RARE DISEASE
Antiphospholipid syndrome
Antiphospholipid syndrome
Antiphospholipid syndrome
Synonyms: APLS, Antiphospholipid antibody syndrome, Classic APLS, Classic antiphospholipid syndrome, Hughes syndrome
Synonyms: APLS, Antiphospholipid antibody syndrome, Classic APLS, Classic antiphospholipid syndrome, Hughes syndrome
Synonyms: APLS, Antiphospholipid antibody syndrome, Classic APLS, Classic antiphospholipid syndrome, Hughes syndrome
Drug discovery
2
drugs
With orphan designations
Overview
Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by venous/arterial thrombosis, recurrent pregnancy loss, or placental insufficiency in the presence of persistently elevated antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, or anti-β2-glycoprotein-I antibodies). It may occur as a primary condition or secondary to autoimmune diseases like systemic lupus erythematosus. Diagnosis requires clinical events plus antibody positivity on ≥2 tests ≥12 weeks apart. Long-term anticoagulation is the mainstay of thrombotic APS management [1][6][14].
Population
Prevalence: 40-50 cases per 100,000 in the US, with 30-40% occurring in SLE patients [2][17]
Demographics: 3:1 female predominance; peak diagnosis between ages 20-50 [1][10][14]
High-risk profiles: Triple antibody positivity (lupus anticoagulant + IgG anticardiolipin + IgG anti-β2GPI) confers greatest thrombotic risk [3][6]
Therapies
Thrombosis: Lifelong warfarin (INR 2-3) for venous events; arterial thrombosis may require INR 3-4 or combined antiplatelet therapy [3][12][15]
Obstetric: Low-molecular-weight heparin + low-dose aspirin for pregnancy, reducing miscarriage risk from >70% to <30% [3][12][14]
Catastrophic APS: Triple therapy with anticoagulants, corticosteroids, and plasma exchange/IVIG (survival ↑ from 54% to 69%) [8][16]
Categories: rare gynecological and obstetric diseases, rare hematological diseases, rare systemic and rheumatological diseases
Research Papers
2,706 drug discovery papers about Antiphospholipid syndrome, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2,706 drug discovery papers about Antiphospholipid syndrome, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-24 | More Than Meets the Eye: Topiramate-Induced Bilateral Secondary Angle Closure Unmasking Secondary Antiphospholipid Syndrome.
To describe a diagnostic challenge in a case of bilateral topiramate-induced secondary angle closure which led to unmasking of systemic lupus erythematosus (SLE) and secondary antiphospholipid syndrome (APS) highlighting the importance of recognizing posterior segment findings that are disproportionate to the expected manifestations of drug-induced angle closure. A 21-year-old female presenting with acute diminution of vision in both eyes, following initiation of oral topiramate for migraine was evaluated. Anterior segment examination, gonioscopy, and ultrasound biomicroscopy were performed to assess angle status. Findings were consistent with bilateral topiramate-induced secondary angle closure. Following intraocular pressure reduction, posterior segment evaluation revealed findings suggestive of retinal vascular occlusive disease and vasculitis in RE and choroidal ischemia in LE. Progressive ischemic changes were noted on serial examinations over the course of the next few days. Systemic workup for autoimmune and hypercoagulable states was added based on fundus findings which were atypical for a case of drug-induced angle closure. The patient tested positive for antinuclear antibody, anti- double stranded DNA antibody, persistent triple-positive antiphospholipid antibodies, leading to a diagnosis of SLE with secondary APS. Despite aggressive immunosuppressive and anticoagulant therapy, RE had poor visual recovery, whereas timely intervention led to visual improvement in LE. The case illustrates that posterior segment findings that are disproportionate to the expected manifestations of topiramate-induced angle closure should prompt urgent evaluation for an underlying systemic autoimmune or hypercoagulable disorder. Careful posterior segment evaluation following normalization of intraocular pressure may reveal vision-threatening pathology and facilitate early multidisciplinary management.
2026-09-15 | Serum from Patients with Antiphospholipid Syndrome Differentially Affects Venous and Microcirculatory Endothelial Cells.
Antiphospholipid syndrome is a systemic autoimmune disease characterized by elevated circulating antiphospholipid antibodies and a predisposition to recurrent venous and arterial thrombosis. The underlying pathophysiology of antiphospholipid syndrome remains under active investigation, with endothelial dysfunction recognized as a key contributor to vascular complications. In this study, we showed that serum from antiphospholipid syndrome patients differentially affects distinct endothelial cell types, leading to variations in migration and angiogenic behavior. Using human umbilical vein endothelial cells and human microvascular endothelial cells, we assessed the biological response to serum exposure. Treatment with antiphospholipid syndrome serum was associated with an enhanced angiogenic phenotype in venous endothelium, with a significant increase in two of the four tubulogenesis parameters assessed and a trend towards increased migration, while microvascular endothelium remained largely unaffected. Consistently, metalloproteinase-9 activity was upregulated, with these effects being more pronounced in venous compared to microvascular endothelium. Moreover, caspase-3 activity remained unchanged, suggesting that caspase-3-dependent apoptosis is unlikely to be a major contributor to the endothelial response observed under these conditions. These results enhance our understanding of the pathogenesis and highlight the distinct endothelial responses to the antiphospholipid environment. Further investigation into the underlying mechanisms may facilitate the development of targeted therapeutic strategies to mitigate vascular complications.
2026-09-15 | Libman-Sacks Endocarditis in Triple-Positive Antiphospholipid Syndrome Following Switch from Warfarin to Rivaroxaban: Improvement After Reinstitution of Warfarin and Escalation of Immunosuppression.
Triple-positive antiphospholipid syndrome (APS) represents a high-risk serologic phenotype associated with recurrent thrombosis and systemic lupus erythematosus (SLE). Direct oral anticoagulants (DOACs), particularly rivaroxaban, have demonstrated inferior outcomes compared with vitamin K antagonists in this population. We report a case of a patient with long-standing SLE and persistently triple-positive APS who developed Libman-Sacks endocarditis following a switch from warfarin to rivaroxaban. The patient had biopsy-proven class V lupus nephritis and had remained clinically stable on long-term warfarin therapy for several years. Transthoracic echocardiography demonstrated underlying rheumatic mitral valve disease with newly developed mobile vegetations measuring 10-15 mm. Blood cultures obtained prior to antibiotic exposure were negative, and inflammatory markers were not suggestive of infection. Rivaroxaban was discontinued, and warfarin was reinstated with bridging therapy. Prednisolone (40 mg daily) was initiated, and follow-up echocardiography demonstrated a reduction in vegetation size with clinical improvement. This case highlights a temporal association between rivaroxaban use and valvular thrombotic lesions in high-risk APS. Improvement was likely multifactorial, reflecting combined effects of anticoagulation, escalation of immunosuppression, and underlying valvular disease. These findings support current recommendations favoring vitamin K antagonists over DOACs in patients with triple-positive APS. Cite this article as: Saleh I, Salman S, Alkady A, Saqabi FA. Libman-Sacks endocarditis in triple-positive antiphospholipid syndrome following switch from warfarin to rivaroxaban: improvement after reinstitution of warfarin and escalation of immunosuppression. Eur J Rheumatol. 2026, 13(2), 0009, doi: 10.5152/ eurjrheum.2026.26009.
2026-09-13 | Remote Adolescent-Onset Chorea Preceding Thrombotic Antiphospholipid Syndrome: A Case Report.
Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by vascular thrombosis and/or obstetric morbidity in the presence of persistent antiphospholipid antibodies. Chorea is an uncommon neurological manifestation, reported in approximately 1% of patients, and is not included among the clinical domains required for classification. We report the case of a 28-year-old woman who presented with acute left-sided sensorimotor deficits. Her only relevant history was an episode of chorea involving the left upper limb at 18 years of age, which resolved spontaneously after an incomplete etiological workup at another institution. Neuroimaging demonstrated a right frontal ischemic lesion, and cardioembolic and large-vessel causes were excluded. Prompted by the prior history of chorea, testing revealed persistently high-titer anticardiolipin IgG and anti-β2-glycoprotein I IgG antibodies, establishing a diagnosis of primary APS. She was started on warfarin and achieved functional independence without recurrent vascular events. This case illustrates that juvenile-onset chorea may represent the heralding manifestation of APS, preceding the qualifying thrombotic event by a decade. An isolated, self-limited chorea of undetermined cause should prompt antiphospholipid antibody testing, as early recognition may allow timely thromboprophylaxis and potentially prevent cerebrovascular events in young patients.
2026-09-10 | A pro-inflammatory cytokine signature characterises thrombotic antiphospholipid syndrome despite stable anticoagulation.
Inflammation contributes to primary antiphospholipid syndrome (PAPS) pathogenesis, but cytokine profiles and associated thrombotic phenotypes remain incompletely defined. A panel of 20 cytokines, chemokines and endothelial activation markers was analysed in 37 PAPS patients on stable anticoagulation and 12 healthy controls (HC). We compared concentrations between groups and performed unsupervised hierarchical clustering and principal component analysis (PCA) to identify inflammatory subgroups. Compared with HC, patients with PAPS exhibited significantly elevated levels of 14/20 analytes: granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-γ, interleukin (IL)-1α, IL-1β, IL-6, IL-10, IL-12p70, IL-13, IL-17a, tumour necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), P-selectin and macrophage inflammatory protein-1β (MIP1β) (all p < 0.05). Unsupervised clustering identified three inflammatory antiphospholipid syndrome (APS) subgroups distinct from HC. A core cytokine signature comprising GM-CSF, IL-6, IL-10, IL-12p70, IL-13 and TNF-α was elevated across all APS clusters. One cluster, enriched for arterial thrombosis, demonstrated a more pronounced inflammatory phenotype, with increased IFN-α. Comparison of phenotypes showed significantly higher concentrations of GM-CSF, IFN-α, IL-1α, IL-4, IL-6, IL-10, IL-17a and TNF-α in arterial versus venous thrombosis. Our findings demonstrate widespread cytokine dysregulation and distinct inflammatory subgroups in PAPS, with arterial thrombosis showing stronger inflammation than venous thrombosis, supporting divergent thrombo-inflammatory mechanisms and potential precision immunomodulatory therapeutic targets.
proteins
2026-09-28 | BAFF-APRIL blockade reveals isotype-specific pathogenic autoantibody remodelling in antiphospholipid syndrome.
