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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.

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 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.

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.

Objective To study ophthalmological manifestations in a well-characterized primary antiphospholipid syndrome (PAPS) cohort (APS-Rio) and compare them with a healthy control group. Methods We examined PAPS patients and controls with an extensive ophthalmological evaluation, which included anamnesis, visual acuity, slit-lamp biomicroscopy, binocular indirect ophthalmoscopy, and retinography of the anterior and posterior segments of the eye. PAPS group also underwent angiography exam and optical coherence tomography using spectral domain technology (SD-OCT). Results 98 PAPS patients and 102 controls were included. The most common symptom in PAPS was amaurosis fugax (34.7% vs. 6.9%; p = .001). In the multivariate analyses, Raynaud’s phenomenon was associated with amaurosis fugax (OR 3.71, CI:1.33–10.32; p = .012), and livedo correlated with hemianopia (OR 6.96, CI:1.11–43.72, p = .038) and diplopia (OR 3.49, CI:1.02–11.53, p = .047). After ophthalmological evaluation, 84 PAPS patients had ocular involvement (1.0% glaucoma, 94.0% posterior findings, 62.7% anterior findings, and 56.6% both posterior and anterior findings). Vascular tortuosity was more frequent in the PAPS group (63.2% vs. 42.2%; p = .002), as well as peripheral tortuosity (29.6% vs. 7.8%; p < .001). After excluding patients with atherosclerotic risk factors, peripheral vascular tortuosity was still statistically associated with PAPS (35.0 vs. 7.8%, p < .001). Triple positivity was more frequent in PAPS patients with peripheral vascular tortuosity than in those without this ocular finding (34.5% vs. 15.9%, p = .041). Conclusion Vasomotor phenomena are importantly related to ocular symptoms in PAPS. Vascular tortuosity was a frequent finding in PAPS patients. Peripheral vascular tortuosity was associated with triple positivity and might be a biomarker of ischemic microvascular retinopathy due to PAPS.

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 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.

To assess predicting factors that might influence systemic lupus erythematosus (SLE) disease activity in women in an extended follow-up period of two years after giving birth with clinical assessments every three months.The study was design as an international retrospective study, enrolling 119 women with a first birth and with a two years follow-up.Joint involvement was present in 80% of patients, acute cutaneous in 64%, haematological in 54%, renal in 41% and 75% of patients were positive for anti-dsDNA. The mean SLE disease activity index 2000 (SLEDAI-2K) at diagnosis was 13.5±6.8 and at first birth was 2.8±4.4. At follow-up, 51.3% of patients had at least one flare after a mean time after birth of 9±6.3 months (mean flare per patient 0.94±1.1). The most frequent flare manifestations were joint involvement (48%), renal (33%), cutaneous (28%) and haematologic (20%). Patients with remission of disease (SLEDAI-2K=0; no clinical or laboratory manifestations of SLE) at conception had significantly lower rates of flares (18/49-37% vs. 43/70-61%; p=0.008). Patients who experienced a flare during pregnancy (17 patients) had higher rates of flares during follow-up (76% vs. 47%; p=0.019), lower time for first flare (4.4±2.3 months vs. 10.3±6.5; p0.001), lower rate of remission of disease at conception (12% vs. 46%; p0.001), lower rates of SLEDAI-2K at conception (5.9±5.6 vs. 2.3±4; p0.001) and lower rates of exclusive breastfeeding (24% vs. 57%: p=0.009). Results were confirmed after performing multivariate analysis.Remission at conception can influence SLE disease positively, even at long-term. Planned pregnancy counseling is fundamental when managing SLE patients.

