Secondary Antiphospholipid Syndrome Research Articles

The Validation of the 2023 ACR/EULAR Antiphospholipid Syndrome Classification Criteria in a Cohort from Turkey.

Our aim was to validate the performance of the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for antiphospholipid syndrome (APS), published in 2023, in an APS cohort. A total of 193 patients, 83 with APS (secondary APS, n = 45; primary APS, n = 38) and 110 without APS (systemic lupus erythematosus (SLE), n = 100; others, n = 10), were included in this study. The performance (sensitivity, specificity and area under the curve (AUC)) of the 2023 ACR/EULAR classification criteria for APS was evaluated and the agreement with the revised Sapporo criteria was compared using the kappa test. In our cohort, the sensitivity and specificity of the 2023 ACR/EULAR classification criteria for APS were 73% and 94%, respectively (AUC: 0.836, 95% CI: 0.772-0.899), while the sensitivity and specificity of the revised Sapporo criteria were 66% and 98%, respectively (95% CI: 0.756-0.888). The performance of the two sets of criteria in our cohort was significantly consistent and significant (p < 0.001). When the sensitivity, specificity and ROC curve analysis were performed again by excluding livedo racemosa, the sensitivity of the new criteria in our cohort was 62% and the specificity was 100% (AUC: 0.813, 95% CI: 0.746-0.881). Although the newly published criteria broaden the scope of APS classification by including clinical findings other than thrombosis and obstetric criteria, their sensitivity in our cohort was low. On the other hand, we found that the specificity of the criteria in our cohort reached 100% when livedo findings were excluded.

Pregnancy outcome predictors in systemic lupus erythematosus: a systematic review and meta-analysis

To enhance patient-tailored preconception risk assessment for women with systemic lupus erythematosus (SLE), knowledge on risk factors associated with adverse pregnancy outcomes is required. Therefore, we did a systematic review and meta-analysis to identify and provide unambiguous effect sizes of preconception predictors of pregnancy outcomes in women with SLE. In this systematic review and meta-analysis, we searched PubMed and Embase for studies reporting preconception predictors of pregnancy outcomes in women with SLE, from database inception to Aug 22, 2023. Studies were included if they presented original, quantitative data on pregnant women with SLE and reported on preconception risk factors on at least one of the outcomes as defined in the protocol. Studies were excluded if they had a sample size of less than 20 patients, were restricted to multiple pregnancies, had unclear timing of prognostication, or exclusively reported a composite outcome. Literature screening, data extraction, and risk-of-bias assessment (quality in prognostic studies tool) were done by two reviewers independently, in a blinded, standardised manner. The reported outcomes included livebirth, pre-eclampsia, small for gestational age, preterm birth, pregnancy loss before and after 20 weeks of gestation, and SLE flares. We computed pooled univariate odds ratios (ORs) and 95% CIs using a random effects model. We assessed heterogeneity using the I2 statistic and prediction intervals. This study is registered with PROSPERO, CRD42022344732. Of the 6705 unique articles identified, 72 (1·1%) were included in the meta-analysis, comprising 10 355 pregnancies in 8065 women with SLE. One potentially eligible study was retracted and therefore removed from our analysis. Previous lupus nephritis was associated with decreased livebirth probability (OR 0·62 [95% CI 0·47-0·81]; I2=0%), increased risk of preterm birth (2·00 [1·55-2·57]; I2=17%), and increased risk of pre-eclampsia (3·11 [2·35-4·12]; I2=0%). Chronic hypertension was associated with increased risk of disease flare (2·50 [1·74-3·58]; I2=0%), preterm birth (2·65 [1·87-3·77]; I2=0%), and pre-eclampsia (5·86 [3·41-10·06]; I2=33%). SLE disease activity at conception or preconception was associated with increased risk of preterm birth (2·91 [1·96-4·33]; I2=21%) and pre-eclampsia (2·32 [1·40-3·83]; I2=0%). Secondary antiphospholipid syndrome was associated with decreased livebirth probability (0·40 [0·27-0·58]; I2=0%), increased risk of pregnancy loss after 20 weeks of gestation (2·77 [1·44-5·31]; I2=0%), and increased risk of preterm birth (1·65 [1·29-2·11]; I2=0%). Across studies, risk-of-bias assessment suggested considerable bias in study attrition and confounding. We identified previous lupus nephritis, chronic hypertension, SLE disease activity before and at conception, and secondary antiphospholipid syndrome as predictors of adverse pregnancy outcomes in women with SLE. These findings contribute to an optimal patient-tailored risk assessment in preconception counselling. None.

Performance of the 2023 American College of Rheumatology/EULAR Classification Criteria for Antiphospholipid Syndrome in a Mexican Cohort.

The objective is to assess the performance of the 2023 American College of Rheumatology/EULAR classification criteria (2023 AECC) for antiphospholipid syndrome (APS) in a Mexican cohort. We enrolled patients with primary APS (PAPS) and secondary APS (SAPS) and a control group of nonautoimmune thrombophilia. We evaluated the fulfillment of the 2023 AECC and the 2006 revised Sapporo classification criteria (2006 RSCC) and their performance against the clinical diagnosis as the gold standard. The baseline Global APS Score (GAPSS) and the Damage Index for APS (DIAPS) at last follow-up were calculated. We included 85 patients with PAPS, 54 with SAPS, and 50 with thrombophilia. According to the 2023 AECC criteria, 69 patients (81.2%) with PAPS, 28 patients (51.9%) with SAPS, and none of the patients with thrombophilia met the criteria. When comparing true positive (TP) (n = 69) versus false negative (n = 16) cases within the PAPS group, TP cases exhibited a higher frequency of thrombotic manifestations and IgM anti-cardiolipin and IgG anti-β2-glycoprotein-I positivity. For PAPS, there was a correlation between the 2023 AECC score and both GAPSS (rho = 0.621, P < 0.0001) and DIAPS scores (rho = 0.433, P < 0.0001). When comparing the 2023 AECC with the 2006 RSCC, a lower sensitivity (81.2% vs 88.2%) but a higher specificity (100.0% vs 92.0%) was observed for PAPS. Similar findings were observed in SAPS. In both PAPS and SAPS, the 2023 AECC have higher specificity than the 2006 RSCC. The main feature of patients with PAPS according to the 2023 AECC was thrombosis. These criteria might identify patients at higher risk of thrombosis and damage accrual.

