Non-criteria Manifestations Research Articles

Update on antiphospholipid antibody syndrome.

Update on antiphospholipid antibody syndrome.

Thrombotic risk stratification by platelet count in patients with antiphospholipid antibodies: a longitudinal study

Thrombotic risk stratification by platelet count in patients with antiphospholipid antibodies: a longitudinal study

Increased heterogeneity of brain perfusion is an early marker of central nervous system involvement in antiphospholipid antibody carriers.

ObjectiveThe non-criteria neuropsychiatric manifestations of antiphospholipid syndrome include headache, dizziness, vertigo, seizure, depression and psychosis. There were still no objective methods qualified to detect the early central nervous system involvement in non-criteria antiphospholipid syndrome. We evaluated the effectiveness of Tc-99m ECD SPECT in assessing circulatory insufficiency in the brains of patients with antiphospholipid antibodies and neuropsychiatric symptoms but without thromboembolism.Materials and methodsPatients with a history of positive antiphospholipid antibodies and neuropsychiatric symptoms composed the case group; patients without antiphospholipid antibody served as the control group. Subjects with a history of thromboembolism or autoantibodies to extractable nuclear antigens were excluded. All patients received Tc-99m ECD SPECT studies and were classified by the number of positive antiphospholipid antibodies they carried. The heterogeneity of brain perfusion was defined as the coefficient of variation of the SPECT signals. Analysis of variance (ANOVA) was applied to evaluate the differences between the groups.ResultsTotal 60 adult patients were included in this study. There were 54 patients in the case group and 6 patients in the control group. The mean age was 38.3 ± 11.5 years. There were 52 women and 8 men. There was no significant difference in the mean brain perfusion between groups (P = 0.69). However, Tc-99m ECD SPECT demonstrated significant heterogeneity of brain perfusion in relation to the number of antiphospholipid antibodies (P = 0.01).ConclusionsThis is the first study demonstrating that Tc-99m ECD SPECT can early detect the increased heterogeneity of brain circulation in non-criteria antiphospholipid antibody carriers.

Current treatment of antiphospholipid syndrome: lights and shadows.

For patients with antiphospholipid syndrome (APS), the consensus is to treat those who develop thrombosis with long-term oral anticoagulation therapy and to prevent obstetric manifestations by use of aspirin and heparin. These recommendations are based on data from randomized controlled trials and observational studies. Despite this body of knowledge, areas of uncertainty regarding the management of APS exist where evidence is scarce or nonexistent. In other words, for a subset of patients the course of management is unclear. Some examples are patients with 'seronegative' APS, those who do not fulfil the formal (clinical or serological) classification criteria for definite APS, and those with recurrent thrombotic events despite optimal anticoagulation. Other challenges include the treatment of clinical manifestations not included in the classification criteria, such as haematologic manifestations (thrombocytopenia and haemolytic anaemia), neurologic manifestations (chorea, myelitis and multiple sclerosis-like lesions), and nephropathy and heart valve disease associated with antiphospholipid antibodies (aPL), as well as the possible withdrawal of anticoagulation treatment in selected cases of thrombotic APS in which assays for aPL become persistently negative. This Review focuses on the current recommendations for thrombotic and obstetric manifestations of APS, as well as the management of difficult cases. Some aspects of treatment, such as secondary prophylaxis of venous thrombosis, are based on strong evidence--the 'lights' of APS treatment. Conversely, other areas, such as the treatment of non-criteria manifestations of APS, are based only on expert consensus or common sense and remain the 'shadows' of APS therapy.

Difficult clinical situations in the antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is characterized by antiphospholipid antibodies (aPL) associated with thrombosis and/or pregnancy morbidity. However, there is a range of other manifestations associated with APS, called non-criteria manifestations that add significant morbidity to this syndrome and, some of them, represent difficult clinical situations to deal with. Other issues such as refractory treatment also represent challenging situations poorly addressed in the literature. Therefore, the purpose of this article is to review the management of difficult clinical situations in APS and provide information to help the readers in their decision-making process.

The significance and management of thrombocytopenia in antiphospholipid syndrome.