Durable suppression of pathogenic autoantibodies remains a central challenge in antibody-mediated autoimmune diseases. We aimed to examine pathogenic autoantibody remodelling under targeted humoral immunotherapy using antiphospholipid syndrome (APS) as a tractable human model. In this study, we used dual blockade of B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) with telitacicept as an immune perturbation in a high-risk triple-positive antiphospholipid antibody (aPL) cohort including primary APS and asymptomatic aPL carriers, integrating longitudinal serology with paired pretreatment and posttreatment peripheral-blood and bone marrow single-cell and B-cell receptor repertoire profiling. Telitacicept induced broad B-lineage contraction but remodelled aPL responses nonuniformly, with consistent immunoglobulin (Ig) M- and IgA-class reductions and heterogeneous IgG-class suppression. This pattern coincided with extensive peripheral B-cell and plasmablast turnover, but greater clonal continuity within class-switched marrow plasma cells. In an exploratory post-hoc analysis of baseline IgG aPL-positive patients, incomplete IgG suppression was associated with greater persistence of pretreatment immunoglobulin heavy constant gamma positive (IGHG⁺) clonotypes and associated secretory programmes, whereas residual marrow IGHG⁺ plasma-cell abundance did not clearly distinguish response groups. Together, these findings define compartment- and isotype-selective remodelling of pathogenic autoantibody responses in APS and identify persistent marrow IGHG⁺ plasma-cell clonotypes as a cellular correlate of incomplete suppression of IgG aPL.
2026-04-09 | β2-Glycoprotein I: structure, mechanisms of autoantibody recognition, and polymorphisms.
Identified in the 1990s as the primary target of antiphospholipid antibodies (aPL) in antiphospholipid syndrome (APS), β2-glycoprotein I (β2GPI) remains a central focus in hematology and immunology. Anti-β2GPI antibodies are important not only for diagnosing APS but also play a key role in causing thrombosis and pregnancy complications in these patients. Elucidating the molecular basis of antibody-β2GPI interactions is therefore critical for advancing APS research and has broad implications for understanding related thrombotic autoimmune disorders. In this review, we summarize recent progress on the structural biology of β2GPI, discuss mechanisms of autoantibody recognition, and provide an update on genetic polymorphisms. By resolving longstanding controversies and uncovering new regulatory principles, structural insights are paving the way for targeted approaches aimed at selectively neutralizing pathogenic autoantibodies without broadly impairing coagulation or immune function, offering promising paths toward transformative APS therapies.
2026-03-12 | Autoimmunity beyond antibodies: alternative roles of beta-2-glycoprotein I in and out of antiphospholipid syndrome?
The term autoimmune disease refers to autoantibody-dependent pathophysiological conditions, in which characterising the autoantibodies is essential, as is studying their target(s), the (auto)antigen(s), which represent the other side of the coin. In this review, we aimed to go further inside the ultimate experimental works on the pathophysiology of Beta-2-Glycoprotein I (B2GPI), the main target of the antiphospholipid antibodies (aPL) in Antiphospholipid Syndrome (APS). This protein is almost unique in the body. It is able to up and down regulate the complement and the coagulative cascade and displays pleiotropic functions that are still to be fully understood. Many recent omics-based experimental approaches have found B2GPI among the proteins involved in both acute and chronic disease conditions. These range from inflammatory diseases to cancer. The protein's ability to modulate biological processes like apoptosis, redox impairment, cardiolipin binding, lipopolysacharide, and circulating mitochondria scavenging suggests its role in homeostasis, both as an acute phase modulator and a tolerogenic spark. We imagined B2GPI as a sentinel protein, patrolling tissues as part of a complex system of interacting molecules: the fine-tuning regulation of its threshold in circulation and on solid-target tissues may hold the key to its reactivity. The aPL might represent the prototypical way of this threshold dysfunction. The change in focus towards the antigen might help APS therapeutic approaches and aid in understanding different clinical outcomes. Moreover, it reveals a fascinating protein, acting like a safety net in the body, whose disruption can lead to a wide range of pathophysiological conditions.
2026-02-23 | Case Report: Telitacicept in the treatment of cSLE-APS: novel therapeutic perspectives on autoimmune thrombotic diseases in children.
Thrombotic antiphospholipid syndrome (APS) in Childhood-onset systemic lupus erythematosus (cSLE) remains a therapeutic frontier. Here, we report the first case of telitacicept (a TACI-Fc fusion protein)- induced remission in cSLE related antiphospholipid syndrome (cSLE-APS), where targeted dual BAFF(B cell-activating factor)/APRIL(a proliferation-inducing ligand) inhibition resolved life-threatening infarctions and achieved sustained disease control. During treatment, corticosteroids were successfully discontinued within six months, and a lupus low disease activity state (LLDAS) was maintained. Our findings indicate that telitacicept's unique ability to regulate B-cell activity could target the dual pathology of cSLE-APS, offering a new therapeutic approach for this serious condition.
2026-01-28 | Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT)-like Syndrome: A Case Report and Some Considerations on a Novel Diagnostic and Therapeutic Challenge.
Background and Clinical Significance: Disorders caused by platelet-activating antibodies targeting platelet factor 4 (PF4) are recognized as the cause of severe thrombotic events and are not restricted to heparin-induced thrombocytopenia (HIT). Case Presentation: We report a 67-year-old man with thrombocytopenia and extensive portal-splenic-mesenteric vein thrombosis complicated by intestinal ischemia. Despite intravenous unfractionated heparin (UFH), his condition worsened toward pulmonary embolism, septic shock, and multi-organ failure. Thrombolysis with alteplase was also ineffective. Both thrombophilia testing and autoimmune panels were negative, including those for antiphospholipid syndrome. An anti-PF4 immune thrombotic disorder was hypothesized. Therefore, argatroban was initiated instead of UFH therapy and intravenous immune globulin (IVIG) was administered. The platelet count increased and the patient's clinical condition progressively improved. An anti-PF4/heparin assay on a blood sample collected before IVIG was highly positive. Platelet activation assays did not demonstrate an increased activation after the addition of heparin (the Heparin-Induced Platelet Activation [HIPA] assay was negative) though increased activation was observed with the addition of PF4 (the PF4-Induced Platelet Activation [PIPA] assay was positive), thus defining a VITT-like syndrome. Conclusions: This case report highlights the crucial function of having adequate laboratory facilities available to disentangle different anti-PF4 disorders for an accurate definition of a specific diagnosis, such as VITT-like syndrome, thereby allowing for the most appropriate therapeutic management of these complex pathological conditions. The clinical suspicion of an anti-PF4 immune disorder should be considered in cases of severe, otherwise unexplained, thrombotic events associated with thrombocytopenia. Specific tests like HIPA and PIPA are essential for definitive diagnosis.
cell therapies
2026-08-20 | Management of systemic lupus erythematosus and antiphospholipid syndrome during CAR-T therapy: insights from two clinical cases.
Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) are autoimmune disorders marked by the presence of pathogenic autoantibodies predominantly produced by B cells. Both conditions are chronic, incurable, and require lifelong treatment. Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a promising treatment for refractory hematological malignancies, with anti-CD19 CAR-T therapy demonstrating high efficacy in relapsed or refractory diffuse large B-cell lymphoma (DLBCL). The profound depletion of B cells induced by anti-CD19 CAR-T therapy suggests that this treatment may influence the clinical course of patients with DLBCL and concomitant SLE or APS. We report two clinical cases of patients diagnosed with both DLBCL and concomitant SLE and APS who underwent anti-CD19 CAR-T therapy at our institution. We describe the lymphoproliferative disease course as well as the serological evolution and longitudinal cytokine profiles measured before and after CAR-T therapy. In both cases, CAR-T therapy resulted in complete and long-lasting metabolic remission of the lymphoproliferative disorder. Concurrently, autoantibody titers stabilized, permitting stepwise de-escalation of the immunomodulatory treatment. These cases demonstrate that CAR-T therapy for DLBCL is feasible and appears safe in patients with concomitant autoimmune disease but requires close monitoring and interdisciplinary management. These findings support further preclinical and clinical investigation of CAR-T therapy as a potential therapeutic approach in patients with DLBCL and concomitant SLE and APS.
2026-04-11 | CD19 CAR-T therapy induces remission in refractory autoimmune hemolytic anemia with ITP and antiphospholipid syndrome.
Autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and antiphospholipid antibody syndrome (APLAS) are B cell-driven autoimmune diseases defined by pathogenic autoantibodies. CD19-directed chimeric antigen receptor (CAR)-T cells have recently demonstrated the ability to reset dysregulated B cells and induce long-lasting remission in refractory systemic autoimmune diseases. Evidence for efficacy in severe, treatment-refractory AIHA, however, is limited. We report the clinical course of a 47-year-old woman with life-threatening cold- and warm-agglutinin AIHA refractory to nine prior treatment lines, accompanied by ITP and APLAS. In an uncontrolled flare, she received a fludarabine/cyclophosphamide-containing lymphodepletion followed by autologous CD19-directed, 4-1BB-costimulated CAR-T cells (zorpocabtagene-autoleucel [Zorpo-cel], 1 × 106/kg) on the basis of compassionate use. Treatment efficacy and safety were assessed over an 11-month follow-up period. Zorpo-cel showed a rapid and sustained B cell depletion. Transfusion independence was achieved by day 7, with hemoglobin normalization by day 25, including resolution of hemolysis markers. Cold-agglutinin titers decreased, and previously elevated antiphospholipid antibodies normalized without recurrence throughout 11 months of follow-up. ITP stabilized. No cytokine release syndrome or neurotoxicity occurred. Mild transaminase elevation and thrombocytopenia were observed, most likely correlating with pre-existing severe iron overload due to erythrocyte transfusions. This case demonstrates that CD19-directed CAR-T cell therapy can induce rapid, durable remission of severe, refractory cold-agglutinin AIHA and simultaneously improve coexisting APLAS and ITP on a favorable toxicity profile. However, more data from controlled clinical trials are needed for final conclusions. This work was funded by Deutsche Forschungsgemeinschaft and Deutsche Krebshilfe.
