Lupus Anticoagulant Antibodies Research Articles

Immune thrombocytopenia in systemic lupus erythematosus: Prevalence, risk factors, and a novel predictive model for risk assessment

IntroductionImmune thrombocytopenia (ITP) is a potentially severe manifestation of systemic lupus erythematosus (SLE) reported in 7–40% of SLE patients. ITP has been associated with a higher risk of organ damage and mortality. ObjectivesTo describe which factors are associated with the presence of ITP in SLE patients. MethodsRetrospective case–control study. Cases were defined as SLE patients who had ever developed ITP and were sex- and age-matched with two controls. A predictive model was constructed to identify SLE patients who were at risk of developing ITP. ResultsITP prevalence in our SLE cohort was 8.35%. Cases had a higher frequency of hemolytic anemia, while controls had a higher prevalence of arthritis at SLE diagnosis. During SLE progression, cases tested positive for anticardiolipin, anti-β2-glycoprotein 1, and lupus anticoagulant antibodies more frequently. Cases received mycophenolic acid and azathioprine more often than controls and had a higher SLICC/ACR score. The model demonstrated a sensitivity of 87.53%, a positive predictive value of 81.92%, a specificity of 80.50%, area under the curve of 83.92%, a F1 of 83% and an overall accuracy of 83.68%. The variables that best explain the model were hemolytic anemia, arthritis, oral ulcers, Raynaud's phenomenon, low C4, low CH50, anticardiolipin and anti-β2GP1 antibodies. ConclusionSLE patients who develop ITP have a distinct phenotype characterized by more hemolytic anemia and less arthritis at SLE onset, and higher prevalence of antiphospholipid syndrome antibodies during SLE progression. This phenotype is associated with heightened organ damage and the need for more intensive therapies and stricter follow-up. Our predictive model has demonstrated an impressive ability to identify SLE patients at risk of developing ITP.

P026 Neurofascin antibodies complicating a case of severe systemic lupus erythematosus

Abstract Background/Aims Juvenile-onset systemic lupus erythematosus (jSLE) is an autoimmune disease that results in increased disease activity and damage compared to adult-onset SLE. There is increased medication burden, severe organ manifestations and higher incidence of renal, cardiovascular and neuropsychiatric (NP) involvement. Anti-nervous system (NS) antibodies are seen across immune mediated diseases including SLE. Myelin oligodendrocyte glycoprotein (MOG) and neurofascin (NF) 186 antibodies are particularly associated with higher frequencies of NP-SLE. These patients can present with the distinct clinical phenotype associated with that antibody (i.e., demyelination with MOG, neuropathy with NF186). Methods We present an SLE patient with progressive neurological features and anti-NF antibodies who responds well to ocrelizumab after modest response to initial immunotherapy. Results An 18 year old female has active jSLE including malar rash, alopecia, arthralgia, aphthous ulcers, headaches. She presents with lower limb and ascending abdominal paraesthesia and left 6th cranial nerve palsy alongside a recent respiratory tract infection. ANA 1:5120 homogenous pattern, high dsDNA, low C3 and C4, thrombocytopenia and antibodies to Sm, Ro, RNP, anti-Rib-P and strongly positive lupus anticoagulant antibodies and low titre anti-cardiolipin (aCL) IgG and IgM. Lumbar puncture is unremarkable. Nerve conduction studies (NCS) demonstrate progressive predominant motor inflammatory neuropathy without demyelination. CT, MRI brain and MRI spine are normal. She is treated as atypical Guillain-Barre Syndrome (GBS)/ Miller-Fischer with 5 days IV immunoglobulin 2g/kg and also for active SLE with 3 days 500mg IV methylprednisolone. She is intubated following worsening dysphagia, dysarthria, muscle weakness and reduced consciousness. Plasma exchange and pulsed cyclophosphamide are subsequently given. Eye and facial movements worsen with NCS showing worsening patchy axonal sensorimotor polyneuropathy. Serial MRI brain is suggestive of posterior reversible encephalopathy syndrome (PRES). Autonomic instability is seen with labile blood pressure and tachycardia. Given the unusual presentation, anti-NF antibodies are tested and identified at 1:3200 positive, NF155 and 186, both IgG1 and IgG2. Given previous adverse reaction to rituximab, she received ocrelizumab which lead to a marked improvement in her sensorimotor symptoms and functionality. C3 and C4 levels show considerable improvement which is sustained and dsDNA levels normalise. B cell depletion therapy was chosen following a small case series of patients with neurofascin antibodies who developed severe autoimmune neuropathies. Half of these patients responded well to rituximab. One proposed mechanism being the targeting of immature CD20+ B cells inhibits plasmablast generation, which may be responsible for neurofascin antibody production early on in the disease. Conclusion Anti-NS antibodies are seen in SLE patients and their presence can suggest increased frequency of NP-SLE suggesting a potential future role as a biomarker. One should consider anti-NF antibody testing in patients with a GBS-like illness with progressive neuropathy, respiratory involvement and autonomic dysfunction despite standard immunotherapy. Disclosure P. Yee: None. M. Mouyis: None.

Safety and efficacy of extended thrombophilia screening directed venous thromboembolic events (VTE) prophylaxis in live liver donors: do we really need extended thrombophilia screening routinely?