Lupus pregnancy outcomes in women with previous adverse outcomes: a prospective cohort study.

The primary objective of this prospective cohort study was to assess the usefulness of a predefined multidisciplinarycare pathway-based management on pregnancy outcome(s) in women with SLE who already had at least one adverse obstetric outcome(s). Between March 2010 and March 2023, all consecutive, consenting women with SLE who already had at least one previous adverse obstetric outcome (preterm labour, pre-eclampsia, termination of pregnancy, miscarriage, intrauterine growth retardation (IUGR), preterm birth, low birth weight (LBW), intrauterine death (IUD) or stillbirth] were prospectively screened and counselled. The protocol comprised preconception and post-natal drug and disease status review, periodic ante-natal visits for the monitoring of pregnancy and drug and disease status review and post-natal drug and disease status review and contraception advice. Therapeutic changes were made as necessary at each visit. A total of 213 women were screened and 197 women (age, 28 ± 6.34years) were enrolled who had 226 pregnancies. Previous poor obstetric outcomes were miscarriage(s), 186; termination of pregnancy, 4; preterm labour, 51; IUGR, 36; IUD or stillbirth, 16; low birth weight (LBW), 44 and pre-eclampsia, 4. Seventy-seven (39%) women had secondary APS and 37 (19%) had a history of lupus nephritis. There were 194/226 (86%) live births [40 LBW (18%); caesarean section in 101 (45%)]. Thirty pregnancies culminated in miscarriages and 2 in IUDs (14%). Sixty-eight patients (30%) experienced lupus flare during pregnancy (36 mild, 20 moderate and 8 severe). Our experience underscores the usefulness of a predefined multidisciplinarycare pathway-based managementfor improving pregnancy outcomes in women with SLE who had previous adverse outcomes. Key Points • In women with SLE who had previous adverse obstetric outcome(s) a risk of poor outcome in subsequent pregnancy remains. • Good pregnancy outcomes in these women could be achieved bypredefined multidisciplinary care pathways focussed on addressing all relevant issues. • Improved access to rheumatology services and collaboration between rheumatologists and obstetricians is key to improving outcomes in SLE pregnancies.

Prevalence of Antiphospholipid Syndrome in Primary Budd Chiari patients and their intervention outcome

Abstract Background Budd-Chiari syndrome (BCS) is a rare but potentially life threatening hepatic disorder that results from obstruction of the hepatic venous outflow tract. Obstruction can occur at any level from the hepatic venules to the right atrium. According to the etiology, BCS can be classified as primary (due to intrinsic intraluminal thrombosis or webs) or secondary (due to intraluminal invasion by a parasite or malignant tumor or extraluminal compression by an abscess, cyst or solid tumor) the clinical presentation of BCS has a wide spectrum and ranges from asymptomatic cases to fulminant hepatic failure The classic triad of abdominal pain, ascites, and hepatomegaly is nonspecific. Aim of the Work To assess the prevelance of Antiphospholipid syndrome (APS) in primary Budd Chiari syndrome (BCS) patients and their management outcome. Patients and Methods Patients presented to BCS outpatient clinic, Tropical medicine department, Ain Shams University Hospitals were enrolled in the study from 2005 to 2020. Some patients with APS have no evidence of any definable associated disease, while, in other patients, APS occurs in association with SLE or another rheumatic or autoimmune disorder. Traditionally, these have been referred to as primary or secondary APS, respectively. Results Regarding laboratory data, Lupus Anticoagulant, ACL IgG antibodies and ACL IgM antibodies were positive in 60 (83.3%), 49 (68.1%) and 27 (37.5%) patients respectively. For 42 patients (58.3%), intervention was performed. TIPSS was performed on 33 (45.8%) patients, while Angioplasty with Stent was performed on 9 (12.5%) patients. There was no intervention in 30 (41.7%) of the patients. In the studied patients, rate of mortality of the total 72 patients was 48.6%. The mean cause of death was Hepatorenal syndrome (31.4%). Conclusion BCS, although infrequent, is not a rare complication in patients with APS and may be the first clinical manifestation of this syndrome. However, no predisposing factor to BCS has been identified in patients with APS. This supports the need for systematic screening for LA and aCL in all cases of hepatic vein thrombosis. In these patients, TIPS placement may be an effective treatment for portal hypertension, but in any case, long-term high intensity anticoagulation treatment is essential in order to prevent recurrent thrombosis. Lupus anticoagulant is much more common than anticardiolipin antibodies (83.3%, 68.1% respectively) among BCS patients due to antiphospholipid syndrome.

Saudi National Clinical Practice Guidelines for Management of Adult Systemic Lupus Erythematosus.

