ABSTRACT The antiphospholipid syndrome (APS) is defined by the development of venous and/or arterial thromboses, often multiple, and pregnancy morbidity (mainly, recurrent fetal losses), in the ...presence of antiphospholipid antibodies (aPL). Some estimates indicate that the incidence of the APS is around 5 new cases per 100,000 persons per year and the prevalence around 40–50 cases per 100,000 persons. The aPL are positive in approximately 13% of patients with stroke, 11% with myocardial infarction, 9.5% of patients with deep vein thrombosis and 6% of patients with pregnancy morbidity. Currently, there is consensus in treating APS patients with thrombosis with long-term oral anticoagulation and to prevent obstetric manifestations with the use of aspirin and heparin. This review summarizes the main knowledge on the clinical and therapeutic aspects of this syndrome.
Treatment of thrombosis in patients with antiphospholipid syndrome (APS) is based on long-term oral anticoagulation and treatment of obstetric manifestations on the use of aspirin and heparin. These ...recommendations are based on randomized controlled trials and observational studies. In detail, patients with definite APS with first venous thrombosis have to be treated with prolonged oral anticoagulation at a target international normalized ratio (INR) of 2.0–3.0. Anticoagulation at INR of 3.0–4.0, isolated antiaggregation, anticoagulation at INR 2.0–3.0 or anticoagulation at INR 2.0–3.0 plus antiaggregation have been proposed for definite APS patients with arterial thrombosis. Regarding obstetric APS, although combined therapy with low-dose aspirin and low-molecular-weight heparin is the mainstay of treatment in women with obstetric APS, the strength of evidence of its efficacy is under discussion.However, there are many grey areas in the field of APS where the evidence is scarce and where the management of certain patients is difficult. Some examples are patients with “seronegative” APS, those who do not display formal (clinical or laboratory) classification criteria for APS, those with refractory APS despite optimal treatment (recurrent thrombotic events despite optimal anticoagulation or recurrent fetal losses despite the combination of aspirin and low molecular weight heparin), and the treatment of clinical manifestations not included in the classification criteria, such as hematologic manifestations (thrombocytopenia and haemolytic anemia), neurologic manifestations (chorea, myelitis or multiple sclerosis-like lesions), nephropathy and heart valve disease associated with antiphospholipid antibodies. In these cases, the recommendations are based on the common sense since the published evidence is scarce, or it does not exist. In cases of catastrophic APS, an aggressive treatment is required. Therefore, early diagnosis is very important to start adequate therapy and decrease the high mortality rate of these patients. Once the diagnosis is made or suspected, searching and treating the precipitating factor, mainly infection, is the first step of treatment. The specific therapy of catastrophic APS is the combination of anticoagulation with heparin, and corticosteroids as first line of treatment. Additionally adding intravenous immunoglobulins and/or plasma exchange have to be considered in life-threatening cases. In patients with associated SLE, intravenous cyclophosphamide has demonstrated be beneficial. In refractory cases, rituximab or eculizumab should be added.
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.
Some patients with positive antiphospholipid antibodies (aPL) have not been included in randomised clinical trials or observational registries and, therefore, information on their risk of thrombotic ...or obstetric recurrence and optimal treatment is scarce.In this session, the existing evidence regarding the management of two laboratory scenarios not covered by the guidelines is presented: (1) patients with antiphospholipid syndrome (APS) clinical manifestations and anti-phospholipid (aPL) positivity not fulfilling APS laboratory criteria, and (2) the possibility of discontinuing anticoagulation in APS patients whose aPLs become persistently negative.Growing evidence suggests a role for low titres and ‘non-criteria’ aPL, especially in obstetric APS. Treatment is not formally recommended but might be considered according to the individual’s risk profile. Regarding the question of whether or not to discontinue anticoagulants after the ‘spontaneous’ disappearance of aPL, there is no definite answer. Retrospective studies seem to suggest that withdrawal of anticoagulation could be safe in certain patients with APS, especially in those with a first provoked venous thrombosis and whose aPL became persistently negative during follow-up.1 2 Still, before the withdrawal can be recommended in routine clinical practice, multicentre and prospective studies are required to validate this hypothesis.ReferencesTektonidou MG, et al. EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann Rheum Dis 2019;78:1296–1304.Pires Da Rosa G, et al. Management of patients with antiphospholipid antibodies: what to do in laboratory scenarios that do not fit the guidelines. Expert Rev Hematol 2021;14:457–466.Learning ObjectivesExplain the main challenges in managing patients with antiphospholipid antibodies when laboratory scenarios don’t fit guidelinesDescribe the options for the treatment of patients in these scenariosDiscuss new trends in research on new markers for the diagnosis of the antiphospholipid syndrome
The catastrophic antiphospholipid syndrome (CAPS) is a life-threating variant of the antiphospholipid syndrome characterized by the development of multiple thrombosis in a short period of time, ...usually ending up in the failure of function of several vital organs. Most CAPS episodes are related to a prothrombotic situation or precipitating factor such as infections, surgical procedures or malignant diseases. In patients with CAPS, the development of multiple thrombosis leads to an important cytokine release that worsens the already critical patient's situation. The disease usually involves the kidneys, the lungs and the heart, although any organ system can be affected. Although occasionally the disease affects large vessels, in the majority of cases it affects small vessels, leading to a disseminated microangiopathic syndrome resembling thrombotic thrombocytopenic purpura. Treatment is based on the administration of anticoagulants, corticosteroids, plasma exchange and/or intravenous immunoglobulins. Cyclophosphamide is recommended in those CAPS cases associated to systemic lupus erythematosus. Additionally, rituximab and eculizumab have been used in refractory cases. Mortality is still around 30% despite current treatment.