The study aimed to determine the prevalence of hereditary thrombophilia, and stratify its severity among live liver donors in Pakistan. Also, the authors evaluated the safety and efficacy of thrombophilia profile testing directed venous thromboembolic events (VTE) prophylaxis while balancing bleeding risk and the need for routine thrombophilia testing before live liver donation among living donor candidates. Protein S (PS), protein C (PC), anti-thrombin (AT) III, and anti-phospholipid antibody panel (APLA) levels were measured in 567 potential donor candidates. Donors were divided into normal, borderline and high-risk groups based on Caprini score. The safety endpoints were VTE occurrence, bleeding complications or mortality. Among 567 donors, 21 (3.7%) were deficient in protein C, and 14 (2.5%) were deficient in anti-thrombin-III. IgM and IgG. Anti-phospholipids antibodies were positive in 2/567 (0.4%) and 2/567 (0.4%), respectively. IgM and IgG lupus anticoagulant antibodies were positive in 3/567 (0.5%) and 3/567 (0.5%), respectively. VTE events, bleeding complications and postoperative living donors liver transplantation-related complications were comparable among the three donor groups (P>0.05). One donor in the normal donor group developed pulmonary embolism, but none of the donors in either borderline or high-risk group developed VTE. The mean length of ICU and total hospital stay were comparable. No donor mortality was observed in all donor groups. Due to thrombophilia testing directed VTE prophylaxis, VTE events were comparable in normal, borderline and high-risk thrombophilia donor groups, but more evaluations are required to determine the lower safe levels for various thrombophilia parameters including PC, PS and AT-III before surgery among living donor candidates.

Determining Thrombogenicity: Using a Modified Thrombin Generation Assay to Detect the Level of Thrombotic Event Risk in Lupus Anticoagulant-Positive Patients.

The aim of this study was to determine the thrombogenicity of lupus anticoagulant (LA) antibodies using a modified thrombin generation assay (TGA) with the addition of activated protein C (APC) in a group of 85 patients with LA-positive samples. Of these, 58 patients had clinical manifestations of antiphospholipid syndrome (APS) according to the Sydney criteria classification, i.e., each patient had thrombosis or foetal loss, and 27 patients did not show any clinical manifestations of APS. A comparison of the two groups' TGA results revealed statistically significant differences (Fisher's test p = 0.0016). The group of patients exhibiting clinical manifestations of APS showed higher thrombogenicity in 56.9% of patients, while the group of patients not yet exhibiting clinical manifestations of APS showed higher thrombogenicity in 25.9% of patients. There were no significant differences in the specificity of the TGA test between the groups of patients exhibiting similar clinical manifestations. Receiver operating characteristic curve analysis showed a more significant relationship (p = 0.0060) for TGA than for LA titre (p = 0.3387). These data suggest that the determination of LA thrombogenicity with the TGA assay leads to an increased prediction of the manifestation of a thromboembolic event. Our findings appear to be particularly relevant for the prediction of thrombotic events in patients with laboratory-expressed APS and no clinical manifestations.

Pattern of disease expression in SLE patients with antiphospholipid antibodies: data from Indian Systemic Lupus Erythematosus Inception cohort (INSPIRE).

Antiphospholipid antibodies (APLA) are present in one-third of systemic lupus erythematosus (SLE) patients, and they are associated with both criteria and non-criteria manifestations. We studied the prevalence, clinical associations, and impact on mortality of APLA in SLE patients from India. Among the Indian SLE inception cohort (INSPIRE), patients who had data on all five routinely performed APLAs [lupus anticoagulant (LA), IgG and IgM anticardiolipin antibody (aCL) and anti-β2-glycoprotein I(β2GPI)] at enrolment were selected. Patients were divided into four categories based on the presence/absence of APLA associated manifestations and presence/absence of the APLA viz SLE-APS, SLE-APLA, SLE: events but no APLA, and SLE: no events, no APLA (reference group). 1035 SLE patients at least 1 APLA antibody was detected in 372 (35.9%). LA was present in 206 (19.9%), aCL in 126 (12.2%) and β2-GPI in 178 (17.2%). There were 88 thrombotic events in 83 patients (8.0%); 73 (82.9%) being arterial; APLA positivity was present in 37 (44.6%) [AOR 1.70 (1.054, 2.76)]. SLE-APS patients were younger and had higher mortality [AOR 4.11 (1.51, 11.3)], neuropsychiatric and hematologic disease. SLE-APLA also had a higher mortality rate [AOR 2.94 (1.06, 8.22)] than the reference group. The mortality was highest in the subset of patients with thrombotic events in the presence of APLA [AOR 7.67 (1.25, 46.9)]. The mere presence of APLA also conferred higher mortality even in the absence of thrombotic events [AOR 3.51 (1.43, 8.63)]. Hematologic manifestations (36.1%) were the most common non-criteria-manifestation. One-third of SLE patients have APLA and its presence is associated with non-criteria hematologic manifestations, arterial thrombosis and higher mortality rate.

Association between TORCH infection and lupus anticoagulant antibody in pregnant women with recurrent abortion.

Abortion is a medical condition that describes pregnancy loss due to various causes including TORCH infections (toxoplasmosis, others (syphilis and hepatitis B), rubella, cytomegalovirus (CMV), and herpes simplex virus (HSV) infection). TORCH infections may pass to the fetus that has low immunity to fight the disease, besides; the complications are much higher during the early stages of pregnancy which may involve abortion. Therefore, investigating the possible factors that could be associated with TORCH infection including the clotting factor lupus anticoagulant antibody is vital. In this study, TORCH antibodies in 33 pregnant women were assessed and then lupus anticoagulant antibodies were tested using Diagnostica Stago STart 4 Hemostasis Analyzer. The serum concentration of immunoglobulin M (IgM) and immunoglobulin G (IgG) for toxoplasma, rubella and CMV were quantitatively determined with Cobas e411. The serum concentration of IgG for rubella and CMV increased in the blood were 90.9% and 66.6% of pregnant women respectively, while toxoplasma results showed an increasing level of IgG in 24.4% of patients. IgM levels for toxoplasma, rubella and CMV are elevated in 6.1%, 3.03% and 24.2% of patients respectively. Lupus anticoagulant antibody is increased in the blood of 72.7% of pregnant women. It was concluded that only rubella and CMV infections cause the increase of lupus anticoagulant antibodies in the tested pregnant women, not toxoplasmosis.