2026-04-09 | Clotting the Gap Between Mitochondria-Mediated Immunity and Mitochondrial Transfer.
Mitochondria are organelles that orchestrate numerous cell functions in addition to providing energy. During viral infection or in case of defects in mitochondrial replication, an intricate mechanism of self-destruction is engaged through the formation of mitochondrial pores. This leads to the release of mitochondrial DNA into the cytoplasm, where it triggers innate immune responses. Platelets constitute the principal source of circulating mitochondria, and increasing evidence demonstrates that they actively release mitochondria, some of which are enclosed within extracellular vesicles. This process is enhanced in autoimmune conditions, occurs in platelet storage, and has been linked to adverse reactions after platelet transfusion. Extracellular mitochondria act as carriers of damage-associated molecular patterns and are targets of antibodies in various pathologies, including antiphospholipid syndrome and cardiomyopathies. Moreover, elevated levels of antimitochondria antibodies have also been associated with increased mortality and cardiovascular risk in systemic lupus erythematosus. Mitochondrial transplantation, a process by which defective mitochondria in a tissue or organ may be replaced by healthy mitochondria, is receiving growing therapeutic interest. Thus, understanding how extracellular mitochondria interact with the immune system is increasingly important. This review summarizes current knowledge on the multifaceted roles of mitochondria in immunity, with a particular focus on platelets and platelet-derived mitochondria as a key biological context.
2025-09-08 | Case Report: Remission of a patient with complex combination of autoimmune diseases by anti-CD19 CAR-T cell therapy.
CAR-T cell therapy has been proven effective in various autoimmune diseases, with most studies utilizing lentiviral-transduced CAR-T cells. In recent years, retroviral vector-transduced CAR-T cells-characterized by a high positivity rate, stable cell lines, and lower plasmid requirements-have attracted increasing attention. This article presents a complex case of a patient with SLE combined with APS and TBIRS. For four years following the diagnosis, the patient underwent conventional steroid therapy and immunotherapy, which yielded unsatisfactory and relapse-prone results. After receiving anti-CD19 CAR-T cells transduced with a retroviral vector, the patient experienced an excellent postoperative recovery without any infusion-related adverse reactions. Post-treatment, the patient's creatinine, anti-dsDNA antibodies, albumin, and glycated hemoglobin levels returned to normal, eliminating the need for ongoing glucocorticoids or hypoglycemic agents. Although there are some available reports of CAR-T cells treating SLE, it is still very rare and significant for successfully treating such a complicated case, especially after proving the unavailability of traditional therapy. Furthermore, this is the first reported case of treating TBIRS syndrome with retroviral vector-transduced CAR-T therapy.
2025-03-06 | Plasmapheresis for lowering the risks of placenta-associated complications in antiphospholipid syndrome
Aim : to study plasmapheresis (PP) effect on antiphospholipid syndrome (APS) treatment during preconception preparation and pregnancy. Materials and Methods . A single-center, prospective, randomized, uncontrolled study was conducted. A total of 137 women aged 22 to 32 years diagnosed with APS-related habitual miscarriage were examined. The patients were stratified as follows: main group consisted of 73 patients underwent a PF course (7 procedures at preconception preparation stage); comparison group – 64 patients not underwent efferent therapy. Antiphospholipid antibodies (APA) circulation was determined by solid-phase immunofluorescence. PР was performed using an intermittent technique. The laboratory study included assessing titers of lupus anticoagulant (LA), anti-cardiolipin antibodies (aCL), anti-β2-glycoprotein 1 antibodies (anti-β2-GP1) and anti-annexin V antibodies (anti-ANX). Antibody titers were measured before and after pregravid preparation. Results . After PР, anti-β2-GР1 titers decreased by 66.6 % (p = 0.00001) in main group. In patients who underwent standard therapy without PР, no significant changes in circulation level of anti-β2-GР1 were noted. LA frequency in main and comparison group decreased by 57.3 % (p = 0.042) and 10.9 % (p = 0.69), respectively. Conclusion . The frequency of detecting elevated AРA levels in women after a course of efferent therapy decreased significantly, whereas standard therapy showed no such effects. PР as part of complex therapy is more appropriate for achieving maximum effect.
antibodies
2026-09-24 | Teclistamab for the treatment of autoantibody-mediated coagulation disorders.
Teclistamab is a bispecific monoclonal antibody that targets B cell maturation antigen (BCMA) on plasma cells and other B lineage cells and CD3 on T cells, thereby redirecting cytotoxic T cells to eliminate BCMA-expressing antibody-producing cells. Autoantibody-mediated coagulation disorders are often driven by long-lived antibody-producing cells that may persist despite conventional immunosuppression or B cell depletion. To investigate whether teclistamab represents a treatment option for patients with refractory or rapidly progressive autoantibody-mediated coagulation disorders. We retrospectively analyzed seven patients with autoantibody-mediated coagulation disorders treated with teclistamab. Diagnoses included acquired von Willebrand disease (n=2), acquired factor XI deficiency (n=2), and catastrophic antiphospholipid syndrome (CAPS; n=3). Five patients had an underlying paraprotein, whereas two CAPS patients had no detectable paraprotein. All seven patients achieved complete remissions (median time to remission: 24 weeks [range: 2-35]) following teclistamab. In the four patients with acquired von Willebrand disease or factor XI deficiency, improvement in the disease-defining coagulation parameter and cessation of bleeding were observed following initiation of teclistamab. In the three patients with CAPS disappearance of antiphospholipid antibodies or normalization of the aPTT-LA was observed and accompanied by clinical stabilization without further thromboembolic events. Treatment was generally well tolerated. Three patients developed grade 1 cytokine release syndrome. One patient developed transient colitis while another patient experienced reversible seronegative inflammatory joint symptoms. All patients received immunoglobulin replacement. Teclistamab treatment was associated with complete remissions in patients with autoantibody-mediated coagulation disorders. These observations warrant further evaluation of teclistamab in selected patients.
2026-08-26 | Diffuse alveolar hemorrhage in primary antiphospholipid syndrome: A case series of six patients.
Antiphospholipid syndrome (APS) is an autoimmune prothrombotic disorder characterized by persistent antiphospholipid antibodies (aPLs). Diffuse alveolar hemorrhage (DAH) is a rare but severe microvascular manifestation of APS associated with high morbidity and mortality. We retrospectively analyzed six consecutive patients with primary APS complicated by DAH who had been followed at our institution between 2018 and 2025. Clinical presentation, laboratory and radiological findings, treatment strategies, and outcomes were evaluated. Median age was 37.5 years (female:male 4:2). DAH was confirmed by bronchoscopy in all patients; triple aPL positivity was present in all. Most patients required hospitalization for severe respiratory failure, and recurrent DAH was frequent. Two patients died: one from uncontrolled DAH complicated by invasive fungal infection, and the other from pulmonary embolism. Two patients had a milder chronic course with fluctuating HRCT infiltrates but no severe hypoxemia. All patients received high-dose glucocorticoids followed by maintenance immunosuppression with rituximab, usually combined with mycophenolate. Adjunctive therapies included plasma exchange, intravenous immunoglobulin, and eculizumab. Antibody titers remained persistently positive in all cases. APS-associated DAH is a life-threatening complication with frequent relapses and poor prognosis, particularly in patients with triple positivity and recurrent DAH. None of the patients achieved long-term remission, and all experienced disease progression despite aggressive immunosuppressive therapy. Early recognition, aggressive immunosuppression, and close monitoring are crucial, while novel therapeutic options are urgently needed.
2026-08-13 | Reported Prevalence of Inherited Thrombophilia in Pregnancy: Impact of Cohort Selection on Screening Implications-A Systematic Review.
Background/Objectives: Inherited thrombophilia (IT) has been extensively investigated as a potential contributor to adverse pregnancy outcomes; however, reported prevalence varies widely across studies. This systematic review aimed to evaluate how cohort selection influences the reported prevalence of inherited thrombophilia in pregnancy and to explore the implications of this variability for clinical interpretation and screening practices. Methods: A systematic review was conducted following PRISMA 2020 guidelines. PubMed, Scopus, Web of Science, and Google Scholar were searched. A total of 5480 records were identified, and 7 observational studies (cohort and case-control) met inclusion criteria. Data were synthesized qualitatively due to heterogeneity. Results: Prevalence ranged from 0% to 14%, depending on population characteristics. The largest cohort study reported an inherited thrombophilia prevalence of 8.1%, comparable to the general population. Higher rates were observed in referral-based and antiphospholipid Syndrome (APS)-associated cohorts, while case-control studies showed no significant differences between affected individuals and controls. Ethnic variability was also observed. Conclusions: These findings should be interpreted as patterns observed across heterogeneous study designs rather than as definitive evidence of causality. Current evidence does not clearly support universal screening in pregnancy; however, the findings should be interpreted cautiously because several included studies were limited by small sample sizes and methodological heterogeneity.
2026-08-12 | Case Report: IVIG as a bridging strategy in high-risk antiphospholipid syndrome with infected cutaneous ulceration and thrombocytopenia.
