Purpose of review Catastrophic antiphospholipid syndrome (CAPS) is a severe manifestation of APS. While affecting only 1% of patients with APS, the condition is frequently fatal if not recognized and treated early. Here, we will review the current approach to diagnosis and treatment of CAPS. Recent findings Data from the international “CAPS registry,” spearheaded by the European Forum on Antiphospholipid Antibodies, have improved our understanding of at-risk patients, typical clinical features, and associated/precipitating diagnoses. Current guidelines also continue to support a role for anticoagulants and glucocorticoids as foundation therapy in all patients. Finally, new basic science and case series suggest that novel therapies, such as rituximab and eculizumab warrant further study. Summary Attention to associated diagnoses such as infection and systemic lupus erythematosus (SLE) are critical at the time of diagnosis. All patients should be treated with anticoagulation, corticosteroids, and possibly plasma exchange. In patients with SLE, cyclophosphamide should also be considered. In refractory or relapsing cases, new therapies such as rituximab and possibly eculizumab may be options, but need further study.

ObjectivesWhile diffuse alveolar haemorrhage (DAH) is recognised as a life-threatening complication of systemic lupus erythematosus (SLE), little is known about its risk factors and response to treatment. We describe 22 cases of DAH in a US lupus cohort of approximately 1000 patients, and compare them to 66 controls from the same outpatient cohort.MethodsWe captured variables pertaining to diagnoses of SLE and secondary antiphospholipid syndrome (APS), and analysed them by univariate testing. Those variables with p values <0.05 were then further considered in a multivariate model. Kaplan-Meier curves were constructed for each group, and survival was analysed by Log-rank test.ResultsOf the 22 patients with DAH, 59% were diagnosed with DAH within 5 years of lupus diagnosis. By univariate testing, several manifestations of SLE and APS were more common in patients with DAH, including history of thrombocytopenia, cardiac valve disease, low C3, leucopenia, neuropsychiatric features, haemolysis, arterial thrombosis, lupus anticoagulant, secondary APS and low C4. On multivariate analysis, history of thrombocytopenia and low C3 were maintained as independent risk factors. Importantly, only two patients had platelet counts <50 000/µL at the time of the DAH episode, arguing that DAH was not simply a haemorrhagic complication of thrombocytopenia. All patients were treated with increased immunosuppression, including various combinations of corticosteroids, plasmapheresis, cyclophosphamide, rituximab and mycophenolate mofetil. Notably, all patients in the cohort survived their initial episode of DAH. While the patients with DAH did well in the short-term, their long-term survival was significantly worse than controls. Several of the deaths were attributable to thrombotic complications after recovering from DAH.ConclusionsTo the best of our knowledge, this is the largest case–control study of lupus DAH to date. History of thrombocytopenia was strongly predictive of DAH (OR ∼40). A number of APS manifestations correlated with DAH by univariate analysis, and deserve further consideration in larger studies.

Objectives Patients with antiphospholipid syndrome (APS) are at risk for subclinical endothelial injury, as well as accelerated atherosclerosis. In the related disease systemic lupus erythematosus, there is a well-established defect in circulating endothelial progenitors, which leads to an accrual of endothelial damage over time. This defect has been at least partially attributed to exaggerated expression of type I interferons (IFNs). We sought to determine whether these pathways are important in APS. Methods We studied 68 patients with primary APS. Endothelial progenitors were assessed by flow cytometry and functional assay. Type I IFN activity was determined by a well-accepted bioassay, while peripheral blood mononuclear cells (PBMCs) were scored for expression of IFN-responsive genes. Results Endothelial progenitors from APS patients demonstrated a marked defect in the ability to differentiate into endothelial cells, a phenotype which could be mimicked by treating control progenitors with APS sera. Elevated type I IFN activity was detected in the circulation of APS patients (a finding that was then replicated in an independent cohort). While IgG depletion from APS sera did not rescue endothelial progenitor function, the dysfunction was successfully reversed by a type I IFN receptor-neutralizing antibody. Conclusions We describe, for the first time to our knowledge, an IFN signature in primary APS and show that this promotes impaired endothelial progenitor function. This work opens the door to novel approaches that may mitigate vascular damage in APS, such as anti-IFN drugs.

Thrombotic events, both arterial and venous, are a major health concern worldwide. Further, autoimmune diseases, such as systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, and antiphospholipid syndrome, predispose to thrombosis, and thereby push the risk for these morbid events even higher. In recent years, neutrophils have been identified as important players in both arterial and venous thrombosis. Specifically, chromatin-based structures called neutrophil extracellular traps (NETs) play a key role in activating the coagulation cascade, recruiting platelets, and serving as scaffolding upon which the thrombus can be assembled. At the same time, neutrophils and NETs are emerging as important mediators of pathogenic inflammation in the aforementioned autoimmune diseases. Here, we first review the general role of NETs in thrombosis. We then posit that exaggerated NET release contributes to the prothrombotic diatheses of systemic lupus erythematosus, ANCA-associated vasculitis, and antiphospholipid syndrome.

Neutrophil extracellular traps (NETs) are chromatin-derived webs extruded from neutrophils in response to either infection or sterile stimulation with chemicals, cytokines, or microbial products. The vast majority of studies have characterized NET release (also called NETosis) in pure neutrophil cultures in vitro. The situation is surely more complex in vivo as neutrophils constantly sample not only pathogens and soluble mediators but also signals from cellular partners, including platelets and endothelial cells. This complexity is beginning to be explored by studies utilizing in vitro co-culture, as well as animal models of sepsis, infective endocarditis, lung injury, and thrombosis. Indeed, various selectins, integrins, and surface glycoproteins have been implicated in platelet–neutrophil interactions that promote NETosis, albeit with disparate results across studies. NETosis can also clearly be regulated by soluble mediators derived from platelets, such as eicosanoids, chemokines, and alarmins. Beyond platelets, the role of the endothelium in modulating NETosis is being increasingly revealed, with adhesive interactions likely priming neutrophils toward NETosis. The fact that the same selectins and surface glycoproteins may be expressed by both platelets and endothelial cells complicates the interpretation of in vivo data. In summary, we suggest in this review that the engagement of neutrophils with activated cellular partners provides an important in vivo signal or “hit” toward NETosis. Studies should, therefore, increasingly consider the triumvirate of neutrophils, platelets, and the endothelium when exploring NETosis, especially in disease states.