The association between antiphospholipid antibodies (aPL) and clinical problems goes beyond what is stated in the antiphospholipid syndrome (APS) classification criteria, namely thrombosis and pregnancy morbidity, and thrombocytopenia is the most common non-criteria hematologic manifestation of aPL with a frequency ranging from 20 to 50%. Thrombocytopenia is rarely severe, and hemorrhage is far less common than thrombosis. However, when anticoagulation is considered, it may constitute a clinical problem with increased bleeding risk. Furthermore, thrombocytopenia represents a risk factor for thrombosis in aPL-positive patients. Therefore, it is important to understand the pathogenesis and the clinical associations of thrombocytopenia to build the right medical approach in aPL-positive patients. In this paper, we review the literature on aPL/APS-associated thrombocytopenia and briefly discuss the other conditions that can result in thrombocytopenia as they have commonalities with APS and their recognition is important to establish the most appropriate treatment strategy.

Diagnosis and management of non-criteria obstetric antiphospholipid syndrome.

Accurate diagnosis of obstetric antiphospholipid syndrome (APS) is a prerequisite for optimal clinical management. The international consensus (revised Sapporo) criteria for obstetric APS do not include low positive anticardiolipin (aCL) and anti β2 glycoprotein I (aβ2GPI) antibodies (< 99th centile) and/or certain clinical criteria such as two unexplained miscarriages, three non-consecutive miscarriages, late pre-eclampsia, placental abruption, late premature birth, or two or more unexplained in vitro fertilisation failures. In this review we examine the available evidence to address the question of whether patients who exhibit non-criteria clinical and/or laboratory manifestations should be included within the spectrum of obstetric APS. Prospective and retrospective cohort studies of women with pregnancy morbidity, particularly recurrent pregnancy loss, suggest that elimination of aCL and/or IgM aβ2GPI, or low positive positive aCL or aβ2GPI from APS laboratory diagnostic criteria may result in missing the diagnosis in a sizeable number of women who could be regarded to have obstetric APS. Such prospective and retrospective studies also suggest that women with non-criteria obstetric APS may benefit from standard treatment for obstetric APS with low-molecular-weight heparin plus low-dose aspirin, with good pregnancy outcomes. Thus, non-criteria manifestations of obstetric APS may be clinically relevant, and merit investigation of therapeutic approaches. Women with obstetric APS appear to be at a higher risk than other women of pre-eclampsia, placenta-mediated complications and neonatal mortality, and also at increased long-term risk of thrombotic events. The applicability of these observations to outcomes in women with non-criteria obstetric APS remains to be determined.

SP0087 Systemic Lupus Erythematosus and the Antiphospholipid Syndrome

SP0087 Systemic Lupus Erythematosus and the Antiphospholipid Syndrome

IgA Antiphospholipid Antibodies and Anti-Domain 1 of Beta 2 Glycoprotein 1 Antibodies are Associated with Livedo Reticularis and Heart Valve Disease in Antiphospholipid Syndrome.

Antiphospholipid syndrome (APS) is an autoimmune disease associated with venous or arterial thrombosis and pregnancy loss, but also infrequently with non-criteria APS manifestations such as thrombocytopenia, livedo reticularis and heart valve disease. The occurrence of antiphospholipid antibodies is necessary to diagnose APS and includes the presence of lupus anticoagulant and anticardiolipin as well as anti-β2-glycoprotein Iantibodies, both in IgM and/or IgG isotype. The aim of this study was to evaluate the associations between antiphospholipid antibodies including IgA isotype and IgG anti-domain Iof β2-glycoprotein I(β-2GPI-D1) and non-criteria-related manifestations ofAPS. Thirty-three consecutive APS patients (26women, 7men, aged 44.1±15years), including 23 (69.7%) subjects with primary APS, were enrolled. Together with standard antiphospholipid antibodies, IgA anticardiolipin, IgA anti-β2-glycoprotein Iand IgG anti-β-2GPI-D1 antibodies in serum samples were evaluated by chemiluminescence using the QUANTA Flash® System. Livedo reticularis (n=8, 24.2%) was associated with increased levels of IgG anti-β-2GPI-D1 (p=0.005), IgA anticardiolipin (p=0.001) and IgA anti-β2-glycoprotein I(p=0.002) antibodies. Heart valve disease (n=9, 27.3%) was observed in patients with higher IgG anti-β-2GPI-D1 (p=0.01). The associations of HVD with increased levels of IgA aCL and IgA anti-β-2GPI tended to be significant (p=0.07). None of antiphospholipid antibodies showed association with thrombocytopenia (n=6, 18.2%). Our study suggests that increased IgA antiphospholipid antibodies and IgG anti-β-2GPI-D1 antibodies may be involved in the development of livedo reticularis and heart valve disease in APS patients.