Severe cutaneous ulceration in antiphospholipid syndrome (APS) with concurrent infection and thrombocytopenia presents a therapeutic dilemma: standard immunosuppression risks worsening infection, while anticoagulation risks hemorrhage. We present a high-risk case successfully managed using intravenous immunoglobulin (IVIG) as a bridging immunomodulatory strategy. A 73-year-old man with triple-positive APS and immune thrombocytopenic purpura (ITP) developed rapidly progressive leg ulcers with clinical features consistent with pyoderma gangrenosum-like disease, complicated by active MRSA and Pseudomonas aeruginosa infection and severe thrombocytopenia (12 × 109/L). Standard therapies were contraindicated: corticosteroids risked worsening infection; anticoagulation risked hemorrhage. The patient received IVIG (0.4 g/kg per dose, every 3 weeks) as primary immunomodulation, concurrent targeted antimicrobial therapy, temporary anticoagulation interruption, and discontinuation of baseline mycophenolate mofetil. Following platelet recovery above 70 × 109/L, therapeutic anticoagulation was resumed with enoxaparin (80 mg subcutaneously twice daily) and aspirin (75 mg daily). Over five months, progressive re-epithelialization culminated in complete healing with platelet recovery. This case supports the feasibility of IVIG as a bridging immunomodulatory strategy in high-risk APS cutaneous disease where standard therapies are contraindicated by concurrent infection and thrombocytopenia. The sequential management approach successfully resolved a clinically challenging scenario. This case illustrates how risk-adapted immunomodulation may enable safe management of complex APS manifestations.
2026-08-10 | Monoclonal Gammopathy of Thrombotic Significance.
Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant precursor to multiple myeloma (MM). While development of end-organ damage in MM largely reflects increasing clonal burden, emerging evidence indicates that qualitative properties of the monoclonal immunoglobulins in MGUS can be directly pathogenic, leading to serious organ injury independent of disease burden. This has led to the recognition of a broader spectrum of disorders collectively termed monoclonal gammopathy of clinical significance (MGCS). MGCS can be further subclassified based on the organ system involved; for example, monoclonal gammopathy of renal significance specifically refers to monoclonal immunoglobulin-driven renal injury. Along these lines, we propose monoclonal gammopathy of thrombotic significance (MGTS) as encompassing thrombotic disorders in which there is definitive, mechanistically supported evidence that a monoclonal (M)-protein associated with a clonal plasma or B-cell disorder directly contributes to thrombosis. Based on current evidence, monoclonal protein-induced immune thrombocytopenia and thrombosis is the only disorder that meets our criteria for MGTS. Other thrombotic disorders, such as thrombotic microangiopathy and antiphospholipid syndrome, may occur in the setting of a monoclonal protein and have biologically plausible M-protein-mediated mechanisms; however, direct evidence implicating the M-protein in thrombosis is currently lacking. Accordingly, we provisionally classify these disorders as thrombotic syndromes associated with M-proteins, pending causal validation. We also highlight thrombotic disease associations with multifactorial pathogenesis that should not be classified as MGTS. Broader recognition of MGTS is essential to advance consensus definitions, establish diagnostic criteria, and develop evidence-based management strategies for this clinically important group of disorders.
other
2025-06-09 | Complex presentation of probable catastrophic antiphospholipid syndrome: diagnostic dilemmas and treatment strategies.
Catastrophic antiphospholipid syndrome (CAPS) is a rare and life-threatening clinical emergency with multiorgan involvement. CAPS presents a significant clinical challenge due to its heterogeneous presentation and can resemble many other systemic thrombotic disorders. Prompt and intensive treatment is essential for patient survival. However, due to its rarity and heterogeneity, evidence-based protocols are scarce, and as such, diagnosis and management rely on guidelines stemming from low-level evidence and expert opinion. We present a patient with antiphospholipid syndrome who developed multiorgan complications and was diagnosed with probable CAPS. Diagnosis was complicated due to thrombotic risk and the heterogeneous nature of CAPS, as well as his unresponsiveness to first-line therapy consisting of anticoagulation and corticosteroids. His treatment was then escalated with plasma exchange, rituximab and cyclophosphamide, to which he responded and improved clinically.
2024-07-25 | Antiphospholipid-exposed trophoblast-derived extracellular vesicles express elevated levels of TLR7/8-activating microRNAs and induce endometrial endothelial activation, in part, through TLR7.
Women with antiphospholipid syndrome (APS) are at high risk for miscarriage and preeclampsia. Unlike pro-thrombotic systemic APS, obstetric APS is associated with insufficient placentation, as well as inflammation and vascular dysfunction at the maternal-fetal interface. Antiphospholipid antibodies (aPL) can target the placental trophoblast and induce inflammation. We reported that aPL trigger trophoblast cells to produce elevated levels of IL-8 through activation of Toll-like receptor 4 (TLR4). Downstream of TLR4, we found this IL-8 response is mediated by a TLR8-activating microRNA (miR), miR-146a-3p, which is also released by the trophoblast via extracellular vesicles (EVs). Since endothelial dysfunction is a feature of obstetric APS, we sought to determine if other miRs that can activate the RNA sensors, TLR7 and/or TLR8, are released by the trophoblast via EVs after exposure to aPL, and if these EVs can activate human endometrial endothelial cells (HEECs). Using a human first trimester extravillous trophoblast cell line we found that aPL elevated their release of small EVs (<150 nm). These extracellular vesicles released from trophoblast cells exposed to aPL expressed elevated levels of TLR7/8-activating miR-21a and miR-29a, in addition to the previously reported miR-146a-3p. Extracellular vesicles from aPL-exposed human trophoblast cells triggered human endometrial endothelial cells to generate an inflammatory IL-8 response, in part through TLR7. This study highlights EVs as a mode of communication between the placenta and the maternal vasculature, as well as a potential role for TLR7/8-activating miRs in contributing to inflammation at the maternal-fetal interface in obstetric APS.
2023-05-17 | Metastasis-associated lung adenocarcinoma transcript 1 induces methyl-CpG-binding domain protein 4 in mice with recurrent spontaneous abortion caused by anti-phospholipid antibody positivity.
Antiphospholipid syndrome is an autoimmune disease characterized by pregnancy-related morbidity, related to persistent positivity of antiphospholipid antibodies (APL). One of the characteristics of pregnancy-related morbidity in patients with antiphospholipid syndrome is recurrent spontaneous abortion (RSA). This study aimed to examine the mechanism through which metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) regulates methyl-CpG-binding domain protein 4 (MBD4) expression in APL-positive RSA. Clinical samples were subjected to microarray analysis to filter differentially expressed genes. RSA mice with APL positivity were generated, followed by adenoviral vector injection to artificially upregulate MALAT1. The effects of MALAT1 on the biological behavior of trophoblast cells were assessed. The downstream mechanism of MALAT1 was analyzed using subcellular fractionation and bioinformatics prediction, and the relationship between MALAT1 and CREB binding protein (CREBBP) or MBD4 was investigated in trophoblast cells. MALAT1 was downregulated in APL-positive RSA patients. MALAT1 was predominantly localized in the nucleus and recruited CREBBP to mediate the MBD4 transcription. In the APL-positive RSA mice overexpressing MALAT1, the expression of soluble Fms-related tyrosine kinase 1 and anticardiolipin antibody and the embryonic resorption rate were decreased, indicating that MALAT1 reduced the occurrence of RSA in mice. Moreover, MALAT1 enhanced proliferation, migration, and invasion of trophoblast cells through recruiting CREBBP to promote MBD4 expression. Silencing of CREBBP or MBD4 increased embryonic resorption rate in RSA mice overexpressing MALAT1. MALAT1 suppresses APL-positive RSA by promoting MBD4 transcription through recruitment of CREBBP to the MBD4 promoter region.
2023-04-24 | Antisense oligonuleotides influences trophoblasts behaviors by changing LncNR_040117 expression in antiphospholipid antibody syndrome-induced recurrent pregnancy loss.
The primary objective of this study was to explore whether antisense oligonucleotides (ASOs) that reduce LncNR_040117 expression in patients with antiphospholipid antibody syndrome (APS)-induced recurrent pregnancy loss (RPL), and further decrease apoptosis and improve trophoblasts invasion through mitogen-activated protein kinase (MAPK) pathways. This paper aimed to provide a new strategy to treat APS-induced RPL. In this study, we used quantitative reverse transcription-polymerase chain reaction (RT-qPCR) to analyze the expression level of LncNR 040117 in HTR-8/SVneo cells following transfection with ASOs. Then we utilized Western blotting to test the expression levels of interleukin-1β (IL-1β), intracellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and key molecules of MAPK pathways, including the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinases (JNK) and p38. In addition, we examined the HTR-8/SVneo cells apoptosis by cell apoptosis assay, and migration and invasion by transwell antibody assay. Each experiment was repeated three times. The data are presented as the means ± SDs, and statistical comparisons were performed using Student's t-test. p < 0.05 was considered significant. Transfected with ASOs, LncNR_040117 was downregulated in trophoblasts compared with APS-induced RPL patients. And LncNR_040117 low expression induced IL-1β and downstream adhesion molecules ICAM-1 and VCAM-1expression level decreased, as well as MAPK pathways downregulation, including the ERK pathway, JNK pathway and p38/MAPK pathway. Furthermore, all these changes resulted in decreased apoptosis and increased migration and invasion of trophoblasts. This study indicated that ASOs that decrease LncNR_040117 expression can reduce apoptosis and enhance the invasion and migration of trophoblasts by regulating the MAPK pathway.
2023-02-10 | Whole blood transcriptome identifies interferon-regulated genes as key drivers in thrombotic primary antiphospholipid syndrome.