An update on anti-protein Z antibodies

Protein Z (PZ) is a vitamin K-dependent protein that acts as a cofactor for the inhibition of activated factor X by the PZ-dependent protease inhibitor, an anticoagulant protein of the serpin superfamily. The presence of antibodies against PZ (aPZ-Abs) was first described in women with unexplained recurrent embryo loss, pre-eclampsia, or foetal death, independently from habitual antiphospholipid/anti-cofactor antibodies. Other studies suggested that aPZ-Ab could be associated with a small birthweight for the gestational age. The mechanism of action of these antibodies is not yet understood. At this time, even aPZ-Abs are frequently observed in patients with lupus anticoagulant or anticardiolipin antibodies, there is no evidence that aPZ-Abs increase systemic venous or arterial thrombotic risk. The comparison of the various published studies shows that the threshold suggesting an obstetric risk is not clearly defined. At present, it is not known whether one isotype of immunoglobulin (G or M, or both) is particularly involved in certain obstetric manifestations, or these antibodies persist during time, or can be induced by infectious diseases. Consequently, detection of these antibodies is not routinely warranted and should only be performed in randomized clinical trials.

Coagulation in Patients with Immune Thrombocytopenia and Other Associated Autoimmune Disorders

Introduction Chronic immune thrombocytopenia (ITP) is characterized by perturbations of immune homeostasis with hyperactivated effector cells as well as defective regulation of the adaptive immune system. It has been reported that, with varying frequency, patients with ITP may also have associated other autoimmune disorders, with circulating autoantibodies such as lupus anticoagulant antibodies (LACs), anti-nuclear antibodies (ANA), anticardiolipin (aCL), anti-beta2-glycoprotein I (anti-beta2GPI), anti-thyroid peroxidase (ATPA), and rheumatoid factor (RF). Objectives To evaluate coagulation in patients with ITP with autoantibodies associated to other autoimmune diseases. Methods This is a prospective study that was approved by the Ethics Committee from Hospital Universitario La Paz. Informed consent was signed before sampling. Adult ITP patients (n=182) without and with associated autoantibodies such as LACs, ANA, aCL, anti-beta2GPI, ATPA, and RF and healthy controls (n=180) were recruited. To evaluate the kinetics of clot formation and fibrinolysis, ROTEM® was performed on fresh platelet rich plasma adjusted to 25x10 9 platelets/L with the subjects own platelet poor plasma (PPP). Recalcification (NATEM) was used to induce coagulation. Clotting time (CT = time from start of measurement until initiation of clotting, in seconds); alpha angle (tangent to the curve at 2 mm amplitude, in degrees, which reflects the rate of fibrin polymerization); maximum clot firmness (MCF = maximum clot firmness, in mm, which reflects the maximum tensile strength of the thrombus); and lysis at 60 min (LI60) were recorded. Thrombin generation was measured in citrated PPP by calibrated automated thrombogram (CAT). To evaluate procoagulant capacity of plasma, coagulation was triggered by proper recalcification and the addition (final concentrations) of 1 pmol/L of recombinant human tissue factor (TF) and 4 µmol/L of phospholipid mixture (PPP-Reagent LOW, Thrombinoscope BV, Maastricht, The Netherlands). Procoagulant activity of microparticles (MPs) associated with their content of either TF or phosphatidylserine (PS) was determined, respectively, with MP reagent (4 µM phospholipids) or PRP reagent (1 pM of recombinant human TF) by CAT. The following parameters were determined: Lag time (LT), or time from the start of the assay until 10 nM thrombin is formed, in min; time-to-peak (ttPeak), or time required to reach the maximum thrombin concentration, in min; peak height (Peak), or maximum thrombin concentration reached, in nM; and endogenous thrombin potential (ETP), or total amount of thrombin generated over time, in nMxmin. Results Fifty of the 182 patients with ITP (27.5%) were positive for autoantibodies associated with other autoimmune diseases, distributed as shown in Table 1. ANA were the most frequent antibodies present in these patients, and 22% had more than one kind of associated antibodies. Patients with ITP without antibodies had a shorter clot formation time (CT) than healthy controls. Presence of associated autoimmune diseases prolongs CT and resulting in values similar to controls. Both groups of patients with ITP had a diminished fibrinolysis (Table 2). Thrombin generation triggered by TF plus phospholipids as well as that dependent on TF content of microparticles (MP-reagent) was impaired in patients with other associated autoimmune disorders as shown by the prolonged LT and the diminution in either ETP or peak of generated thrombin (Table 2). When thrombin generation relayed on phospholipids of MPs, all patients with ITP generated less thrombin. Conclusion Association of other autoimmune diseases with ITP seemed to produce a delay in clot formation and in thrombin generation whereas did not affect the diminished fibrinolysis observed in ITP patients. Work supported by Instituto de Salud Carlos III (ISCIII) (PI19/00772, PI22/01489), co-funded by the European Union.

The Immunodiagnostic Utility of Antinuclear Antibody Patterns: A Prediction for Renal Involvement in Systemic Lupus Erythematosus Patients in the Western Region of Saudi Arabia.