Background: Coronavirus disease 19 (COVID-19) has an increased risk of coagulopathy with high frequency of antiphospholipid antibodies (aPL). The recent reports of thrombosis associated with the adenovirus-based vaccines raises concern that SARS-CoV-2 immunization in primary antiphospholipid syndrome (PAPS) patients may trigger a dysregulated immune response with possible clotting complications. Therefore, the objectives of this study were to assess immunogenicity, aPL production and safety of Sinovac-Coronavac in PAPS patients.Methods: This prospective controlled phase 4 study of SARS-CoV-2-naïve 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. Safety and aPL production were also assessed. Results: Forty-four PAPS patients and 132 CG had 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) and GMT [50.2(95%CI 34.5-73.2) vs. 61.7 (95%CI 52.8-72.3), p=0.249] as well as NAb positivity (77.4% vs. 78.7%, p=0.440), and NAb-activity [64.3% (49.0-77.0) vs. 60.9% (45.6-81.3), p=0.689]. Of note, for D28, the antibody response was very low and also similar in both groups SC (25.8% vs. 30.6% p=0.609). Antiphospholipid levels remained stable throughout the study at D0 vs D28 vs D69 (IgG aCL, p=0.058; IgM aCL, p=0.091; IgG aβ2GPI, p=0.513 and IgM aβ2GPI, p=0.468). Thrombotic event up to 6 months or other moderate/severe side effects were not observed.Conclusions: We provide novel evidence that Sinovac-CoronaVac vaccine has a high immunogenicity and excellent safety profile in PAPS. We further demonstrated that this vaccine did not trigger thrombosis or induced changes in aPL-related antibodies production. Our findings strongly support the recommendation of SARS-CoV-2 vaccination for PAPS patients.Trial registration: ClinicalTrials.gov - Identifier: NCT04754698 first registered on February 8th, 2021.

ObjectiveThere is a broad spectrum of eye involvement in antiphospholipid syndrome (APS). The majority of descriptions are presented as case reports that include mostly APS patients secondary to systemic lupus erythematosus (SLE), with no compelling evidence in primary APS (PAPS). This study aimed to describe ocular manifestations in our well-defined PAPS cohort (APS-Rio) and then perform a systematic literature review (SLR) of ocular manifestations in patients with APS or positivity to aPL without SLE.MethodsWe retrospectively analyzed PAPS patients followed at our outpatient clinics. All patients fulfilled Sydney APS classification criteria (2006). We evaluated them for ocular symptoms and previous ocular diagnoses. Antiphospholipid antibodies and clinical APS manifestations were compared between patients with and without ocular manifestations. For the SLR, electronic databases were searched up to November 2019.ResultsWe studied 105 PAPS patients; 90.5% were female and 56.2% were Caucasian. We found ocular manifestations in 37.1% of our cohort. Thrombosis was the main criteria manifestation (95.2%) and lupus anticoagulant was the most prevalent antibody. Ophthalmologic diagnoses were present in 7 patients, with 5 having retinal vessels thromboses. Amaurosis fugax was the leading complaint, present in 30 patients. In the univariate analysis, amaurosis fugax was related to livedo (p = 0.005), Raynaud’s phenomenon (p = 0.048) and the presence of anticardiolipin antibody (≥40 GPL/MPL) (p = 0.041). Hemianopia was associated with arterial hypertension (p = 0.049). In the multivariate analysis, the only association found was between livedo and amaurosis fugax (OR 4.09, 95%CI 1.5–11.11, p = 0.006). Our SLR incorporated 96 articles of ocular manifestations in patients with PAPS or positivity to aPL without SLE. Ocular findings varied from 5 to 88%, including anterior and posterior segments, orbital and neuro-ophthalmologic changes.ConclusionThere is little evidence on ocular manifestations in PAPS. We described an association between livedo and amaurosis fugax. Prospective studies are needed to promote the best treatment and avoid blindness in PAPS patients.

Opportunistic infections can cause manifestations that resemble neuropsychiatric systemic lupus erythematosus and they can also trigger lupus flares. Therefore, central nervous system infections as differential diagnosis in neuropsychiatric systemic lupus erythematosus may be difficult, leading to delayed diagnosis and specific treatment. Central nervous system infection in systemic lupus erythematosus is not common but, if left misdiagnosed and not treated promptly, can be fatal. Complementary diagnosis tests are generally non-specific and disappointing. Caution with immunosuppressive drug treatment should be emphasized while an opportunistic infection cannot be ruled out. In this review, we discuss the various types of central nervous system infections reported in systemic lupus erythematosus patients, highlighting the importance of their early recognition in order to improve morbidity and mortality. Prevention with vaccination is a recommended approach.