Pathogenesis of antiphospholipid syndrome (APS) isn't fully elucidated. We aimed to identify gene signatures characterizing thrombotic primary APS (thrPAPS) and subgroups at high risk for worse outcomes. We performed whole blood next-generation RNA-sequencing in 62 patients with thrPAPS and 29 age-/sex-matched healthy controls (HCs), followed by differential gene expression analysis (DGEA) and enrichment analysis. We trained models on transcriptomics data using machine learning. DGEA of 12.306 genes revealed 34 deregulated genes in thrPAPS versus HCs; 33 were upregulated by at least 2-fold, and 14/33 were type I and II interferon-regulated genes (IRGs) as determined by interferome database. Machine learning applied to deregulated genes returned 79% accuracy to discriminate thrPAPS from HCs, which increased to 82% when only the most informative IRGs were analyzed. Comparison of thrPAPS subgroups versus HCs showed an increased presence of IRGs among upregulated genes in venous thrombosis (21/23, 91%), triple-antiphospholipid antibody (aPL) positive (30/50, 60%), and recurrent thrombosis (19/42, 45%) subgroups. Enrichment analysis of upregulated genes in triple-aPL positive patients revealed terms related to 'type I interferon signaling pathway' and 'innate immune response'. DGEA among thrPAPS subgroups revealed upregulated genes, including IRGs, in patients with venous versus arterial thrombosis (n = 11, 9 IRGs), triple-aPL versus non-triple aPL (n = 10, 9 IRGs), and recurrent versus non-recurrent thrombosis (n = 10, 3 IRGs). Upregulated IRGs may better discriminate thrPAPS from HCs than all deregulated genes in peripheral blood. Taken together with DGEA data, IRGs are highly expressed in thrPAPS and high-risk subgroups of triple-aPL and recurrent thrombosis, with potential treatment implications.
small molecules
2026-09-24 | More Than Meets the Eye: Topiramate-Induced Bilateral Secondary Angle Closure Unmasking Secondary Antiphospholipid Syndrome.
To describe a diagnostic challenge in a case of bilateral topiramate-induced secondary angle closure which led to unmasking of systemic lupus erythematosus (SLE) and secondary antiphospholipid syndrome (APS) highlighting the importance of recognizing posterior segment findings that are disproportionate to the expected manifestations of drug-induced angle closure. A 21-year-old female presenting with acute diminution of vision in both eyes, following initiation of oral topiramate for migraine was evaluated. Anterior segment examination, gonioscopy, and ultrasound biomicroscopy were performed to assess angle status. Findings were consistent with bilateral topiramate-induced secondary angle closure. Following intraocular pressure reduction, posterior segment evaluation revealed findings suggestive of retinal vascular occlusive disease and vasculitis in RE and choroidal ischemia in LE. Progressive ischemic changes were noted on serial examinations over the course of the next few days. Systemic workup for autoimmune and hypercoagulable states was added based on fundus findings which were atypical for a case of drug-induced angle closure. The patient tested positive for antinuclear antibody, anti- double stranded DNA antibody, persistent triple-positive antiphospholipid antibodies, leading to a diagnosis of SLE with secondary APS. Despite aggressive immunosuppressive and anticoagulant therapy, RE had poor visual recovery, whereas timely intervention led to visual improvement in LE. The case illustrates that posterior segment findings that are disproportionate to the expected manifestations of topiramate-induced angle closure should prompt urgent evaluation for an underlying systemic autoimmune or hypercoagulable disorder. Careful posterior segment evaluation following normalization of intraocular pressure may reveal vision-threatening pathology and facilitate early multidisciplinary management.
2026-09-15 | Serum from Patients with Antiphospholipid Syndrome Differentially Affects Venous and Microcirculatory Endothelial Cells.
Antiphospholipid syndrome is a systemic autoimmune disease characterized by elevated circulating antiphospholipid antibodies and a predisposition to recurrent venous and arterial thrombosis. The underlying pathophysiology of antiphospholipid syndrome remains under active investigation, with endothelial dysfunction recognized as a key contributor to vascular complications. In this study, we showed that serum from antiphospholipid syndrome patients differentially affects distinct endothelial cell types, leading to variations in migration and angiogenic behavior. Using human umbilical vein endothelial cells and human microvascular endothelial cells, we assessed the biological response to serum exposure. Treatment with antiphospholipid syndrome serum was associated with an enhanced angiogenic phenotype in venous endothelium, with a significant increase in two of the four tubulogenesis parameters assessed and a trend towards increased migration, while microvascular endothelium remained largely unaffected. Consistently, metalloproteinase-9 activity was upregulated, with these effects being more pronounced in venous compared to microvascular endothelium. Moreover, caspase-3 activity remained unchanged, suggesting that caspase-3-dependent apoptosis is unlikely to be a major contributor to the endothelial response observed under these conditions. These results enhance our understanding of the pathogenesis and highlight the distinct endothelial responses to the antiphospholipid environment. Further investigation into the underlying mechanisms may facilitate the development of targeted therapeutic strategies to mitigate vascular complications.
2026-09-15 | Libman-Sacks Endocarditis in Triple-Positive Antiphospholipid Syndrome Following Switch from Warfarin to Rivaroxaban: Improvement After Reinstitution of Warfarin and Escalation of Immunosuppression.
Triple-positive antiphospholipid syndrome (APS) represents a high-risk serologic phenotype associated with recurrent thrombosis and systemic lupus erythematosus (SLE). Direct oral anticoagulants (DOACs), particularly rivaroxaban, have demonstrated inferior outcomes compared with vitamin K antagonists in this population. We report a case of a patient with long-standing SLE and persistently triple-positive APS who developed Libman-Sacks endocarditis following a switch from warfarin to rivaroxaban. The patient had biopsy-proven class V lupus nephritis and had remained clinically stable on long-term warfarin therapy for several years. Transthoracic echocardiography demonstrated underlying rheumatic mitral valve disease with newly developed mobile vegetations measuring 10-15 mm. Blood cultures obtained prior to antibiotic exposure were negative, and inflammatory markers were not suggestive of infection. Rivaroxaban was discontinued, and warfarin was reinstated with bridging therapy. Prednisolone (40 mg daily) was initiated, and follow-up echocardiography demonstrated a reduction in vegetation size with clinical improvement. This case highlights a temporal association between rivaroxaban use and valvular thrombotic lesions in high-risk APS. Improvement was likely multifactorial, reflecting combined effects of anticoagulation, escalation of immunosuppression, and underlying valvular disease. These findings support current recommendations favoring vitamin K antagonists over DOACs in patients with triple-positive APS. Cite this article as: Saleh I, Salman S, Alkady A, Saqabi FA. Libman-Sacks endocarditis in triple-positive antiphospholipid syndrome following switch from warfarin to rivaroxaban: improvement after reinstitution of warfarin and escalation of immunosuppression. Eur J Rheumatol. 2026, 13(2), 0009, doi: 10.5152/ eurjrheum.2026.26009.
2026-09-13 | Remote Adolescent-Onset Chorea Preceding Thrombotic Antiphospholipid Syndrome: A Case Report.
Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by vascular thrombosis and/or obstetric morbidity in the presence of persistent antiphospholipid antibodies. Chorea is an uncommon neurological manifestation, reported in approximately 1% of patients, and is not included among the clinical domains required for classification. We report the case of a 28-year-old woman who presented with acute left-sided sensorimotor deficits. Her only relevant history was an episode of chorea involving the left upper limb at 18 years of age, which resolved spontaneously after an incomplete etiological workup at another institution. Neuroimaging demonstrated a right frontal ischemic lesion, and cardioembolic and large-vessel causes were excluded. Prompted by the prior history of chorea, testing revealed persistently high-titer anticardiolipin IgG and anti-β2-glycoprotein I IgG antibodies, establishing a diagnosis of primary APS. She was started on warfarin and achieved functional independence without recurrent vascular events. This case illustrates that juvenile-onset chorea may represent the heralding manifestation of APS, preceding the qualifying thrombotic event by a decade. An isolated, self-limited chorea of undetermined cause should prompt antiphospholipid antibody testing, as early recognition may allow timely thromboprophylaxis and potentially prevent cerebrovascular events in young patients.
2026-09-10 | A pro-inflammatory cytokine signature characterises thrombotic antiphospholipid syndrome despite stable anticoagulation.
Inflammation contributes to primary antiphospholipid syndrome (PAPS) pathogenesis, but cytokine profiles and associated thrombotic phenotypes remain incompletely defined. A panel of 20 cytokines, chemokines and endothelial activation markers was analysed in 37 PAPS patients on stable anticoagulation and 12 healthy controls (HC). We compared concentrations between groups and performed unsupervised hierarchical clustering and principal component analysis (PCA) to identify inflammatory subgroups. Compared with HC, patients with PAPS exhibited significantly elevated levels of 14/20 analytes: granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-γ, interleukin (IL)-1α, IL-1β, IL-6, IL-10, IL-12p70, IL-13, IL-17a, tumour necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), P-selectin and macrophage inflammatory protein-1β (MIP1β) (all p < 0.05). Unsupervised clustering identified three inflammatory antiphospholipid syndrome (APS) subgroups distinct from HC. A core cytokine signature comprising GM-CSF, IL-6, IL-10, IL-12p70, IL-13 and TNF-α was elevated across all APS clusters. One cluster, enriched for arterial thrombosis, demonstrated a more pronounced inflammatory phenotype, with increased IFN-α. Comparison of phenotypes showed significantly higher concentrations of GM-CSF, IFN-α, IL-1α, IL-4, IL-6, IL-10, IL-17a and TNF-α in arterial versus venous thrombosis. Our findings demonstrate widespread cytokine dysregulation and distinct inflammatory subgroups in PAPS, with arterial thrombosis showing stronger inflammation than venous thrombosis, supporting divergent thrombo-inflammatory mechanisms and potential precision immunomodulatory therapeutic targets.
proteins
2026-09-28 | BAFF-APRIL blockade reveals isotype-specific pathogenic autoantibody remodelling in antiphospholipid syndrome.
Durable suppression of pathogenic autoantibodies remains a central challenge in antibody-mediated autoimmune diseases. We aimed to examine pathogenic autoantibody remodelling under targeted humoral immunotherapy using antiphospholipid syndrome (APS) as a tractable human model. In this study, we used dual blockade of B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) with telitacicept as an immune perturbation in a high-risk triple-positive antiphospholipid antibody (aPL) cohort including primary APS and asymptomatic aPL carriers, integrating longitudinal serology with paired pretreatment and posttreatment peripheral-blood and bone marrow single-cell and B-cell receptor repertoire profiling. Telitacicept induced broad B-lineage contraction but remodelled aPL responses nonuniformly, with consistent immunoglobulin (Ig) M- and IgA-class reductions and heterogeneous IgG-class suppression. This pattern coincided with extensive peripheral B-cell and plasmablast turnover, but greater clonal continuity within class-switched marrow plasma cells. In an exploratory post-hoc analysis of baseline IgG aPL-positive patients, incomplete IgG suppression was associated with greater persistence of pretreatment immunoglobulin heavy constant gamma positive (IGHG⁺) clonotypes and associated secretory programmes, whereas residual marrow IGHG⁺ plasma-cell abundance did not clearly distinguish response groups. Together, these findings define compartment- and isotype-selective remodelling of pathogenic autoantibody responses in APS and identify persistent marrow IGHG⁺ plasma-cell clonotypes as a cellular correlate of incomplete suppression of IgG aPL.