To provide evidence-based clinical practice recommendations for managing Systemic Lupus Erythematosus (SLE) in Saudi Arabia. This EULAR-adapted national guideline in which a multidisciplinary task force utilized the modified Delphi method to develop 31 clinical key questions. A systematic literature review was conducted to update the evidence since the EULAR publication. After reaching a consensus agreement, two rounds of voting and group discussion were conducted to generate consolidated recommendations/statements. A significant number of patients in Saudi Arabia experience delays in accessing rheumatologists, highlighting the significance of timely referral to SLE specialists or rheumatologists to ensure accurate diagnosis and prompt treatment. The primary goal of Glucocorticoid (GC) therapy in SLE patients is to establish disease control with a minimum dose and duration. Steroid-sparing agent utilization facilitates steroid-sparing goals. Hydroxychloroquine is recommended for all SLE patients, though physicians must carefully monitor toxicity and prioritize regular medication adherence assessment. SLE management during pregnancy starts from preconception time by assessing disease activity, major organ involvement, hypercoagulability status, and concomitant diseases that may negatively impact maternal and fetal outcomes. Multidisciplinary care with close monitoring may optimize both maternal and fetal outcomes. For patients with antiphospholipid antibodies, low-dose aspirin prophylaxis is recommended. Also, Long-term anticoagulant medications are fundamental to prevent secondary antiphospholipid syndrome due to high thrombosis recurrence. This Saudi National Clinical Practice guidelines for SLE management provide evidence-based recommendations and guidance for healthcare providers in Saudi Arabia who are managing patients with SLE. These guidelines will help to standardize healthcare service, improve provider education, and perhaps lead to better treatment outcomes for SLE patients.

Mental disorders in antiphospholipid syndrome patients: association with clinical and immunological manifestations of the disease

The aim of this work is to clarify the association between the clinical and psychopathological features of mental disorders (MD) and the clinical and immunological features of antiphospholipid syndrome (APS).Material and methods. The study included 107 patients (34 (31.8%) men and 73 (68.2%) women) aged 18 to 69 years (40.6±10.4 years (M±SD)), 54 (50.5%) – with primary APS (PAPS), established according to the international criteria of 2006 and 53 (49.5%) patients – with reliable diagnosis of systemic lupus erythematosus (SLE), according to the European Alliance of Associations for Rheumatology/American College of Rheumatology (EULAR/ ACR) 2019 criteria, with a secondary APS. Risk of thrombosis in APS was assessed by the GAPSS (Global Anti-Phospholipid Syndrome Score). MD were diagnosed by a psychiatrist in accordance with 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) and Diagnostic and Statistical Manual of mental disorders, 5th edition (DSM-5).Results. Mental disorders are detected in the vast majority of patients with APS (98 (91.6%)), predominantly in anxiety-depressive spectrum disorders (ADSD; 90 (84.1%)). Depressive disorders are not associated with a high risk of thrombosis according to the GAPSS, but more severe variants of depression are more common in patients with high anti-β2 -glycoprotein I (anti-β2 GP1) and low/moderate anti cardiolipin (aCL) antibodies. Anxiety disorders were diagnosed only in patients with a high risk of thrombosis according to GAPSS, high aCL and IgG anti-β2 GP1. Schizotypal disorder was identified only in patients with a high risk of thrombosis and positive anti-phosphatidylserine/prothrombin complex antibodies (aPS/PT) regardless of class, and also more often in patients with high IgG anti-β2 GP1. Epilepsy was observed only in patients with positive aPS/PT, regardless of class. Cognitive impairment (CI), mostly mild and moderate, was found in the vast majority of patients with APS (102 (95.3%)). Dementia was detected in 7 (6.5%) patients, and only in those who had acute or transient cerebrovascular accident. When compared with the general population, dementia developed at an earlier age (up to 65 years). For patients with a high risk of thrombosis, moderate CI is more typical. CI and their severity are not associated with the duration of APS, but are associated with positivity for IgG aPS/PT, acute or transient cerebrovascular accident and the duration of comorbid ADSD.Conclusion. A high frequency of MD in patients with APS revealed. Associations of MD with clinical and immunological manifestations of APS were determined. CI in patients with APS is heterogeneous and are associated with both clinical and immunological manifestations of APS and MD. Identification of CI and determination of their characteristics should be confirmed by clinical, psychopathological and pathopsychological methods in order to personalize their correction within the partnership model of care.

Predictors of damage accrual and its impact on health-related quality of life of thrombotic antiphospholipid syndrome: Independent validation of the damage index for antiphospholipid syndrome (DIAPS).

We aim to independently assess the validity of the damage index for antiphospholipid syndrome (DIAPS) in thrombotic antiphospholipid syndrome (APS) patients by exploring the prevalence and risk factors of organ damage and evaluating its impact on health-related quality of life (HR-QoL). Cross-sectional study including all thrombotic APS patients (Sydney criteria) attending a Portuguese tertiary centre. Damage was assessed using the DIAPS, and HR-QoL using the 3- and 5-level EuroQol HR-QoL (EQ-D5-3L and 5L), and Visual Analogue Scale (VAS) applied via a phone questionnaire. Spearman's correlation between DIAPS and the HR-QoL scales was performed. Risk factors for damage accrual and HR-QoL impairment were explored using univariate and multivariate logistic regression. Among the 108 patients (female, 65.7%; white, 90.7%; primary APS, 75.9%; median disease duration, 6years), damage (DIAPS≥1) developed in 48.2% of patients (mean ± SD DIAPS, 3.08 ± 1.83). DIAPS's neuropsychiatric domain was the most affected (24.2%), followed by the peripheral vascular domain (20.3%). No clinical, demographic nor laboratory parameters were significantly associated with damage. Regarding HR-QoL, pain/discomfort, anxiety/depression and usual activities domains were the most frequently impaired in both scales. DIAPS's domains correlated similarly with the EQ-5D-3L and 5L scales' individual domains. Female sex, medical disorders, secondary APS and type of presenting thrombosis (arterial) increased the risk of HR-QoL impairment. Total DIAPS was associated with higher odds of mobility, self-care and pain/discomfort impairment in both EQ-5D-3L and 5L scales but lost its independent risk in multivariable analysis. This external validation of DIAPS reinforces the ability of the score to correlate with HR-QoL while also highlighting risk factors for HR-QoL impairment other than damage accrual.