Objectives Previous studies have noted associations between the immunofluorescence patterns of antinuclear autoantibodies (ANA) and the autoimmune responses seen in systemic lupus erythematosus (SLE). In this study, the authors tested the hypothesis of whether ANA patterns predict renal involvement in SLE patients. Method A retrospective study was carried out on consecutive SLE patients who had ANA staining pattern dataand who were screened for renal involvement defined as all-stage proteinuria or chronic kidney disease (CKD) at a referral tertiary center in western Saudi Arabia from December 2021 to February 2022. Demographic data and levels of lupus immune markers including ANA titers, anti-double-stranded deoxyribonucleic acid antibodies (anti-dsDNA), complements C3 and C4, anticardiolipin (aCL) immunoglobulin (Ig) G and IgM, anti-β2 glycoprotein (β2-IgM and β2-IgG), and lupus anticoagulant (LA) antibodies were collected. Result Among 243 patients included, 25.1% had renal involvement (95% confidence interval {CI}=19.8-31.0). A mixed ANA pattern was associated with a higher prevalence of renal involvement (46.2%), followed by homogenous (26.5%) and speckled (25.6%) patterns, compared with 4.5% for the other patterns (p=0.044). No further association of renal involvement was observed with other biological markers. Adjusted logistic regression showed age (odds ratio {OR}=0.95; 95% CI=0.92-0.97) and mixed ANA pattern (OR=26.66; 95% CI=2.53-281.11) to be independently associated with renal involvement, explaining 12.6% of the variance. Conclusion A mixed homogenous/speckled ANA staining pattern is associated with an increased risk of renal involvement, independent of ANA titer or other lupus immune markers. The potential clinical applications of the ANA staining pattern in SLE should be explored in various subtypes of SLE and patient groups.

Endothelial dysfunction, thrombophilia, and nailfold capillaroscopic features in livedoid vasculopathy

BackgroundLivedoid vasculopathy (LV) is a rare, disabling disease characterized by painful ulcers, livedo reticularis and atrophy blanche. Hypercoagulation, endothelial, and microcirculatory dysfunction are believed to be responsible for the pathogenesis of this difficult-to-treat disease. ObjectivesThis study sought to investigate the frequency of endothelial dysfunction, hypercoagulability, and nailfold capillaroscopic features in LV patients to shed light on its etiology. MethodsThis case-control study included 16 patients with LV, 24 with systemic sclerosis (SSc), and 23 control subjects. Serum markers of endothelial dysfunction soluble endoglin, endocan, endothelin-1, lipoprotein a, plasminogen activator inhibitor-1 (PAI-1), soluble thrombomodulin, and von Willebrand factor were measured using enzyme-linked immunosorbent assays. Flow-mediated dilation and carotid intima-media thickness were examined as markers of endothelial dysfunction, and microcirculation was assessed with nailfold capillaroscopy. Thrombophilia-related parameters, including gene polymorphisms of factor V Leiden, prothrombin, PAI-1 genes, methylenetetrahydrofolate reductase (MTHFR) and factor XIII mutation and serum levels of protein C, protein S, antithrombin, homocysteine, D-dimer and antiphospholipid antibodies were investigated in LV patients. ResultsPlasminogen activator inhibitor-1 and soluble thrombomodulin levels were significantly higher in LV patients compared to control subjects (2.3 [2.05–2.79] ng/ml vs. 1.89 [1.43–2.33] ng/ml, p = 0.007; 1.15 [0.88–1.4] ng/ml vs. 0.76 [0.56–0.9] ng/ml, p = 0.004, respectively). Flow-mediated dilation was 25.4 % lower in the LV patients compared to the control group (14.77 % [11.26–18.26] vs. 19.80 % [16.47–24.88], p = 0.034). Capillaroscopic features, including ramifications (75 % vs. 8.7 %, p < 0.001), avascular areas (25 % vs. 0 %, p = 0.011) and dilatations (33.2 % vs. 0 %, p = 0.016), were significantly higher in LV patients than in controls. LV patients had multiple biochemical or genetic abnormalities related to thrombophilia, including heterozygous factor V Leiden mutations (6.3 %), MTHFR (C677T) mutations (heterozygous 43.8 %, homozygous 18.8 %), MTHFR (A1298C) mutations (heterozygous 37.5 %, homozygous 12.5 %), factor XIII heterozygous mutation (12.5 %), antithrombin deficiency (31.3 %), protein S deficiency (12.5 %), hyperhomocysteinemia (31.3 %), D-dimer elevation (25 %), anti-β2-glycoprotein I (12.5 %), lupus anticoagulant antibodies (6.3 %), and anticardiolipin antibodies (6.3 %). ConclusionsIn conclusion, LV patients were characterized by an increased presence of thrombophilia-related parameters, and also exhibited vascular endothelial and microcirculatory dysfunction, resembling SSc. These findings support the complex interaction of thrombophilia, endothelial dysfunction, and microcirculation dysregulation in the pathogenesis of LV. Thus, the treatment of LV patients should be individualized, based on the identification of the predominant pathological pathways.

