular and/or non-thrombotic aPL-related manifestations in half. Thrombocytopenia was the most frequent among those selected aPL-related manifestations; however, approximately one-third received IS specifically for that indication. Diffuse alveolar hemorrhage was frequently treated with IS followed by AIHA and aPL-N. Systematic controlled studies are urgently needed to better define the role of IS in APS.

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.

Distinct features of youth-onset primary antiphospholipid syndrome.

BACKGROUND: Characteristics of primary APS (PAPS) in the youth population have never been studied. In contrast with children, pregnancy is genuinely relevant in the youth age, and understanding clinical characteristics of PAPS patients within this specific age stratum may also provide insights regarding the well-known risk of poor obstetric outcomes during the adolescence. OBJECTIVE: To evaluate clinical and laboratory characteristics of patients with youth-onset PAPS (15-24 years) and compare them with adult-onset PAPS (over 24 years old). METHODS: This was a cross-sectional study derived from two rheumatology outpatient clinics. Patients who fulfilled Sidney criteria and who were 15 years of age or older at disease onset were included. Secondary APS patients were excluded. We subdivided patients into two groups: youth- (15-24 years) and adult-onset (over 24 years) and compared them regarding demographic characteristics, criteria and non-criteria manifestations, cardiovascular risk factors, and aPL status. For the pregnancy outcomes analysis, ever-pregnant patients were divided in three groups: youth-onset, early adult-onset (25-34 years), and late adult-onset (35-49 years). RESULTS: A total of 250 consecutive PAPS patients were included. Groups had a comparable female and Caucasian distribution. We found a similar disease duration (14.0±7.9 vs 17.0±10.1 years, p = 0.079) and similar rates of thrombotic arterial (34.2% vs. 42.0%, p = 0.250) and venous events (69.7% vs. 69.5%, p = 0.975) between them. Skin ulcers were more frequent in the youth-onset group (17.1% vs. 4.0%, p = 0.001), whereas nephropathy was less common (1.3% vs. 8.0%, p = 0.039). No differences were observed for the other criteria and non-criteria manifestations. The adult-onset group presented more frequently with hypertension (p = 0.002), hyperlipidemia (p = 0.008), and smoking (p = 0.003). The youth-onset group presented a higher frequency of obstetric events as the first manifestation of PAPS (30.3% vs. 21.7%, p = 0.005), with worse pregnancy outcomes, namely, fetal death (58.5% vs. 46.4% vs. 24.1%, p = 0.012) and premature delivery (35.8% vs. 19.0% vs. 10.3%, p = 0.016). Of note, all groups had a comparable number of pregnancies (2.81±2.52 vs 2.74±2.07, p = 0.899). CONCLUSION: This study provides novel evidence that youth-onset PAPS presents a higher frequency of obstetric complications as its first manifestation, with an increased risk of fetal death and preterm delivery. Early recognition of this condition by obstetricians is essential to improve prognosis.

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.

COVID-19 and antiphospholipid antibodies: A position statement and management guidance from AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION).

Coronavirus disease 2019 (COVID-19) is associated with a high rate of thrombosis. Prolonged activated partial thromboplastin times (aPTT) and antiphospholipid antibodies (aPL) are reported in COVID-19 patients. The majority of publications have not reported whether patients develop clinically relevant persistent aPL, and the clinical significance of new aPL-positivity in COVID-19 is currently unknown. However, the reports of aPL-positivity in COVID-19 raised the question whether common mechanisms exist in the pathogenesis of COVID-19 and antiphospholipid syndrome (APS). In both conditions, thrombotic microangiopathy resulting in microvascular injury and thrombosis is hypothesized to occur through multiple pathways, including endothelial damage, complement activation, and release of neutrophil extracellular traps (NETosis). APS-ACTION, an international APS research network, created a COVID-19 working group that reviewed common mechanisms, positive aPL tests in COVID-19 patients, and implications of COVID-19 infection for patients with known aPL positivity or APS, with the goals of proposing guidance for clinical management and monitoring of aPL-positive COVID-19 patients. This guidance also serves as a call and focus for clinical and basic scientific research.

A multicentre study of 244 pregnancies in undifferentiated connective tissue disease: maternal/fetal outcomes and disease evolution.

OBJECTIVES: To investigate fetal/perinatal and maternal outcomes from a large multicentre cohort of women diagnosed with UCTD. METHODS: This multicentre retrospective cohort study describes the outcomes of 224 pregnancies in 133 consecutive women with a diagnosis of UCTD, positive for ANA and aged <45 years old at study inclusion. RESULTS: Of the 224 pregnancies analysed, 177 (79%) resulted in live births, 45 (20.1%) in miscarriages (defined as pregnancy loss before 12 weeks' gestation), 2 (0.9%) in stillbirths (pregnancy loss after 20 weeks' gestation) and 6 (2.7%) cases showed intrauterine growth restriction. Miscarriages and stillbirths were strongly associated with the presence of aPL and ENA antibodies (P < 0.05). Maternal pregnancy complications were as follows: 5 (2.2%) cases developed pre-eclampsia, 11 (4.9%) cases gestational hypertension and 12 (5.4%) cases gestational diabetes. Joint involvement represented the most frequent clinical manifestation of the cohort (57.9%), followed by RP (40.6%), photosensitivity (32.3%) and haematological manifestations (27.1%). The rate of disease evolution of our cohort from a diagnosis of UCTD to a diagnosis of definite CTD was 12% within a mean time of 5.3 ± 2.8 years. With a total follow-up after first pregnancy of 1417 patient-years, we observed the evolution to a defined CTD in one out of every 88 patient- years. CONCLUSION: In our multicentre cohort, women with UCTD had a live birth rate of 79%. Women with UCTD should be referred to specialist follow-up when planning a pregnancy. ENA profiling and aPL testing should be mandatory in this setting, and further therapeutic approaches and management should be planned accordingly.