A CLINICAL CASE OF CRITICAL ISCHEMIA OF THE LOWER LIMB DUE TO ANTIPHOSPHOLIPID SYNDROME IN A PATIENT WITH NEWLY DIAGNOSED SYSTEMIC LUPUS ERYTHEMATOSUS

Background. Antiphospholipid syndrome (APS) is a systemic autoimmune disease with a wide range of vascular and obstetric manifestations associated with thrombotic and inflammatory mechanisms initiated by antiphospholipid antibodies.&#x0D; Aims: to demonstrate an early onset of secondary APS in the newly diagnosed systemic lupus erythematosus, data literature analysis.&#x0D; Materials and methods. We analyzed the clinical case of the patient, similar clinical cases that were published, and the latest diagnostic criteria, and recommendations for the diagnosis, treatment, and prevention of APS.&#x0D; Description of the clinical case. The patient, 27 years old, was admitted to the Rheumatology department at Communal non-commercial institution "Olexandrivska Clinical Hospital" in April 2023 with complaints of phantom pain of the amputated toes of the right foot, chilliness of the hands and feet, and joint pain. &#x0D; She has been ill since January 2021, and since then, she has had joint pain and discoloration of the skin of her fingers and feet in the cold. Significant worsening started in January 2022. The patient was hospitalized at the National Scientific Center of Surgery and Transplantology named after O.O. Shalimov, and the distal phalanges of the 1-3 toes of the right foot were amputated. As far as the patient previously had COVID-19, and took a combined oral contraceptive comprehensive differential diagnosis was carried out. The examination in the Rheumatology department revealed systemic lupus erythematosus according to diagnostic criteria ACR/EULAR 2019 and secondary antiphospholipid syndrome based on ACR/EULAR criteria 2023. The patient was prescribed hydroxychloroquine, methylprednisolone, nifedipine, iloprost, and warfarin. The patient was discharged in good condition and continues treatment ambulatory under rheumatologist control.&#x0D; Conclusion. This clinical case demonstrates the importance of a multidisciplinary approach in patients with APS. Patients with venous or arterial thrombotic events, especially young adults without risk factors, should be screened for antiphospholipid antibodies.

Cerebrovascular disease in patients with antiphospholipid antibody syndrome: a transcranial Doppler and magnetic resonance imaging study.

Transcranial Doppler (TCD) and brain MRI may be useful in evaluating patients with APS, helping to stratify the risk of cerebrovascular ischaemic events in this population. This study aimed to assess the frequency of brain MRI abnormalities in patients with primary antiphospholipid syndrome, secondary antiphospholipid syndrome and SLE and correlate to TCD findings. The study, conducted over four years at two autoimmune disease referral centres, included 22 primary antiphospholipid syndrome patients, 24 secondary antiphospholipid syndrome patients, 27 SLE patients without APS and 21 healthy controls. All participants underwent TCD to assess cerebral haemodynamics, detect microembolic signals and evaluate right-to-left shunts, followed by brain MRI and magnetic resonance angiography. MRI scans were reviewed for acute microembolism, localized cortical infarctions, border infarctions, lacunar infarctions, ischaemic lesions, white matter hyperintensity, micro and macro haemorrhages and arterial stenosis ≥50% of the cervical carotid artery, by two neuroradiologists blinded to the clinical data. Brain MRI findings were similar between the groups, except for lacunar infarction, more frequent in patients with secondary antiphospholipid syndrome (P = 0.022). Patients with intracranial stenosis detected by TCD had a higher frequency of territorial infarction (40% vs 7.5%, P = 0.02), lacunar (40% vs 11.3%, P = 0.075) and border zone infarcts (20% vs 1.9%, P = 0.034). Patients with intracranial stenosis presented a higher frequency of territorial, lacunar and border zone infarcts, suggesting that evaluating the intracranial vasculature should not be neglected in patients with APS and stroke.

Type I interferon pathway activation across the antiphospholipid syndrome spectrum: associations with disease subsets and systemic antiphospholipid syndrome presentation.