Tuberculosis (TB) is a millenarian chronic infection and, yet, remains a major global health problem. The interaction between systemic lupus erythematosus (SLE) and TB is complex, as one seems to be a risk factor for the development of the other. SLE patients are more likely to develop TB, that is more frequently extrapulmonary, with more extensive pulmonary involvement, and with a higher relapse rate.Different studies suggest that TB is more prevalent in SLE patients and that TB may actually be a risk factor for the development of the disease. Molecular and epidemiological data suggest that TB may be involved in the pathogenesis of SLE.We reviewed the most relevant aspects of TB infection in SLE patients, including the burden of TB, its role in inducing flare and its perpetuation, risk evaluation and prevention, and pearls and pitfalls when assessing extrapulmonary TB in SLE patients. We conclude that a high suspicion of TB in SLE patients from endemic countries should be kept in mind, especially in those with nephritis and high cumulative doses of corticosteroids.

The current treatment for antiphospholipid syndrome (APS) with thrombotic manifestation is long-term anticoagulation. Vitamin K antagonists (VKA) are usually the agents of choice. However, VKA limitations, such as unpredictable anticoagulation effects due to interaction with diet and other drugs, require regular monitoring. This may impact on patients' quality of life. Since the approval of new oral anticoagulants (NOAC) for non-valvular atrial fibrillation and deep vein thrombosis prevention, much has been speculated about its use in APS patients. We report here a series of eight APS patients with failure of thrombotic prevention during rivaroxaban use. All patients had venous thrombosis as the initial manifestation of APS, and two of them also had arterial manifestations. Three patients had triple antibody positivity. Five patients developed arterial events during the treatment with rivaroxaban. Until the results of ongoing trials of rivaroxaban for APS are presented, NOAC should not be recommended to APS patients. Our preliminary experience as well cases previously reported in the literature suggest that there is a high-risk group that is less protected with rivaroxaban, namely those with previous arterial thrombosis or triple positivity. VKA remains to be the mainstay treatment for thrombotic APS.

Current therapeutic recommendations for thrombosis prevention in patients with antiphospholipid syndrome (APS) are limited to anticoagulation with vitamin K antagonists (VKA) or heparins and to anti-platelet aggregating agents. Maintaining optimized anticoagulation to prevent recurrent thrombosis or bleeding remains a therapeutic challenge. Although there are important ongoing trials with direct oral anticoagulants, they still aim the same target. New insights about pathophysiology in APS have revealed a myriad of potential pathways to be investigated as treatment targets. A radical shift from a hematological/coagulative approach to an immunological one will probably represent the near future of APS treatment. We reviewed the therapeutic trends and potential future treatments.

Catastrophic antiphospholipid syndrome (CAPS) is a rare and life-threatening disease. It is characterized by multiple arterial and/or venous thrombotic events, including the microcirculation, occurring in a short period, and can affect any system. Catastrophic antiphospholipid syndrome can occur in individuals with known APS under treatment, or it can be its first manifestation; in most cases, there is a triggering factor that can be identified. In this case report, we report a case of CAPS with multiple thromboses at unusual sites, including the lungs, coronary arteries, stomach, thyroid, gastrocnemius muscles, lymph nodes, and bladder, in a patient with previous diagnosis of systemic lupus erythematosus.

Antiphospholipid Syndrome (APS) is an autoimmune disease characterized by recurrent thromboses and fetal losses with the presence of antiphospholipid antibodies. The main treatment to prevent recurrent thrombotic events is oral anticoagulation with vitamin K antagonist (VKA), which requires frequent monitoring and dosage adjustments. Outpatient anticoagulation monitoring has its limitations, such as patients spending long hours between the testing procedure and waiting for the results to be adjusted. To optimize this adjustment and to improve APS patients-doctors relationship, we developed a website to help monitor APS patients, called Antiphospholipid Syndrome On Cloud or APSOnCloud. To test it, since March 2014 to March 2016, we registered 20 patients with APS that have inserted 132 international normalized ratio (INR) values. Sixty two percent were out of range and it took on average 7 hours for the doctor in charge to adjust these values. The mean time in therapeutic range was 58.1%. Our preliminary experience in monitoring VKA oral anticoagulation on APSOnCloud suggests that patients with APS might benefit from this web-based monitoring.