P-337 Does Endometriosis Have More Detrimental Effect on Ovarian Reserve in the Presence of Autoimmunity? A Prospective Observational Study

Abstract Study question Is the coexistence of autoimmunity more harmful to ovarian reserve in endometriosis patients? Summary answer The presence of autoimmunity does have additional harm to ovarian reserve in patients with endometriosis. What is known already It is known that endometriosis has a negative impact on ovarian reserve via different pathways. The presence of inflammation, increased reactive oxygen substances, and iron deposits in ovarian endometrioma have detrimental effects on the ovarian reserve. Although endometriosis was reported to have co-incidence with immunologic disorders up to 50%, there is not enough publication to assess the impact of autoimmunity on ovarian reserve in endometriosis. Study design, size, duration A prospective observational study including 100 women with endometriosis was performed between January 2022 and January 2023 in the endometriosis center of a tertiary university hospital. Participants/materials, setting, methods Patients who were diagnosed with endometriosis, under age 40, without confirmed systemic disease, enrolled in the study. All patients were assessed by physical examination and routine ultrasound check. Endometriosis diagnosis was based on that assessment or verified previous surgery. The blood samples were collected from all patients. Serum anti-mullerian hormone (AMH) and immunologic panel tests (anti-nuclear antibody profile, lupus anticoagulant antibody, thyroid antibodies) were analyzed. Main results and the role of chance A total of 99 patients were enrolled in the analysis (one patient was excluded because of missing parameters). Patients were divided into two groups depending on the presence of any autoimmune antibody. There were 58 patients with negative test (autoimmune (-) group) and 41 patients with at least one positive antibody (autoimmune (+) group). The demographic parameters, including age, fertility situation, abuse, pain scores, endometrioma diameter, and laterality, were similar between the groups. The anti-mullerian hormone levels were significantly lower in the autoimmune (+) group, (Respectively with interquartile ranges; 2.2 ng/ml (0.6-5.3) vs. 0.9 ng/ml (0.19-3.6), p = 0.01) When the results were adjusted according to the age and surgical history, the significant negative effect of autoimmunity on the ovarian reserve disappeared (p = 0.156). Limitations, reasons for caution The lack of sufficient studies in this area makes our results important. The small sample size and lack of subgroup analysis depending on different autoimmune diseases limit the study's strength. Wider implications of the findings This observational study revealed that almost half of the endometriosis patients have autoimmunity. However, the results supported the existing data; the impact of autoimmunity on ovarian reserve in endometriosis is a novel research field, and the present study suggests it should be further investigated in endometriosis patients. Trial registration number Not Applicable

Recurrent MiscarriageGreen-top Guideline No. 17.

In this guideline, recurrent miscarriage has been defined as three or more first trimester miscarriages. However, clinicians are encouraged to use their clinical discretion to recommend extensive evaluation after two first trimester miscarriages, if there is a suspicion that the miscarriages are of pathological and not of sporadic nature. Women with recurrent miscarriage should be offered testing for acquired thrombophilia, particularly for lupus anticoagulant and anticardiolipin antibodies, prior to pregnancy. [Grade C] Women with second trimester miscarriage may be offered testing for Factor V Leiden, prothrombin gene mutation and protein S deficiency, ideally within a research context. [Grade C] Inherited thrombophilias have a weak association with recurrent miscarriage. Routine testing for protein C, antithrombin deficiency and methylenetetrahydrofolate reductase mutation is not recommended. [Grade C] Cytogenetic analysis should be offered on pregnancy tissue of the third and subsequent miscarriage(s) and in any second trimester miscarriage. [Grade D] Parental peripheral blood karyotyping should be offered for couples in whom testing of pregnancy tissue reports an unbalanced structural chromosomal abnormality [Grade D] or there is unsuccessful or no pregnancy tissue available for testing. [GPP] Women with recurrent miscarriage should be offered assessment for congenital uterine anomalies, ideally with 3D ultrasound. [Grade B] Women with recurrent miscarriage should be offered thyroid function tests and assessment for thyroid peroxidase (TPO) antibodies. [Grade C] Women with recurrent miscarriage should not be routinely offered immunological screening (such as HLA, cytokine and natural killer cell tests), infection screening or sperm DNA testing outside a research context. [Grade C] Women with recurrent miscarriage should be advised to maintain a BMI between 19 and 25 kg/m2 , smoking cessation, limit alcohol consumption and limit caffeine to less than 200 mg/day. [Grade D] For women diagnosed with antiphospholipid syndrome, aspirin and heparin should be offered from a positive test until at least 34 weeks of gestation, following discussion of potential benefits versus risks. [Grade B] Aspirin and/or heparin should not be given to women with unexplained recurrent miscarriage. [Grade B] There are currently insufficient data to support the routine use of PGT-A for couples with unexplained recurrent miscarriage, while the treatment may carry a significant cost and potential risk. [Grade C] Resection of a uterine septum should be considered for women with recurrent first or second trimester miscarriage, ideally within an appropriate audit or research context. [Grade C] Thyroxine supplementation is not routinely recommended for euthyroid women with TPO who have a history of miscarriage. [Grade A] Progestogen supplementation should be considered in women with recurrent miscarriage who present with bleeding in early pregnancy (for example 400 mg micronised vaginal progesterone twice daily at the time of bleeding until 16 weeks of gestation). [Grade B] Women with unexplained recurrent miscarriage should be offered supportive care, ideally in the setting of a dedicated recurrent miscarriage clinic. [Grade C].

Role of β2‐glycoprotein I in the pathogenesis of the antiphospholipid syndrome

AbstractAntiphospholipid syndrome (APS) is typically characterized by increased levels of three classes of antiphospholipid antibodies, namely lupus anticoagulant, anti‐β2‐glycoprotein I (anti‐β2GPI), and anticardiolipin antibodies. β2‐Glycoprotein (β2GPI) is a phospholipid‐binding protein composed of five domains (DI–V) and a major antigen in APS. β2GPI is expressed on the surfaces of several cell types, including endothelial cells, monocytes, trophoblast cells, and platelets. Its binding to the anti‐β2GPI antibody triggers downstream signaling events and ultimately exerts a variety of cellular effects. β2GPI modulates hemostasis and the complement system, as well as playing an important role in APS‐associated vascular injury. Therefore, studying β2GPI will help elucidate the pathogenesis of APS and improve the treatment of patients with this condition. This review will mainly focus on the structure and function of β2GPI, as well as its implication in the pathogenesis of APS.