PReS-FINAL-2296: Thrombocytopenia as a unique manifestation of antiphospholipid syndrome: a case report in the pediatric age

The primary manifestation of the antiphospholipid antibody syndrome (APS) is thrombosis, which forms the core of the classification criteria for this syndrome. However, multiple other noncriteria manifestations have been attributed to APS, some of which do not appear to have thrombosis as part of the pathophysiology, although they may be mediated by autoantibodies. Examples of these manifestations include neuropathy, thrombocytopenia, and cardiac valvular disease. Of importance, these manifestations of APS may not respond well to anticoagulation, and therefore additional therapies are needed.

A pilot open‐label phase II trial of rituximab for non‐criteria manifestations of antiphospholipid syndrome

The primary objective of this study was to evaluate the safety of rituximab in antiphospholipid antibody (aPL)-positive patients with non-criteria manifestations of antiphospholipid syndrome (APS). The secondary objectives were to evaluate the effect of rituximab on the aPL profile and to evaluate the efficacy of rituximab treatment for non-criteria manifestations of APS. In this 12-month, phase II pilot study, adult aPL-positive patients with thrombocytopenia, cardiac valve disease, skin ulcer, aPL nephropathy, and/or cognitive dysfunction received 2 doses of rituximab (1,000 mg) on days 1 and 15. Antiphospholipid antibody profiles and clinical outcome measures, which were categorized as complete response, partial response, no response, or recurrence, were analyzed at preset time points. Two of 19 patients experienced infusion reactions, resulting in early termination. Twelve serious adverse events and 49 nonserious adverse events were recorded. All patients who had positive results of lupus anticoagulant, anticardiolipin, and anti-β(2)-glycoprotein I antibody tests at baseline had positive results at 24 weeks and 52 weeks. The numbers of patients with a complete response, a partial response, no response, and recurrence for the clinical outcome measures at 24 weeks were as follows: for thrombocytopenia, 1, 1, 2, and 0, respectively; for cardiac valve disease, 0, 0, 3, and not analyzed, respectively; for skin ulcer, 3, 1, 0, and 1, respectively; for aPL nephropathy, 0, 1, 0, and 0, respectively; and for cognitive dysfunction, 3, 1, 1, and not analyzed, respectively. The results of this uncontrolled and nonrandomized pilot study suggest that the safety of rituximab in aPL-positive patients is consistent with the safety profile of rituximab. Despite causing no substantial change in aPL profiles, rituximab may be effective in controlling some but not all non-criteria manifestations of APS.

Clinical manifestations of antiphospholipid syndrome (APS) with and without antiphospholipid antibodies (the so-called ‘seronegative APS’)

Clinical manifestations of antiphospholipid syndrome (APS) with and without antiphospholipid antibodies (the so-called ‘seronegative APS’)

Task Force on Catastrophic Antiphospholipid Syndrome (APS) and Non-criteria APS Manifestations (I): catastrophic APS, APS nephropathy and heart valve lesions

The objectives of the 'Task Force on Catastrophic Antiphospholipid Syndrome (APS) and Non-criteria APS Manifestations' were to assess the clinical utility of the international consensus statement on classification criteria and treatment guidelines for the catastrophic APS, to identify and grade the studies that analyse the relationship between the antiphospholipid antibodies and the non-criteria APS manifestations and to present the current evidence regarding the accuracy of these non-criteria APS manifestations for the detection of patients with APS. This article summarizes the studies analysed on the catastrophic APS, APS nephropathy and heart valve lesions, and presents the recommendations elaborated by the Task Force after this analysis.