•CAPS is characterized by the development of multiple thrombosis in a short period of time, mainly affecting small vessels.•Most CAPS episodes are related to a precipitating factor such as infections, surgical procedures or malignant diseases.•The disease usually involves the kidneys, the lungs and the heart, although any organ system can be affected.•Treatment is based on the administration of anticoagulants, corticosteroids, plasma exchange and/or intravenous immunoglobulins.•Rituximab and eculizumab have also been used in refractory cases. However, mortality is still around 30% despite treatment.
The catastrophic antiphospholipid syndrome (APS) is a potentially life-threatening condition, the diagnosis of which requires a high degree of clinical awareness on the part of attending physicians. ...Patients with APS present with 1) clinical evidence of multiple organ involvement developed over a very short time; 2) histopathologic evidence of multiple small-vessel occlusions; and 3) laboratory confirmation of the presence of antiphospholipid antibodies, usually in high titer. A combination of anticoagulants, corticosteroids, intravenous immunoglobulins, and plasma exchanges is the basic treatment for all patients with this severe condition. Unfortunately, despite current therapies, the mortality rate is still high (around 30%). However, once patients with catastrophic APS have recovered, they usually follow a stable course with continued anticoagulation and few patients present with a relapse of the catastrophic episode.
Diffuse alveolar hemorrhage (DAH) has been described in a number of systemic autoimmune diseases, including systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), Behçet’s disease, ...microscopic polyarteritis, cryoglobulinaemic vasculitis, Henoch-Schönlein purpura, Goodpasture’s syndrome, granulomatous vasculitis and others.1The potential clinical importance of this complication needs to be stressed. It is likely that the true frequency is significantly higher than the very low prevalence suggested by the paucity of reported cases. Diffuse alveolar hemorrhage syndromes are notoriously difficult to diagnose. In the majority of cases, there is little or no haemoptysis, even with large volume intra-alveolar bleeding. The radiological signs are sometimes florid but often highly non-specific, consisting of amorphous ground-glass attenuation on chest radiography or high-resolution computed scans of the thorax. Invasive or semi-invasive evaluation is generally required, specifically bronchoscopy, with or without a surgical lung biopsy.In general, in treated autoimmune diseases, infiltrative lung disorders can, for practical therapeutic purposes, be divided broadly into opportunistic infection, which demands specific antimicrobial therapy and a reduction in immunosuppression, and a wide range of immunologically mediated processes, which demand the opposite approach: intensification of immunosuppressive therapy. Refinement of the differential diagnosis in the latter group is important, but less important than the exclusion of infection. Bronchoalveolar lavage (BAL) to exclude infection has been the pivotal investigation that has allowed an empirical immunosuppressive approach. A pragmatic approach of standard immunosuppressive therapy after the exclusion of infection is not, in itself, sufficient. Active steps must be taken to diagnose DAH.2Learning ObjectivesExplain the main challenges in the differential diagnosis of alveolar hemorrhage in SLEDescribe the options for the treatment of alveolar hemorrhage in SLEDiscuss new trends in research on new markers for alveolar hemorrhage in SLEReferencesMartínez-Martínez MU, Oostdam DAH, Abud-Mendoza C. Diffuse Alveolar Hemorrhage in Autoimmune Diseases. Curr Rheumatol Rep. 2017;19(5):27.Asherson RA, Cervera R, Wells AU. Diffuse alveolar hemorrhage: a nonthrombotic antiphospholipid lung syndrome?Semin Arthritis Rheum. 2005;35(3):138–42.