Primary Antiphospholipid Syndrome Presenting with Cerebellar Stroke and Positive Titres of Anti-β2 Glycoprotein-1 Antibody Only: A Case Report (P9-5.026)

<h3>Objective:</h3> To describe a case of Primary Antiphospholipid Syndrome presenting with Cerebellar Stroke and positive titres of anti-β2 glycoprotein-1 antibody only. <h3>Background:</h3> Antiphospholipid syndrome (APS) is an autoimmune disease where the presence of antiphospholipid antibodies leads to the development of arterial and/or venous thromboses and obstetric complications. Amongst the myriad of presentations, APS can manifest in the form of cerebrovascular stroke. However, overlapping clinico-radiological findings and a lack of classic APS features can sometimes pose a diagnostic dilemma. <h3>Design/Methods:</h3> NA <h3>Results:</h3> A 31-year-old female presented with occipital headache and difficulty in walking. Neurological examination revealed ataxia, dysdiadochokinesia and intention tremor. Preliminary laboratory findings revealed raised ESR along with normal CRP, aPTT and PT levels. MRI brain showed an acute infarct in the right cerebellar hemisphere and right postero-lateral upper medulla. MRA Head &amp; Neck revealed an occluded intracranial right vertebral artery with an extracranial segment showing multifocal occlusions with aorta and its major branches unaffected. These features and the absence of fever, rash, joint pain or obstetric complications led to the consideration of stroke due to Takayasu Arteritis. Treatment was initiated with corticosteroids, anticoagulants and antiplatelet drugs. However, on review of other laboratory tests, notably the auto-immune profile showed the presence of anti-ß2 glycoprotein-I antibodies with negligible titres of lupus anticoagulant and anti-cardiolipin antibody. This pointed towards a diagnosis of Primary Antiphospholipid Syndrome, which was confirmed after 12 weeks when repeat laboratory tests indicated the presence of IgM anti-ß2 glycoprotein-I antibodies. The patient is now on lifelong Warfarin therapy and is leading a symptom-free life. <h3>Conclusions:</h3> This case illustrates the potential of anti-β2 glycoprotein-1 antibody to cause a cerebellar stroke in the absence of other commonly involved antibodies. It also highlights the value of a holistic stroke workup. Recognition of APS is imperative for the timely administration of treatment and to prevent a recurrence. <b>Disclosure:</b> Mr. Shah has nothing to disclose. Mr. Shah has nothing to disclose. Dr. Nagrani has nothing to disclose.

Chorea as the Initial Manifestation of Antiphospholipid Syndrome (P9-5.020)

<h3>Objective:</h3> To discuss a rare case of chorea presenting as the initial manifestation of autoimmune disease. <h3>Background:</h3> Autoimmune chorea, including paraneoplastic, post-infectious, and idiopathic etiologies, is one of the leading causes of adult-onset chorea behind Huntington’s and vascular diseases.¹ In particular, in primary antiphospholipid syndrome (APS) and systemic lupus erythematosus, chorea is the initial manifestation of disease in 0.9 to 2% of cases.^1,2 <h3>Design/Methods:</h3> Verbal and written consent were obtained from the patient. <h3>Results:</h3> 73-year-old female with PMH of ITP, left MCA ischemic stroke, SDH, and DVT on anticoagulation who presented initially to ED with choreoathetoid movements starting 3 days prior to admission. History was unremarkable for triggering factor. Head imaging was unremarkable for acute intracranial process. B12, folate, TSH, electrolytes, RPR, serum copper, ANA, anti-dsDNA, SS-A, SS-B, Smith, and RNP antibodies negative. Lupus anticoagulant, β2 glycoprotein, and anti-cardiolipin antibodies positive. EEG unremarkable. Pelvic ultrasound negative. Genetic testing for Huntington’s negative. LP normal with exception of positive Coxsackie B1–B6 and A24 antibodies. After five-day course of IVIg, movements improved and she was discharged on no immunosuppression. Five weeks later, patient returned to ED with worsening of choreoathetoid movements. Repeat head CT again negative for acute pathology. Repeated spinal was unremarkable. Patient received Solumedrol 1g for four days with significant improvement in symptoms, and discharged on Prednisone 60 mg daily with recommendation to follow-up with rheumatology and neurology. On follow-up several months later, patient maintained on Prednisone 5 mg daily with no recurrence of choreoathetoid movements. <h3>Conclusions:</h3> While chorea is not the most commonly reported movement disorder in the context of autoimmune disease, it is often a delayed diagnosis, resulting in recurrent admissions and healthcare costs. Laboratory testing for autoimmune disorders should be included in the initial work-up of new-onset chorea to establish the diagnosis and properly treat as to prevent development of fulminant disease. <b>Disclosure:</b> Ms. Alayon has nothing to disclose. Mrs. Goodis has nothing to disclose. Dr. Feinberg has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Acadia. Dr. Feinberg has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Catalyst. Dr. Feinberg has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for eisai. Dr. Feinberg has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Argenx. Dr. Feinberg has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Abbvie. Dr. Feinberg has stock in Amarin. Stuart N. Kieran, MD has nothing to disclose. Dr. Wirkowski has nothing to disclose.

Antiphospholipid Antibodies Occurrence in Acute SARS-CoV-2 Infection without Overt Thrombosis.