While the type I interferon (IFN-I) pathway is crucial in autoimmunity, its role in antiphospholipid antibody (aPL)-positive subjects, including aPL carriers and antiphospholipid syndrome (APS) patients, is poorly understood. This study aims at characterizing IFN-I pathway activation within the spectrum of aPL-positive subsets. A total of 112 patients [29 aPL carriers, 31 primary APS (PAPS), 25 secondary APS (SAPS), 27 systemic lupus erythematosus (SLE) patients without aPL, and 44 healthy controls (HCs)] were recruited. IFI6, IFI44, IFI44L, MX1, IFI27, OAS1, and RSAD2 gene expression was evaluated in whole blood, and a composite index (IFN score) was calculated. An overall activation of the IFN-I pathway was observed across the entire APS spectrum, with differences among genes based on the specific disease subset. The composite score revealed quantitative differences across subsets, being elevated in aPL carriers and PAPS patients compared to HCs (both p < 0.050) and increasing in SAPS (p < 0.010) and SLE patients (p < 0.001). An unsupervised cluster analysis identified three clusters, and correspondence analyses revealed differences in clusters usage across APS subsets (p < 0.001). A network analysis revealed different patterns characterizing different subsets. The associations between IFN-I pathway activation and clinical outcomes differed across APS subsets. Although no differences in gene expression were observed in systemic APS, the network analyses revealed specific gene-gene patterns, and a distinct distribution of the clusters previously identified was noted (p = 0.002). IFN-I pathway activation is a common hallmark among aPL-positive individuals. Qualitative and quantitative differences across the APS spectrum can be identified, leading to the identification of distinct IFN-I signatures with different clinical values beyond traditional categorization.

Antiphospholipid Antibodies Are Major Risk Factors for Non-Thrombotic Cardiac Complications in Systemic Lupus Erythematosus.

In systemic lupus erythematosus (SLE), cardiovascular complications are among the leading causes of death. Cardiovascular risk in SLE is even higher in the presence of antiphospholipid antibodies or secondary antiphospholipid syndrome (APS). The aim of this retrospective, single-center study was to investigate the occurrence of antiphospholipid antibodies and non-thrombotic cardiac manifestations in 369 SLE patients. We also assessed the clinical and laboratory characteristics of the patients to reveal the risk factors for cardiac manifestations. Patients were divided into two groups based on the presence of antiphospholipid antibodies (APA); 258 (69.9%) patients were APA positive, and 111 (30.1%) patients were APA negative. Mitral and tricuspid insufficiency, aortic stenosis and pulmonary arterial hypertension were more common in APA-positive patients. Anticardiolipin IgG showed the strongest correlation with any non-thrombotic cardiac manifestations. Based on our results, the adjusted global antiphospholipid syndrome score (aGAPSS) above 8.5 is predictive of valvulopathies and ischemic heart disease, while aGAPSS above 9.5 is predictive of cardiomyopathies. The presence of antiphospholipid antibodies may affect the development of cardiac manifestations in SLE. Periodic cardiological and echocardiographic screening of patients without cardiac complaints, as well as regular monitoring of antiphospholipid antibodies, have great importance during the treatment of SLE patients.

Systemic risk factors of retinopathy in patients with systemic lupus erythematosus.

To investigate the risk factors of lupus retinopathy (LR) in patients with systemic lupus erythematosus (SLE). This is a retrospective, cross-sectional study. LR patients admitted at Peking Union Medical College Hospital from June 2013 to April 2023 were reviewed. Age- and gender-matched SLE patients without retinopathy were selected as controls. Medical records including clinical manifestations, laboratory data and ophthalmic examination were collected. Univariate and multivariate logistic regression analyses were conducted. One hundred and twelve LR patients (198 eyes) were included, with 12 cases (14 eyes) presenting with retinal macrovascular obstruction, and 100 cases (184 eyes) only exhibiting microvasculopathy. Multivariate analysis indicated the presence of haemolytic anaemia, decreased haemoglobin (HGB) and higher relative percentage of neutrophils were independent risk factors for LR (p < 0.05). The first two were also risk factors for retinal microvasculopathy, whereas secondary antiphospholipid syndrome (APS) was for macrovascular obstruction. In male group, LR had significant associations with decreased HGB, no matter which types of retinopathy (p < 0.05). In female group, LR was significantly associated with haemolytic anaemia, presence of antiphospholipid antibodies, decreased white blood cells and relative high percentage of neutrophils. Specifically, haemolytic anaemia (p = 0.002) was significantly associated with retinal microvasculopathy, and APS (p = 0.003) was significantly associated with macrovasculature obstruction. LR was related to haemolytic anaemia, decreased HGB levels and higher percentage of neutrophils. Retinal microvasculopathy accounted for most cases and macrovasculature obstructions were rare. Male and female patients have distinct risk factors. Early ophthalmic screening is recommended especially for those with risk factors of LR.

Analysis of clinical, immunological characteristics, damage, and survival in 300 Turkish systemic lupus erythematosus patients.

This retrospective study aimed to conduct a comprehensive analysis of Turkish Systemic Lupus Erythematosus (SLE) patients of Caucasian ethnicity, focusing on their clinical, immunological, and therapeutic characteristics, damage accural and mortality. We carried out a retrospective assessment of 300 SLE patients diagnosed between 2001 and 2017 at Kocaeli University Rheumatology Clinic. Demographic data, clinical manifestations, immunological profiles, treatment approaches, disease-related damage, and survival information were collected. The study population had a significant female predominance (89%) with a mean age of disease onset of 35.4 (SD:13.3) years. Hematological (72.6%) and mucocutaneous (72%) manifestations were the most common clinical findings, followed by arthritis (66.3%). Females had higher frequency of photosensitivity (p = 0.019), malar rash (p < 0.001), and alopecia (p = 0.014). Anti-dsDNA antibodies were detected in 61.6% of patients, while 57% of patients had hypocomplementemia. Secondary antiphospholipid syndrome was observed in 15.3% of patients; the most common manifestations included deep venous thrombosis (32.6%) and cerebrovascular accidents (30.4%). Lupus Nephritis (LN) affected 40.3% of the cohort. The most common pathologic finding was Class IV LN (30.5%). Eventually, 13 (4.3%) patients developed chronic kidney disease (CKD) and 4 had renal replacement therapies. Patients with LN had higher usage of pulse steroids, azathioprin, mycophenolate mofetil, cyclophosphamide, and rituximab (p < 0.001 for each). In the juvenile-onset group (n = 31, 10.3%), an increased occurrence of malar rash (p = 0.009), nephritis (p = 0.034), hypocomplementemia (p = 0.001), positive anti-dsDNA (p = 0.007), anti-Sm (p = 0.046), anti-rib-P (p = 0.014) antibodies were observed. At least one damage parameter was observed in 32.6% patients with musculoskeletal manifestations being the most common. Thirteen patients were diagnosed with various malignancies, with cervical cancer being the most common (4 cases). The total 5 and 10-year survival rates were 92.5% and 86.7%, respectively. However, patients with CKD, had lower survival rates; 75% at 3 years and 60% at 15 years. Regression analysis demonstrated an association of CKD and history of infections with decreased survival (p = 0.02, each). Ethnicity and geography influence the clinical diversity of SLE. Recognizing these disparities is crucial for tailoring patient care. Future inception cohort studies in Turkish SLE patients are necessary to address the limitations of retrospective research.