2026-04-09 | β2-Glycoprotein I: structure, mechanisms of autoantibody recognition, and polymorphisms.
Identified in the 1990s as the primary target of antiphospholipid antibodies (aPL) in antiphospholipid syndrome (APS), β2-glycoprotein I (β2GPI) remains a central focus in hematology and immunology. Anti-β2GPI antibodies are important not only for diagnosing APS but also play a key role in causing thrombosis and pregnancy complications in these patients. Elucidating the molecular basis of antibody-β2GPI interactions is therefore critical for advancing APS research and has broad implications for understanding related thrombotic autoimmune disorders. In this review, we summarize recent progress on the structural biology of β2GPI, discuss mechanisms of autoantibody recognition, and provide an update on genetic polymorphisms. By resolving longstanding controversies and uncovering new regulatory principles, structural insights are paving the way for targeted approaches aimed at selectively neutralizing pathogenic autoantibodies without broadly impairing coagulation or immune function, offering promising paths toward transformative APS therapies.
2026-03-12 | Autoimmunity beyond antibodies: alternative roles of beta-2-glycoprotein I in and out of antiphospholipid syndrome?
The term autoimmune disease refers to autoantibody-dependent pathophysiological conditions, in which characterising the autoantibodies is essential, as is studying their target(s), the (auto)antigen(s), which represent the other side of the coin. In this review, we aimed to go further inside the ultimate experimental works on the pathophysiology of Beta-2-Glycoprotein I (B2GPI), the main target of the antiphospholipid antibodies (aPL) in Antiphospholipid Syndrome (APS). This protein is almost unique in the body. It is able to up and down regulate the complement and the coagulative cascade and displays pleiotropic functions that are still to be fully understood. Many recent omics-based experimental approaches have found B2GPI among the proteins involved in both acute and chronic disease conditions. These range from inflammatory diseases to cancer. The protein's ability to modulate biological processes like apoptosis, redox impairment, cardiolipin binding, lipopolysacharide, and circulating mitochondria scavenging suggests its role in homeostasis, both as an acute phase modulator and a tolerogenic spark. We imagined B2GPI as a sentinel protein, patrolling tissues as part of a complex system of interacting molecules: the fine-tuning regulation of its threshold in circulation and on solid-target tissues may hold the key to its reactivity. The aPL might represent the prototypical way of this threshold dysfunction. The change in focus towards the antigen might help APS therapeutic approaches and aid in understanding different clinical outcomes. Moreover, it reveals a fascinating protein, acting like a safety net in the body, whose disruption can lead to a wide range of pathophysiological conditions.
2026-02-23 | Case Report: Telitacicept in the treatment of cSLE-APS: novel therapeutic perspectives on autoimmune thrombotic diseases in children.
Thrombotic antiphospholipid syndrome (APS) in Childhood-onset systemic lupus erythematosus (cSLE) remains a therapeutic frontier. Here, we report the first case of telitacicept (a TACI-Fc fusion protein)- induced remission in cSLE related antiphospholipid syndrome (cSLE-APS), where targeted dual BAFF(B cell-activating factor)/APRIL(a proliferation-inducing ligand) inhibition resolved life-threatening infarctions and achieved sustained disease control. During treatment, corticosteroids were successfully discontinued within six months, and a lupus low disease activity state (LLDAS) was maintained. Our findings indicate that telitacicept's unique ability to regulate B-cell activity could target the dual pathology of cSLE-APS, offering a new therapeutic approach for this serious condition.
2026-01-28 | Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT)-like Syndrome: A Case Report and Some Considerations on a Novel Diagnostic and Therapeutic Challenge.
Background and Clinical Significance: Disorders caused by platelet-activating antibodies targeting platelet factor 4 (PF4) are recognized as the cause of severe thrombotic events and are not restricted to heparin-induced thrombocytopenia (HIT). Case Presentation: We report a 67-year-old man with thrombocytopenia and extensive portal-splenic-mesenteric vein thrombosis complicated by intestinal ischemia. Despite intravenous unfractionated heparin (UFH), his condition worsened toward pulmonary embolism, septic shock, and multi-organ failure. Thrombolysis with alteplase was also ineffective. Both thrombophilia testing and autoimmune panels were negative, including those for antiphospholipid syndrome. An anti-PF4 immune thrombotic disorder was hypothesized. Therefore, argatroban was initiated instead of UFH therapy and intravenous immune globulin (IVIG) was administered. The platelet count increased and the patient's clinical condition progressively improved. An anti-PF4/heparin assay on a blood sample collected before IVIG was highly positive. Platelet activation assays did not demonstrate an increased activation after the addition of heparin (the Heparin-Induced Platelet Activation [HIPA] assay was negative) though increased activation was observed with the addition of PF4 (the PF4-Induced Platelet Activation [PIPA] assay was positive), thus defining a VITT-like syndrome. Conclusions: This case report highlights the crucial function of having adequate laboratory facilities available to disentangle different anti-PF4 disorders for an accurate definition of a specific diagnosis, such as VITT-like syndrome, thereby allowing for the most appropriate therapeutic management of these complex pathological conditions. The clinical suspicion of an anti-PF4 immune disorder should be considered in cases of severe, otherwise unexplained, thrombotic events associated with thrombocytopenia. Specific tests like HIPA and PIPA are essential for definitive diagnosis.
cell therapies
2026-08-20 | Management of systemic lupus erythematosus and antiphospholipid syndrome during CAR-T therapy: insights from two clinical cases.
Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) are autoimmune disorders marked by the presence of pathogenic autoantibodies predominantly produced by B cells. Both conditions are chronic, incurable, and require lifelong treatment. Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a promising treatment for refractory hematological malignancies, with anti-CD19 CAR-T therapy demonstrating high efficacy in relapsed or refractory diffuse large B-cell lymphoma (DLBCL). The profound depletion of B cells induced by anti-CD19 CAR-T therapy suggests that this treatment may influence the clinical course of patients with DLBCL and concomitant SLE or APS. We report two clinical cases of patients diagnosed with both DLBCL and concomitant SLE and APS who underwent anti-CD19 CAR-T therapy at our institution. We describe the lymphoproliferative disease course as well as the serological evolution and longitudinal cytokine profiles measured before and after CAR-T therapy. In both cases, CAR-T therapy resulted in complete and long-lasting metabolic remission of the lymphoproliferative disorder. Concurrently, autoantibody titers stabilized, permitting stepwise de-escalation of the immunomodulatory treatment. These cases demonstrate that CAR-T therapy for DLBCL is feasible and appears safe in patients with concomitant autoimmune disease but requires close monitoring and interdisciplinary management. These findings support further preclinical and clinical investigation of CAR-T therapy as a potential therapeutic approach in patients with DLBCL and concomitant SLE and APS.
2026-04-11 | CD19 CAR-T therapy induces remission in refractory autoimmune hemolytic anemia with ITP and antiphospholipid syndrome.
Autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and antiphospholipid antibody syndrome (APLAS) are B cell-driven autoimmune diseases defined by pathogenic autoantibodies. CD19-directed chimeric antigen receptor (CAR)-T cells have recently demonstrated the ability to reset dysregulated B cells and induce long-lasting remission in refractory systemic autoimmune diseases. Evidence for efficacy in severe, treatment-refractory AIHA, however, is limited. We report the clinical course of a 47-year-old woman with life-threatening cold- and warm-agglutinin AIHA refractory to nine prior treatment lines, accompanied by ITP and APLAS. In an uncontrolled flare, she received a fludarabine/cyclophosphamide-containing lymphodepletion followed by autologous CD19-directed, 4-1BB-costimulated CAR-T cells (zorpocabtagene-autoleucel [Zorpo-cel], 1 × 106/kg) on the basis of compassionate use. Treatment efficacy and safety were assessed over an 11-month follow-up period. Zorpo-cel showed a rapid and sustained B cell depletion. Transfusion independence was achieved by day 7, with hemoglobin normalization by day 25, including resolution of hemolysis markers. Cold-agglutinin titers decreased, and previously elevated antiphospholipid antibodies normalized without recurrence throughout 11 months of follow-up. ITP stabilized. No cytokine release syndrome or neurotoxicity occurred. Mild transaminase elevation and thrombocytopenia were observed, most likely correlating with pre-existing severe iron overload due to erythrocyte transfusions. This case demonstrates that CD19-directed CAR-T cell therapy can induce rapid, durable remission of severe, refractory cold-agglutinin AIHA and simultaneously improve coexisting APLAS and ITP on a favorable toxicity profile. However, more data from controlled clinical trials are needed for final conclusions. This work was funded by Deutsche Forschungsgemeinschaft and Deutsche Krebshilfe.
2026-04-09 | Clotting the Gap Between Mitochondria-Mediated Immunity and Mitochondrial Transfer.
Mitochondria are organelles that orchestrate numerous cell functions in addition to providing energy. During viral infection or in case of defects in mitochondrial replication, an intricate mechanism of self-destruction is engaged through the formation of mitochondrial pores. This leads to the release of mitochondrial DNA into the cytoplasm, where it triggers innate immune responses. Platelets constitute the principal source of circulating mitochondria, and increasing evidence demonstrates that they actively release mitochondria, some of which are enclosed within extracellular vesicles. This process is enhanced in autoimmune conditions, occurs in platelet storage, and has been linked to adverse reactions after platelet transfusion. Extracellular mitochondria act as carriers of damage-associated molecular patterns and are targets of antibodies in various pathologies, including antiphospholipid syndrome and cardiomyopathies. Moreover, elevated levels of antimitochondria antibodies have also been associated with increased mortality and cardiovascular risk in systemic lupus erythematosus. Mitochondrial transplantation, a process by which defective mitochondria in a tissue or organ may be replaced by healthy mitochondria, is receiving growing therapeutic interest. Thus, understanding how extracellular mitochondria interact with the immune system is increasingly important. This review summarizes current knowledge on the multifaceted roles of mitochondria in immunity, with a particular focus on platelets and platelet-derived mitochondria as a key biological context.