Task Force on Catastrophic Antiphospholipid Syndrome (APS) and Non-criteria APS Manifestations (II): thrombocytopenia and skin manifestations

The objectives of the 'Task Force on Catastrophic Antiphospholipid Syndrome (APS) and Non-criteria APS Manifestations' were to assess the clinical utility of the international consensus statement on classification criteria and treatment guidelines for the catastrophic APS, to identify and grade the studies that analyze the relationship between the antiphospholipid antibodies and the non-criteria APS manifestations, and to present the current evidence regarding the accuracy of these non-criteria APS manifestations for the detection of patients with APS. This article summarizes the studies analyzed on thrombocytopenia and skin manifestations, and presents the recommendations elaborated by the Task Force after this analysis.

Non-criteria manifestations of antiphospholipid syndrome

Only few studies have addressed the pathogenesis and treatment of the non-criteria manifestations of antiphospholipid antibodies (aPL) such as thrombocytopenia, nephropathy, cardiac valve disease, cognitive dysfunction, skin ulcers, or diffuse pulmonary hemorrhage. There is no consensus on the management of these manifestations; they may occur despite full-dose anticoagulation or may not improve if anticoagulation is initiated after their discovery. This brief review may help physicians in the management of the non-criteria manifestations of aPL.

Moderate versus high-titer persistently anticardiolipin antibody positive patients: Are they clinically different and does high-titer anti-β2-glycoprotein-I antibody positivity offer additional predictive information?

The association between antiphospholipid antibodies (aPL) and clinical events is stronger with a positive lupus anticoagulant (LA) test, higher anticardiolipin antibody (aCL) titers, and/or higher anti-beta(2)-glycoprotein-I antibody (abeta( 2)GPI) titers. The objective of this study was to determine the clinical characteristics of persistently high-titer (> or =80 U) aCL-positive patients compared with those with persistent moderate aCL titers (40-79 U). Second, we analyzed whether high-titer abeta(2)GPI test adds predictive information in persistently moderate-to-high titer aCL-positive patients. In this cross-sectional study, the primary analysis compared the clinical and aPL characteristics of 58 patients with at least two moderate-titer aCL results to another 85 patients with at least two high-titer aCL results. In the secondary analysis of patients with at least two abeta(2)GPI test results, we compared 29 patients with 'aCL 40-79 U and abeta( 2)GPI < 80 U' profiles with 8 patients with 'aCL 40-79U and abeta(2)GPI > or = 80 U', and also compared 27 patients with 'aCL > 80 U and abeta(2)GPI < 80 U' with 32 patients with 'aCL > 80 U and abeta(2)GPI > or = 80 U'. Although aPL-related vascular and pregnancy events were similar between the moderate- and high-titer aCL groups, the number of patients with positive LA tests (RR 2.06, CI 1.38-3.08, p < 0.01) and with at least one non-criteria aPL manifestation (RR 1.66, CI 1.20-2.30, p = 0.0005) were significantly higher in the high-titer aCL group. While magnetic resonance imaging (MRI) white matter changes were statistically more common in the high-titer aCL group (RR 2.03, CI 1.04-3.94, p = 0.02), there was a trend towards increased prevalence of livedo reticularis, cardiac valve disease, and cognitive dysfunction occurring in the high-titer aCL group. The secondary analysis showed that MRI white matter changes, cardiac valve disease, and cognitive dysfunction were proportionally more common in the high-titer abeta( 2)GPI groups, suggesting a linear relationship between non-criteria aPL manifestations and aPL titers. Our results suggest that patients with high aCL titers, compared with those with moderate titers, are more likely to have a positive LA test and a higher prevalence of non-criteria aPL manifestations. Furthermore, high-titer abeta(2)GPI positivity may further increase the prevalence of non-criteria aPL manifestations in moderate- or high-titer aCL-positive patients.