Targeting the tissue factor coagulation initiation complex prevents antiphospholipid antibody development

AbstractAntiphospholipid antibodies (aPL) in primary or secondary antiphospholipid syndrome (APS) are a major cause for acquired thrombophilia, but specific interventions preventing autoimmune aPL development are an unmet clinical need. Although autoimmune aPL cross react with various coagulation regulatory proteins, lipid-reactive aPL, including those derived from patients with COVID-19, recognize the endolysosomal phospholipid lysobisphosphatidic acid presented by the cell surface–expressed endothelial protein C receptor. This specific recognition leads to complement-mediated activation of tissue factor (TF)–dependent proinflammatory signaling and thrombosis. Here, we show that specific inhibition of the TF coagulation initiation complex with nematode anticoagulant protein c2 (NAPc2) prevents the prothrombotic effects of aPL derived from patients with COVID-19 in mice and the aPL–induced proinflammatory and prothrombotic activation of monocytes. The induction of experimental APS is dependent on the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, and NAPc2 suppresses monocyte endosomal reactive oxygen species production requiring the TF cytoplasmic domain and interferon-α secretion from dendritic cells. Latent infection with murine cytomegalovirus causes TF cytoplasmic domain–dependent development of persistent aPL and circulating phospholipid-reactive B1 cells, which is prevented by short-term intervention with NAPc2 during acute viral infection. In addition, treatment of lupus prone MRL-lpr mice with NAPc2, but not with heparin, suppresses dendritic-cell activation in the spleen, aPL production and circulating phospholipid-reactive B1 cells, and attenuates lupus pathology. These data demonstrate a convergent TF-dependent mechanism of aPL development in latent viral infection and autoimmune disease and provide initial evidence that specific targeting of the TF initiation complex has therapeutic benefits beyond currently used clinical anticoagulant strategies.

Non-pharmacological rehabilitation interventions for individuals with antiphospholipid syndrome: A scoping review.

The objective of this study was to explore what non-pharmacological interventions have been examined for individuals with antiphospholipid syndrome (APS). We conducted a systematic literature search of the databases PubMed, Embase, Scopus, Web of Science, CINAHL, and ClinicalTrials.gov from 1983-Feb. 2023. Our scoping review included studies that examined non-pharmacological interventions for individuals with APS using patient-reported outcome measures. We excluded studies that reported physiological outcomes only. The review yielded one case study on the safety and efficacy of an exercise program for a 15-year-old male with secondary APS using physiological and patient-reported outcome measures. Despite the lack of evidence of non-pharmacological interventions for individuals with APS, one excluded study reported that individuals with APS want guidance about physical activity and exercise. We also found several types of potentially relevant non-pharmacological interventions for individuals with lupus, a disease that often co-occurs with APS. Non-pharmacological interventions may offer a solution for addressing some non-thrombotic or non-obstetric APS symptoms, such as neurological, physical, and cognitive symptoms that are not well-controlled by anticoagulation. Due to the unique risks associated with APS, research is needed to determine the safety and efficacy of non-pharmacological interventions, particularly those involving exercise. Adopting a comprehensive, multidisciplinary approach to managing patients with APS and involving rehabilitation professionals, who are experts in the design and delivery of non-pharmacological interventions, may provide a foundation for developing and testing novel interventions that improve health outcomes while also fulfilling unmet needs reported by patients.

Portrait of a patient with systemic lupus erythematosus for the prescription of the type I interferon inhibitor anifrolumab