2025-09-08 | Case Report: Remission of a patient with complex combination of autoimmune diseases by anti-CD19 CAR-T cell therapy.
CAR-T cell therapy has been proven effective in various autoimmune diseases, with most studies utilizing lentiviral-transduced CAR-T cells. In recent years, retroviral vector-transduced CAR-T cells-characterized by a high positivity rate, stable cell lines, and lower plasmid requirements-have attracted increasing attention. This article presents a complex case of a patient with SLE combined with APS and TBIRS. For four years following the diagnosis, the patient underwent conventional steroid therapy and immunotherapy, which yielded unsatisfactory and relapse-prone results. After receiving anti-CD19 CAR-T cells transduced with a retroviral vector, the patient experienced an excellent postoperative recovery without any infusion-related adverse reactions. Post-treatment, the patient's creatinine, anti-dsDNA antibodies, albumin, and glycated hemoglobin levels returned to normal, eliminating the need for ongoing glucocorticoids or hypoglycemic agents. Although there are some available reports of CAR-T cells treating SLE, it is still very rare and significant for successfully treating such a complicated case, especially after proving the unavailability of traditional therapy. Furthermore, this is the first reported case of treating TBIRS syndrome with retroviral vector-transduced CAR-T therapy.
2025-03-06 | Plasmapheresis for lowering the risks of placenta-associated complications in antiphospholipid syndrome
Aim : to study plasmapheresis (PP) effect on antiphospholipid syndrome (APS) treatment during preconception preparation and pregnancy. Materials and Methods . A single-center, prospective, randomized, uncontrolled study was conducted. A total of 137 women aged 22 to 32 years diagnosed with APS-related habitual miscarriage were examined. The patients were stratified as follows: main group consisted of 73 patients underwent a PF course (7 procedures at preconception preparation stage); comparison group – 64 patients not underwent efferent therapy. Antiphospholipid antibodies (APA) circulation was determined by solid-phase immunofluorescence. PР was performed using an intermittent technique. The laboratory study included assessing titers of lupus anticoagulant (LA), anti-cardiolipin antibodies (aCL), anti-β2-glycoprotein 1 antibodies (anti-β2-GP1) and anti-annexin V antibodies (anti-ANX). Antibody titers were measured before and after pregravid preparation. Results . After PР, anti-β2-GР1 titers decreased by 66.6 % (p = 0.00001) in main group. In patients who underwent standard therapy without PР, no significant changes in circulation level of anti-β2-GР1 were noted. LA frequency in main and comparison group decreased by 57.3 % (p = 0.042) and 10.9 % (p = 0.69), respectively. Conclusion . The frequency of detecting elevated AРA levels in women after a course of efferent therapy decreased significantly, whereas standard therapy showed no such effects. PР as part of complex therapy is more appropriate for achieving maximum effect.
antibodies
2026-09-24 | Teclistamab for the treatment of autoantibody-mediated coagulation disorders.
Teclistamab is a bispecific monoclonal antibody that targets B cell maturation antigen (BCMA) on plasma cells and other B lineage cells and CD3 on T cells, thereby redirecting cytotoxic T cells to eliminate BCMA-expressing antibody-producing cells. Autoantibody-mediated coagulation disorders are often driven by long-lived antibody-producing cells that may persist despite conventional immunosuppression or B cell depletion. To investigate whether teclistamab represents a treatment option for patients with refractory or rapidly progressive autoantibody-mediated coagulation disorders. We retrospectively analyzed seven patients with autoantibody-mediated coagulation disorders treated with teclistamab. Diagnoses included acquired von Willebrand disease (n=2), acquired factor XI deficiency (n=2), and catastrophic antiphospholipid syndrome (CAPS; n=3). Five patients had an underlying paraprotein, whereas two CAPS patients had no detectable paraprotein. All seven patients achieved complete remissions (median time to remission: 24 weeks [range: 2-35]) following teclistamab. In the four patients with acquired von Willebrand disease or factor XI deficiency, improvement in the disease-defining coagulation parameter and cessation of bleeding were observed following initiation of teclistamab. In the three patients with CAPS disappearance of antiphospholipid antibodies or normalization of the aPTT-LA was observed and accompanied by clinical stabilization without further thromboembolic events. Treatment was generally well tolerated. Three patients developed grade 1 cytokine release syndrome. One patient developed transient colitis while another patient experienced reversible seronegative inflammatory joint symptoms. All patients received immunoglobulin replacement. Teclistamab treatment was associated with complete remissions in patients with autoantibody-mediated coagulation disorders. These observations warrant further evaluation of teclistamab in selected patients.
2026-08-26 | Diffuse alveolar hemorrhage in primary antiphospholipid syndrome: A case series of six patients.
Antiphospholipid syndrome (APS) is an autoimmune prothrombotic disorder characterized by persistent antiphospholipid antibodies (aPLs). Diffuse alveolar hemorrhage (DAH) is a rare but severe microvascular manifestation of APS associated with high morbidity and mortality. We retrospectively analyzed six consecutive patients with primary APS complicated by DAH who had been followed at our institution between 2018 and 2025. Clinical presentation, laboratory and radiological findings, treatment strategies, and outcomes were evaluated. Median age was 37.5 years (female:male 4:2). DAH was confirmed by bronchoscopy in all patients; triple aPL positivity was present in all. Most patients required hospitalization for severe respiratory failure, and recurrent DAH was frequent. Two patients died: one from uncontrolled DAH complicated by invasive fungal infection, and the other from pulmonary embolism. Two patients had a milder chronic course with fluctuating HRCT infiltrates but no severe hypoxemia. All patients received high-dose glucocorticoids followed by maintenance immunosuppression with rituximab, usually combined with mycophenolate. Adjunctive therapies included plasma exchange, intravenous immunoglobulin, and eculizumab. Antibody titers remained persistently positive in all cases. APS-associated DAH is a life-threatening complication with frequent relapses and poor prognosis, particularly in patients with triple positivity and recurrent DAH. None of the patients achieved long-term remission, and all experienced disease progression despite aggressive immunosuppressive therapy. Early recognition, aggressive immunosuppression, and close monitoring are crucial, while novel therapeutic options are urgently needed.
2026-08-13 | Reported Prevalence of Inherited Thrombophilia in Pregnancy: Impact of Cohort Selection on Screening Implications-A Systematic Review.
Background/Objectives: Inherited thrombophilia (IT) has been extensively investigated as a potential contributor to adverse pregnancy outcomes; however, reported prevalence varies widely across studies. This systematic review aimed to evaluate how cohort selection influences the reported prevalence of inherited thrombophilia in pregnancy and to explore the implications of this variability for clinical interpretation and screening practices. Methods: A systematic review was conducted following PRISMA 2020 guidelines. PubMed, Scopus, Web of Science, and Google Scholar were searched. A total of 5480 records were identified, and 7 observational studies (cohort and case-control) met inclusion criteria. Data were synthesized qualitatively due to heterogeneity. Results: Prevalence ranged from 0% to 14%, depending on population characteristics. The largest cohort study reported an inherited thrombophilia prevalence of 8.1%, comparable to the general population. Higher rates were observed in referral-based and antiphospholipid Syndrome (APS)-associated cohorts, while case-control studies showed no significant differences between affected individuals and controls. Ethnic variability was also observed. Conclusions: These findings should be interpreted as patterns observed across heterogeneous study designs rather than as definitive evidence of causality. Current evidence does not clearly support universal screening in pregnancy; however, the findings should be interpreted cautiously because several included studies were limited by small sample sizes and methodological heterogeneity.
2026-08-12 | Case Report: IVIG as a bridging strategy in high-risk antiphospholipid syndrome with infected cutaneous ulceration and thrombocytopenia.
Severe cutaneous ulceration in antiphospholipid syndrome (APS) with concurrent infection and thrombocytopenia presents a therapeutic dilemma: standard immunosuppression risks worsening infection, while anticoagulation risks hemorrhage. We present a high-risk case successfully managed using intravenous immunoglobulin (IVIG) as a bridging immunomodulatory strategy. A 73-year-old man with triple-positive APS and immune thrombocytopenic purpura (ITP) developed rapidly progressive leg ulcers with clinical features consistent with pyoderma gangrenosum-like disease, complicated by active MRSA and Pseudomonas aeruginosa infection and severe thrombocytopenia (12 × 109/L). Standard therapies were contraindicated: corticosteroids risked worsening infection; anticoagulation risked hemorrhage. The patient received IVIG (0.4 g/kg per dose, every 3 weeks) as primary immunomodulation, concurrent targeted antimicrobial therapy, temporary anticoagulation interruption, and discontinuation of baseline mycophenolate mofetil. Following platelet recovery above 70 × 109/L, therapeutic anticoagulation was resumed with enoxaparin (80 mg subcutaneously twice daily) and aspirin (75 mg daily). Over five months, progressive re-epithelialization culminated in complete healing with platelet recovery. This case supports the feasibility of IVIG as a bridging immunomodulatory strategy in high-risk APS cutaneous disease where standard therapies are contraindicated by concurrent infection and thrombocytopenia. The sequential management approach successfully resolved a clinically challenging scenario. This case illustrates how risk-adapted immunomodulation may enable safe management of complex APS manifestations.
2026-08-10 | Monoclonal Gammopathy of Thrombotic Significance.
Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant precursor to multiple myeloma (MM). While development of end-organ damage in MM largely reflects increasing clonal burden, emerging evidence indicates that qualitative properties of the monoclonal immunoglobulins in MGUS can be directly pathogenic, leading to serious organ injury independent of disease burden. This has led to the recognition of a broader spectrum of disorders collectively termed monoclonal gammopathy of clinical significance (MGCS). MGCS can be further subclassified based on the organ system involved; for example, monoclonal gammopathy of renal significance specifically refers to monoclonal immunoglobulin-driven renal injury. Along these lines, we propose monoclonal gammopathy of thrombotic significance (MGTS) as encompassing thrombotic disorders in which there is definitive, mechanistically supported evidence that a monoclonal (M)-protein associated with a clonal plasma or B-cell disorder directly contributes to thrombosis. Based on current evidence, monoclonal protein-induced immune thrombocytopenia and thrombosis is the only disorder that meets our criteria for MGTS. Other thrombotic disorders, such as thrombotic microangiopathy and antiphospholipid syndrome, may occur in the setting of a monoclonal protein and have biologically plausible M-protein-mediated mechanisms; however, direct evidence implicating the M-protein in thrombosis is currently lacking. Accordingly, we provisionally classify these disorders as thrombotic syndromes associated with M-proteins, pending causal validation. We also highlight thrombotic disease associations with multifactorial pathogenesis that should not be classified as MGTS. Broader recognition of MGTS is essential to advance consensus definitions, establish diagnostic criteria, and develop evidence-based management strategies for this clinically important group of disorders.
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2025-06-09 | Complex presentation of probable catastrophic antiphospholipid syndrome: diagnostic dilemmas and treatment strategies.
Catastrophic antiphospholipid syndrome (CAPS) is a rare and life-threatening clinical emergency with multiorgan involvement. CAPS presents a significant clinical challenge due to its heterogeneous presentation and can resemble many other systemic thrombotic disorders. Prompt and intensive treatment is essential for patient survival. However, due to its rarity and heterogeneity, evidence-based protocols are scarce, and as such, diagnosis and management rely on guidelines stemming from low-level evidence and expert opinion. We present a patient with antiphospholipid syndrome who developed multiorgan complications and was diagnosed with probable CAPS. Diagnosis was complicated due to thrombotic risk and the heterogeneous nature of CAPS, as well as his unresponsiveness to first-line therapy consisting of anticoagulation and corticosteroids. His treatment was then escalated with plasma exchange, rituximab and cyclophosphamide, to which he responded and improved clinically.
2024-07-25 | Antiphospholipid-exposed trophoblast-derived extracellular vesicles express elevated levels of TLR7/8-activating microRNAs and induce endometrial endothelial activation, in part, through TLR7.
Women with antiphospholipid syndrome (APS) are at high risk for miscarriage and preeclampsia. Unlike pro-thrombotic systemic APS, obstetric APS is associated with insufficient placentation, as well as inflammation and vascular dysfunction at the maternal-fetal interface. Antiphospholipid antibodies (aPL) can target the placental trophoblast and induce inflammation. We reported that aPL trigger trophoblast cells to produce elevated levels of IL-8 through activation of Toll-like receptor 4 (TLR4). Downstream of TLR4, we found this IL-8 response is mediated by a TLR8-activating microRNA (miR), miR-146a-3p, which is also released by the trophoblast via extracellular vesicles (EVs). Since endothelial dysfunction is a feature of obstetric APS, we sought to determine if other miRs that can activate the RNA sensors, TLR7 and/or TLR8, are released by the trophoblast via EVs after exposure to aPL, and if these EVs can activate human endometrial endothelial cells (HEECs). Using a human first trimester extravillous trophoblast cell line we found that aPL elevated their release of small EVs (<150 nm). These extracellular vesicles released from trophoblast cells exposed to aPL expressed elevated levels of TLR7/8-activating miR-21a and miR-29a, in addition to the previously reported miR-146a-3p. Extracellular vesicles from aPL-exposed human trophoblast cells triggered human endometrial endothelial cells to generate an inflammatory IL-8 response, in part through TLR7. This study highlights EVs as a mode of communication between the placenta and the maternal vasculature, as well as a potential role for TLR7/8-activating miRs in contributing to inflammation at the maternal-fetal interface in obstetric APS.
2023-05-17 | Metastasis-associated lung adenocarcinoma transcript 1 induces methyl-CpG-binding domain protein 4 in mice with recurrent spontaneous abortion caused by anti-phospholipid antibody positivity.
Antiphospholipid syndrome is an autoimmune disease characterized by pregnancy-related morbidity, related to persistent positivity of antiphospholipid antibodies (APL). One of the characteristics of pregnancy-related morbidity in patients with antiphospholipid syndrome is recurrent spontaneous abortion (RSA). This study aimed to examine the mechanism through which metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) regulates methyl-CpG-binding domain protein 4 (MBD4) expression in APL-positive RSA. Clinical samples were subjected to microarray analysis to filter differentially expressed genes. RSA mice with APL positivity were generated, followed by adenoviral vector injection to artificially upregulate MALAT1. The effects of MALAT1 on the biological behavior of trophoblast cells were assessed. The downstream mechanism of MALAT1 was analyzed using subcellular fractionation and bioinformatics prediction, and the relationship between MALAT1 and CREB binding protein (CREBBP) or MBD4 was investigated in trophoblast cells. MALAT1 was downregulated in APL-positive RSA patients. MALAT1 was predominantly localized in the nucleus and recruited CREBBP to mediate the MBD4 transcription. In the APL-positive RSA mice overexpressing MALAT1, the expression of soluble Fms-related tyrosine kinase 1 and anticardiolipin antibody and the embryonic resorption rate were decreased, indicating that MALAT1 reduced the occurrence of RSA in mice. Moreover, MALAT1 enhanced proliferation, migration, and invasion of trophoblast cells through recruiting CREBBP to promote MBD4 expression. Silencing of CREBBP or MBD4 increased embryonic resorption rate in RSA mice overexpressing MALAT1. MALAT1 suppresses APL-positive RSA by promoting MBD4 transcription through recruitment of CREBBP to the MBD4 promoter region.
2023-04-24 | Antisense oligonuleotides influences trophoblasts behaviors by changing LncNR_040117 expression in antiphospholipid antibody syndrome-induced recurrent pregnancy loss.
The primary objective of this study was to explore whether antisense oligonucleotides (ASOs) that reduce LncNR_040117 expression in patients with antiphospholipid antibody syndrome (APS)-induced recurrent pregnancy loss (RPL), and further decrease apoptosis and improve trophoblasts invasion through mitogen-activated protein kinase (MAPK) pathways. This paper aimed to provide a new strategy to treat APS-induced RPL. In this study, we used quantitative reverse transcription-polymerase chain reaction (RT-qPCR) to analyze the expression level of LncNR 040117 in HTR-8/SVneo cells following transfection with ASOs. Then we utilized Western blotting to test the expression levels of interleukin-1β (IL-1β), intracellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and key molecules of MAPK pathways, including the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinases (JNK) and p38. In addition, we examined the HTR-8/SVneo cells apoptosis by cell apoptosis assay, and migration and invasion by transwell antibody assay. Each experiment was repeated three times. The data are presented as the means ± SDs, and statistical comparisons were performed using Student's t-test. p < 0.05 was considered significant. Transfected with ASOs, LncNR_040117 was downregulated in trophoblasts compared with APS-induced RPL patients. And LncNR_040117 low expression induced IL-1β and downstream adhesion molecules ICAM-1 and VCAM-1expression level decreased, as well as MAPK pathways downregulation, including the ERK pathway, JNK pathway and p38/MAPK pathway. Furthermore, all these changes resulted in decreased apoptosis and increased migration and invasion of trophoblasts. This study indicated that ASOs that decrease LncNR_040117 expression can reduce apoptosis and enhance the invasion and migration of trophoblasts by regulating the MAPK pathway.
2023-02-10 | Whole blood transcriptome identifies interferon-regulated genes as key drivers in thrombotic primary antiphospholipid syndrome.
Pathogenesis of antiphospholipid syndrome (APS) isn't fully elucidated. We aimed to identify gene signatures characterizing thrombotic primary APS (thrPAPS) and subgroups at high risk for worse outcomes. We performed whole blood next-generation RNA-sequencing in 62 patients with thrPAPS and 29 age-/sex-matched healthy controls (HCs), followed by differential gene expression analysis (DGEA) and enrichment analysis. We trained models on transcriptomics data using machine learning. DGEA of 12.306 genes revealed 34 deregulated genes in thrPAPS versus HCs; 33 were upregulated by at least 2-fold, and 14/33 were type I and II interferon-regulated genes (IRGs) as determined by interferome database. Machine learning applied to deregulated genes returned 79% accuracy to discriminate thrPAPS from HCs, which increased to 82% when only the most informative IRGs were analyzed. Comparison of thrPAPS subgroups versus HCs showed an increased presence of IRGs among upregulated genes in venous thrombosis (21/23, 91%), triple-antiphospholipid antibody (aPL) positive (30/50, 60%), and recurrent thrombosis (19/42, 45%) subgroups. Enrichment analysis of upregulated genes in triple-aPL positive patients revealed terms related to 'type I interferon signaling pathway' and 'innate immune response'. DGEA among thrPAPS subgroups revealed upregulated genes, including IRGs, in patients with venous versus arterial thrombosis (n = 11, 9 IRGs), triple-aPL versus non-triple aPL (n = 10, 9 IRGs), and recurrent versus non-recurrent thrombosis (n = 10, 3 IRGs). Upregulated IRGs may better discriminate thrPAPS from HCs than all deregulated genes in peripheral blood. Taken together with DGEA data, IRGs are highly expressed in thrPAPS and high-risk subgroups of triple-aPL and recurrent thrombosis, with potential treatment implications.
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Drug Discovery Landscape
2 orphan drug designations for Antiphospholipid syndrome.
2 orphan drug designations for Antiphospholipid syndrome.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
certolizumab pegol | antibodies | FDA | UCB, Inc. | |
Hydroxychloroquine | small molecules | EMA | Cristina Belizna |
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