We sought to determine the prevalence of antiphospholipid antibodies (aPLs) and their correlation with COVID-19 severity (in terms of clinical and laboratory parameters) in patients without thrombotic events during the early phase of infection. This was a cross-sectional study with the inclusion of hospitalized COVID-19 patients from a single department during the COVID-19 pandemic (April 2020-May 2021). Previous known immune disease or thrombophilia along with long-term anticoagulation and patients with overt arterial or venous thrombosis during SARS-CoV-2 infection were excluded. In all cases, data on four criteria for aPL were collected, namely lupus anticoagulant (LA), IgM and IgG anticardiolipin antibodies (aCL), as well as IgG anti-β2 glycoprotein I antibodies (aβ2GPI). One hundred and seventy-nine COVID-19 patients were included, with a mean age of 59.6 (14.5) years and a sex ratio of 0.8 male: female. LA was positive in 41.9%, while it was strongly positive in 4.5%; aCL IgM was found in 9.5%, aCL IgG in 4.5%, and aβ2GPI IgG in 1.7% of the sera tested. Clinical correlation: LA was more frequently expressed in severe COVID-19 cases than in moderate or mild cases (p = 0.027). Laboratory correlation: In univariate analysis, LA levels were correlated with D-dimer (p = 0.016), aPTT (p = 0.001), ferritin (p = 0.012), C-reactive protein (CRP) (p = 0.027), lymphocyte (p = 0.040), and platelet (p < 0.001) counts. However, in the multivariate analysis, only the CRP levels correlated with LA positivity: OR (95% CI) 1.008 (1.001-1.016), p = 0.042. LA was the most common aPL identified in the acute phase of COVID-19 and was correlated with infection severity in patients without overt thrombosis.

Lupus Anticoagulant and Anticardiolipin Antibody IgG are Associated with Increased Atherosclerosis at the Suprainguinal Elastic and Infrainguinal Muscular Arteries in the Abdomen and Lower Extremities

PurposeWhether antiphospholipid antibodies (aPLs) cause atherosclerosis in certain arteries with specific compositions and locations remains unknown. We investigated the relationship between aPLs and their association with locations of atherosclerosis in the arteries of the abdomen and lower extremities.MethodsOf 2273 patients, 697 who underwent computed tomography angiography of the abdomen and lower extremities and aPL evaluation were included. Atherosclerosis distribution score (ADS) was employed to quantify atherosclerosis severity. Multiple linear regression analysis was performed using the ADS of the suprainguinal elastic and infrainguinal muscular arteries as dependent variables and all aPLs, conventional risk factors of atherosclerosis, and coagulation-related factors as independent variables.ResultsIn the suprainguinal elastic and infrainguinal muscular arteries, common risk factors for higher ADS were age, smoking, hypertension, higher glycated hemoglobin, male sex, decreased protein S, and increased homocysteine. Lupus anticoagulant (LA) and increased triglyceride level in the suprainguinal elastic arteries and anticardiolipin antibody (aCL) immunoglobulin (Ig)G, longer alcohol consumption duration, and increased fibrinogen level in the infrainguinal muscular arteries were also risk factors for higher ADS.ConclusionLA and aCL IgG were associated with atherosclerosis in the suprainguinal elastic and infrainguinal muscular arteries, respectively. aPLs could predict the location of atherosclerosis.

Frequency and predictors for chronic thromboembolic pulmonary hypertension after a first unprovoked pulmonary embolism: Results from PADIS studies

BackgroundChronic thromboembolic pulmonary hypertension (CTEPH) is a life‐threatening complication of a pulmonary embolism (PE) whose incidence and predictors are not precisely determined. ObjectiveTo determine the frequency and predictors for CTEPH after a first unprovoked PE. Patients/MethodsIn a randomized trial comparing an additional 18‐month warfarin versus placebo in patients after a first unprovoked PE initially treated with vitamin K antagonist for 6 months, we applied recommended CTEPH screening strategies through an 8‐year follow‐up to determine cumulative incidence of CTEPH. CTEPH predictors were estimated using Cox models. Pulmonary vascular obstruction (PVO) and systolic pulmonary arterial pressure (sPAP) at PE diagnosis and 6 months were studied by receiver operating curves analysis. All CTEPH cases and whether they were incident or prevalent were adjudicated. ResultsDuring a median follow‐up of 8.7 years, nine CTEPH cases were diagnosed among 371 patients, with a cumulative incidence of 2.8% (95% confidence interval [CI] 0.95–4.64), and of 1.31% (95% CI 0.01–2.60) after exclusion of five cases adjudicated as prevalent. At PE diagnosis, PVO > 45% and sPAP > 56 mmHg were associated with CTEPH with a hazard ratio (HR) of 33.00 (95% CI 1.64–667.00, p = .02) and 12.50 (95% CI 2.10–74.80, p < .01), respectively. Age > 65 years, lupus anticoagulant antibodies and non‐O blood groups were also predictive of CTEPH. PVO > 14% and sPAP > 34 mmHg at 6 months were associated with CTEPH (HR 63.90 [95% CI 3.11–1310.00, p < .01]and HR 17.2 [95% CI 2.75–108, p < .01]). ConclusionAfter a first unprovoked PE, CTEPH cumulative incidence was 2.8% during an 8‐year follow‐up. PVO and sPAP at PE diagnosis and at 6 months were the main predictors for CTEPH diagnosis.