In recent years the use of monoclonal antibodies that block activity of type I interferon (IFN) or its receptors has become the new approach in the pharmacotherapy of systemic lupus erythematosus (SLE).Objective: to characterize patients with SLE treated with the type I IFN receptor inhibitor anifrolumab (AFM, Saphnelo®).Material and methods. The prospective 12-month study included 21 patients with SLE who met the 2012 SLICC criteria. Standard laboratory and immunological markers for SLE were examined in all patients. The SLEDAI-2K index was used to determine the activity of SLE and the CLASI index was used to determine the severity of the mucocutaneous syndrome. Organ damage was assessed using the SLICC/ACR Damage Index (DI). The LupusQol and FACIT-Fatigue questionnaires were used to analyze health-related quality of life (HRQoL).Results and discussion. Female patients prevailed in the study, female/male ratio – 17 (81%)/4 (19%), median age – 31 [27; 46] years, disease duration – 9 [6.0; 11.0] years. The majority of patients (86%) had moderate or high disease activity according to the SLEDAI-2K index. Among the clinical manifestations of SLE, skin and mucous membranes lesions predominated (81%). Non-erosive polyarthritis of varying severity was observed in 66% of cases. Serositis showed 24% of patients (pleurisy, pericarditis), 43% had hematological abnormalities (hemolytic anemia, leukopenia, lymphopenia) and 14% - urinary syndrome (daily proteinuria up to 0.5 g/l and/or urinary sediment – leukocytes/erythrocytes/cylinders up to 5 in the field of view in the absence of urinary tract infection). All patients had immunological disorders. 14% of them were diagnosed with antiphospholipid syndrome (APS) and 43% with Sjögren's syndrome.All patients received hydroxychloroquine, 95% received glucocorticoids (GC) from 5 to 60 mg/day, 66% received immunosuppressants (cyclophosphamide, mycophenolate mofetil, azathioprine, methotrexate). 33% of patients had anamnesis of treatment with biologic disease modifying antirheumatic drugs (rituximab, belimumab, dual anti-B-cell therapy) and Janus kinase inhibitor baricitinib. All patients experienced a significant deterioration in HRQoL.Conclusion. The indications for prescribing AFM to 21 patients with SLE were: active SLE according to SLEDAI-2K and/or CLASI with predominant involvement of skin, its appendages and development of polyarthritis with immunological disorders, intolerance/ineffectiveness of previous standard therapy and inability to achieve low average daily doses of oral GCs. Other clinical manifestations in some patients were: serositis, mild hematological disorders (Coombs-positive anemia, leukopenia), urinary syndrome. AFM could be prescribed for a combination of SLE with secondary APS and Sjögren's syndrome as well as for a high DI SLICC.

Regulatory B Cells Evaluation in Systemic Lupus Erythematosus Patients with Subclinical Atherosclerosis and Secondary Antiphospholipid Syndrome.

The current knowledge of human studies that address B cells in Systemic Lupus Erythematosus (SLE) patients with subclinical atherosclerosis remains insufficient. We aimed to evaluate the contribution of Breg cells in SLE and secondary antiphospholipid syndrome (APS) patients taking into consideration its relation to subclinical atherosclerosis and the disease activity. Thirty SLE patients and 23 controls were included. Systemic Lupus Erythematosus Disease Activity Index-2000 was estimated. Evaluation of Breg cells percentage using flow cytometry was done. All participants underwent carotid doppler ultrasound examination for measurements of the intima-media thickness of the common carotid artery (cIMT). The coronary artery calcium scoring was calculated using the Agatston method. The mean± SD of age was 32.60±8.34 years, while of the age of onset was 28.27±7.60 years. Twenty-three patients (76.7%) had subclinical atherosclerosis. There was a highly significant difference in Breg cells between SLE and APS patients with subclinical atherosclerosis and controls (P= 0.001, 0.005). SLE and APS patients had significantly higher mean cIMT than control (P=0.01, 0.050). Breg cells had 70% sensitivity and 87% specificity for diagnosing of SLE (P=0.01). Multivariate regression analysis indicated that low Breg cells were predictive for the disease activity (OR=1.76, 95% CI=1.21- 2.85; P= 0.01). SLE patients had a high frequency of subclinical atherosclerosis, those and patients with secondary APS had a high risk of plaque formation. We found a contribution of Breg cells in SLE patients with subclinical atherosclerosis. Breg cells are considered a good predictor of diagnosis of SLE.

The Bioluminescent Modified Ham Test Identifies the Classical Pathway As the Major Driver of Complement Activation in Atypical Hemolytic Uremic Syndrome and Primary Antiphospholipid Syndrome

Introduction: The role of complement is increasingly recognized in disease pathogenesis, however diagnostic assays are limited by low predictive value, technical requirements, and inability to assess relative contributions of each pathway of complement (classical, alternative, or lectin). The traditional mHam was developed as a functional assay of complement-mediated eukaryotic cell death in atypical hemolytic uremic syndrome (aHUS). However, broader use of the assay has been limited by inter-operator dependence and technical requirements. We have developed a bioluminescent mHam that is robust and easily performed (no cell washes or exogenous reagent addition) and utilizes an autonomously bioluminescent HEK293 cell line to allow for real-time assessment of changes in metabolic health due to complement activation. Given both HEK293 and endothelial cells lack complement receptor 1 (CR1), a crucial regulator of the classical pathway (CP), this assay measures complement activity of greater relevance to disease pathogenesis. Methods: The bioluminescent mHam uses LiveLight (LL) HEK293 cells (490 BioTech) engineered to stably express the bacterial luciferase ( lux) and flavin reductase genes ( luxF) to create autonomous bioluminescence. A PIGA null clone (LL PIGA- HEK293) was created through proaerolysin selection (removing GPI-anchored complement regulators CD55 and CD59). To perform the assay, 40,000 cells were harvested with trypsin/EDTA and plated as triplicates in gelatin veronal buffer (GVB ++,80 µL). Serum (20 µL) was added after specified treatments (heat inactivation or inhibitor addition). Activity was monitored by serial luminescence measurements every 5 min at 37 °C. A relative luminescence of &amp;lt;25% at one hour is designated as positive based upon lowest replicate of any healthy control. Results: The bioluminescent mHam, unlike the original mHam, provides continuous measurement of complement activity (example tracing Figure 1). The complement specificity of the luminescent changes were demonstrated with heat inactivation, terminal complement blockade with eculizumab, and calcium/magnesium dependence. The relative contribution of CP to changes in luminescence was confirmed with the specific CP inhibitor sutimlimab as well as use of pathway specific buffers. Healthy control (HC) samples show a relative luminescence of 53.7% (95%CI 44.0-63.4) with no difference observed in acute thrombotic thrombocytopenic purpura (TTP) (mean 56.2%, 95%CI 41.2-71.2, p=&amp;gt;0.9999). We next utilized samples of aHUS patients known to be in remission, off complement inhibitor therapy. A large proportion of these patients have ongoing assay positivity even in the traditional mHam (9 of 13 in one unpublished cohort). The bioluminescent mHam shows that 5 of 6 aHUS patients in remission have ongoing positivity (mean 17.56%, 95%CI -10.5-45.6, p=0.0131). An acute aHUS sample showed similar results (17.8% after plasmapheresis). Unexpectedly, the relative luminescence is rescued by addition of either C1s or C5 inhibitors, but use of alternative pathway (AP) inhibitors has no significant rescuing effect ( Figure 1-2). Of aHUS patients tested while on complement inhibition, 91% (10/11) show greater than 88% blockade ( Figure 2 aHUS on therapy) . Finally, in one cohort, the traditional mHam was positive in 52% (14/27) of primary antiphospholipid syndrome (PAPS) cases and 15% (10/66) of secondary APS (SAPS) (unpublished data). Thus far, the bioluminescent mHam shows abnormal complement activity in 92% (12/13) of PAPS and 17% (2/12) of patients in SAPS ( Figure 2). Again, complement inhibition with C1s or C5 inhibitors abrogated the effect in a dose dependent manner. Conclusions: The bioluminescent mHam test is an exquisitely sensitive real-time measure of abnormal complement activity. It is easy to perform, more closely approximates the complement regulators on renal endothelium, can be utilized for therapeutic monitoring, and has already offered novel disease insights through the use of specific pathway inhibitors. Although aHUS is traditionally categorized as a disorder of the AP, these results suggest the “trigger” mediating disease pathology is the classical pathway. Also, we show that a large proportion of primary APS patients have abnormal CP activation responsive to C1s and C5 inhibition, suggesting the disease may be responsive to complement-based therapeutics.

Evaluation of the Efficacy and Safety during Treatment with TPO-Ras in 40 SLE-ITP and APS-ITP Patients

Objectives: Thrombopoietin receptor agonists (TPO-RAs) have emerged over the last decade as a therapeutic option in primary immune thrombocytopenia (ITP). TPO-RAs have demonstrated their efficacy in more than 70% of cases and are taking an increasingly important place in second line therapy. However, to date, no prospective cohort has been able to question the efficacy and safety of TPO-RAs in systemic lupus erythematosus (SLE-ITP) and antiphospholipid syndrome (APS-ITP) patients, particularly regarding venous and arterial thrombosis risks in this population. Methods: This multicenter retrospective cohort study was conducted from 2012 to 2023 in seven hospitals belonging to the French national network for adult ITP. We assessed the efficacy and the tolerance of TPO-RAs on a large retrospective cohort with a long follow-up of patients with ITP associated with 1) SLE or 2) primary or secondary APS or 3) with antinuclear antibodies (ANA) and anti-dsDNA or anti-Sm antibodies or 4) with ANA and at least one antiphospholipid antibody (APA) without thrombotic events (TEs). We studied the efficacy according the international criteria of response (Rodeghiero et al, Blood 2009) and the incidence of TEs, the risk factors for the occurrence of thrombosis, the management of TPO-RAs and their combination with antiplatelet agents or anticoagulants. Results: We included 40 ITP patients treated with TPO-RAs; 28 SLE-ITP, four APS-ITP, four with both SLE and APS, and four with significant ANA and APA positivity without definite SLE or APS. Five patients were triple positive for APA. The median duration of follow up was 46 months (1-132). The overall response rate was 84.2% for patients treated with romiplostim and 71% for those treated with eltrombopag after failure of standard treatments such as corticosteroids, intravenous immunoglobulins, rituximab and immunosuppressive agents. Eight TEs occurred in seven (17.5%) patients at a median of 119 days (IQR=171.5) after eltrombopag (n=4) or romiplostim (n=4) initiation with a median exposure duration of 37 days (13-119) for romiplostim and 255 days (30-807) for eltrombopag. Two venous TEs were observed including one cerebral vein thrombosis and one pulmonary embolism. We observed six arterial thrombotic events, such as myocardial infarctions and ischemic strokes including one fatal catastrophic APS. Four of these patients had a history of APS, and most had thrombotic risk factors and positive APA. TPO-RAs were continued after TEs in two patients for a total duration of 20 and 53 months in association with an antiplatelet agent for one patient and a combination of an antiplatelet agent and an anticoagulant for the second one without a new TE thereafter. TPO-RAs were transiently stopped and then reintroduced due to ITP flare in two patients. A new episode of myocardial infarction occurred in one of them despite association with antiplatelet agents requiring TPO-RAs definitive arrest. Conclusion: We confirmed the effectiveness of TPO-RAs in over 70% of SLE-ITP and APS-ITP patients who failed to respond to corticosteroids, intravenous immunoglobulins, rituximab and/or standard immunosuppressive agents. Nevertheless, these findings highlight the need to carefully consider the potential benefits and thrombotic risks before initiating TPO-RAs, especially in elderly patients with thrombotic risk factors and positive APA or a confirmed APS. Further studies are needed to evaluate more precisely the TEs risk factors of these agents in this specific population, in order to better select SLE and APS-ITP patients who could benefit from them.