Neuropsychiatric manifestations are associated with increased mortality in Indian patients with lupus: A single centre retrospective observational study

To study the prevalence of different NPSLE manifestations in our cohort and to compare clinical and immunological features and outcomes including mortality of patients with NPSLE and SLE controls without NP involvement. This was a retrospective study in a tertiary care referral centre. All patients of SLE seen in the last 10 years and fulfilling the SLICC criteria with neuropsychiatric manifestations as per the ACR definitions were included. Patients of SLE without NP involvement were sequentially assigned as controls in a ratio of 1:2. Of the 769 patients diagnosed with SLE from Jan 2011 to December 2020, 128 (16.6%) had NPSLE manifestations as per the ACR definitions. The commonest NPSLE manifestation was seizures (6.5%) followed by cerebrovascular accident (3.9%). NPSLE manifestation occurred at the first presentation of SLE in 99/128 (77.3%) patients and 58 (45.3%) patients had more than one NPSLE manifestation. Lupus anticoagulant and anticardiolipin antibody were tested in 120 patients and were positive in 16 (13.3%) and 12 (10%), respectively. No difference was found in anti-ribosomal p, lupus anticoagulant and anticardiolipin antibodies between the cases and controls. Twenty-one (16.4%) deaths occurred in patients with NPSLE (median follow-up of 40 months) as compared to 13 (5%) in controls (median follow-up of 32 months) (p = <0.001). The cumulative survival of patients with NPSLE was lower as compared to controls (p < 0.001). Relapse of NPSLE was seen in 11(8.6%) patients and was associated with mortality (p = 0.017). Seizures and cerebrovascular accidents are the commonest NPSLE syndromes in our patients. The presence of NPSLE was associated with high mortality in Indian patients with lupus.

Development of severe fingertip ulcers, pulmonary hypertension, and scleroderma renal crisis in a patient with systemic sclerosis and anti‐PL12 antibodies

A 50-year-old Japanese woman with limited cutaneous-type SSc presented with severe gangrene in the fingertips of the hands and hypertension, tested positive for anti-PL-12 antibodies. She was diagnosed with acute heart failure owing to scleroderma renal crisis and pulmonary arterial hypertension. Therapeutic agents for pulmonary arterial hypertension were also effective for the digital gangrene. A 50-year-old Japanese woman received prednisolone treatment (2.5 mg/2 days) for systemic sclerosis (SSc) and interstitial pneumonia for approximately 15 years. She suddenly developed severe pain, cold sensation, and digital cyanosis and was treated with intravenous alprostadil (10 μg/day). Two days later, she presented with acute exacerbations of hepatic (aspartate aminotransferase, 4400 IU/L; alanine aminotransferase, 1997 IU/L), renal (creatinine, 2.14 mg/dl), and respiratory (blood oxygen saturation, 77% on room air) functions. Upon admission to the hospital, she presented with increased blood pressure (160/80 mmHg), and within a week developed severe gangrene in the second-to-fifth fingertips of the right hand and the second and fourth fingertips of the left hand (Figure 1A). A modified Rodnan skin score of 2, Raynaud's phenomenon, and nailfold bleeding were observed. Scleroderma was noted only in the extremities and was confirmed by histopathological examination of the forearm lesions. The patient tested positive for anti-nuclear (40×, cytoplasmic), aminoacyl-tRNA synthetase (ARS, 170 index), and PL-12 antibodies,1 but tested negative for anti-topoisomerase 1, centromere, RNA polymerase III, ribonucleoprotein, cardiolipin, anti-cardiolipin β2-glycoprotein I complex, lupus anticoagulant, and myeloperoxidase antineutrophil cytoplasmic antibodies. The findings from lung perfusion scintigraphy were normal. Computed tomography showed mild interstitial pneumonia. The trans-tricuspid pressure gradient (assessed by echocardiography), mean pulmonary arterial pressure, and levels of N-terminal prohormone of brain natriuretic peptide all showed marked elevation to 65 mmHg (normal, <35 mmHg), 50 mmHg (<25 mmHg), and 62,991 pg/ml, respectively. The patient was diagnosed with limited cutaneous-type SSc with anti-PL12 antibodies, acute heart failure, and congestive liver failure, owing to scleroderma renal crisis (SRC) and pulmonary arterial hypertension (PAH). The cardiac, renal, and hepatic functions of the patient improved after 5 days of treatment with continuous hemodiafiltration and a combination of an angiotensin-converting enzyme inhibitor and a Ca-channel antagonist. Endothelin receptor antagonist, phosphodiesterase-type 5 inhibitor, and selective prostacyclin receptor agonist were systemically administered (Figure 1B), and absolute ethanol and a sucrose povidone-iodine ointment were topically applied on the gangrenous fingertips. Seven months later, re-epithelialization in the fingertips was observed (Figure 1C). Anti-synthetase syndrome is often associated with the development of specific clinical symptoms, such as Raynaud's phenomenon, mechanic's hands, polyarthritis, interstitial pneumonia, and myositis.2 Anti-ARS antibodies, including anti-PL12 antibodies, are typically specific to polymyositis/dermatomyositis. The frequency of SSc in patients positive for anti-ARS antibodies is relatively low (3.6%).2 A few cases of SSc with anti-PL12 antibodies have been reported. However, there are no reported cases of this condition with digital gangrene, PAH, and SRC. Generally, SRC or PAH develops in SSc patients with anti-RNA polymerase III or anti-centromere antibodies, respectively.3, 4 Therapeutic agents for PAH are often effective for the concurrent treatment of digital ulcers and gangrene in patients with SSc.5 In this case, we prevented the progression of gangrene and achieved cure through a combination treatment with multiple anti-PAH agents. This approach may be useful for the treatment of patients with SSc who develop refractory digital ulcers and/or gangrene. Approval of the research protocol: N/A. Informed consent: Acquired. Registry and the Registration No. of the study/trial: N/A. Animal Studies: N/A. The authors declare no conflicts of interest.