Our objective was to update the EULAR recommendations for the management of systemic lupus erythematosus (SLE), based on emerging new evidence. We performed a systematic literature review ...(01/2007-12/2017), followed by modified Delphi method, to form questions, elicit expert opinions and reach consensus. Treatment in SLE aims at remission or low disease activity and prevention of flares. Hydroxychloroquine is recommended in all patients with lupus, at a dose not exceeding 5 mg/kg real body weight. During chronic maintenance treatment, glucocorticoids (GC) should be minimised to less than 7.5 mg/day (prednisone equivalent) and, when possible, withdrawn. Appropriate initiation of immunomodulatory agents (methotrexate, azathioprine, mycophenolate) can expedite the tapering/discontinuation of GC. In persistently active or flaring extrarenal disease, add-on belimumab should be considered; rituximab (RTX) may be considered in organ-threatening, refractory disease. Updated specific recommendations are also provided for cutaneous, neuropsychiatric, haematological and renal disease. Patients with SLE should be assessed for their antiphospholipid antibody status, infectious and cardiovascular diseases risk profile and preventative strategies be tailored accordingly. The updated recommendations provide physicians and patients with updated consensus guidance on the management of SLE, combining evidence-base and expert-opinion.
The objective was to develop evidence-based recommendations for the management of antiphospholipid syndrome (APS) in adults. Based on evidence from a systematic literature review and expert opinion, ...overarching principles and recommendations were formulated and voted. High-risk antiphospholipid antibody (aPL) profile is associated with greater risk for thrombotic and obstetric APS. Risk modification includes screening for and management of cardiovascular and venous thrombosis risk factors, patient education about treatment adherence, and lifestyle counselling. Low-dose aspirin (LDA) is recommended for asymptomatic aPL carriers, patients with systemic lupus erythematosus without prior thrombotic or obstetric APS, and non-pregnant women with a history of obstetric APS only, all with high-risk aPL profiles. Patients with APS and first unprovoked venous thrombosis should receive long-term treatment with vitamin K antagonists (VKA) with a target international normalised ratio (INR) of 2-3. In patients with APS with first arterial thrombosis, treatment with VKA with INR 2-3 or INR 3-4 is recommended, considering the individual's bleeding/thrombosis risk. Rivaroxaban should not be used in patients with APS with triple aPL positivity. For patients with recurrent arterial or venous thrombosis despite adequate treatment, addition of LDA, increase of INR target to 3-4 or switch to low molecular weight heparin may be considered. In women with prior obstetric APS, combination treatment with LDA and prophylactic dosage heparin during pregnancy is recommended. In patients with recurrent pregnancy complications, increase of heparin to therapeutic dose, addition of hydroxychloroquine or addition of low-dose prednisolone in the first trimester may be considered. These recommendations aim to guide treatment in adults with APS. High-quality evidence is limited, indicating a need for more research.
Antiphospholipid syndrome (APS) is an autoimmune disease characterised by vascular thrombosis and pregnancy morbidity in the presence of antiphospholipid antibodies (aPL), mainly lupus anticoagulant ...(LA), anticardiolipin antibodies (aCL) and anti-β2-glycoprotein I antibodies (anti-β2GPI). Precision Medicine can benefit the specific profiles of patients with refractory thrombotic and/or obstetric APS and those with catastrophic APS.Hydroxychloroquine and low-dose steroid, alone or combined, may be an option for pregnant APS patients with a previous pregnancy refractory to conventional therapy. Intravenous immunoglobulins and plasma exchange, alone or combined, could be considered in refractory high-risk pregnant APS patients.1 2 Evidence on the management of recurrent thrombosis despite vitamin K antagonists (VKA) treatment is limited. After evaluating other risk factors for thrombosis (e.g., traditional cardiovascular risk factors, cancer, other thrombophilic states) and investigating the adherence to VKA treatment, increase of target international normalised ratio (INR) to 3–4, or INR 2–3 with the addition of low dose aspirin, or switching to low molecular weight heparin may be considered. Adjunctive therapy with antimalarials or statins could also be considered.Management of catastrophic APS is challenging. The higher recovery rate is achieved by the combination of anticoagulation, plus glucocorticoids, plus plasma exchange and/or intravenous immunoglobulins. New therapeutic approaches include rituximab and eculizumab.Learning ObjectivesExplain the main unmet needs in the management of the APS in SLEDescribe the options for the treatment of refractory thrombotic and obstetric manifestations of APSDiscuss the current recommendations for the management of catastrophic APS casesDiscuss new trends in research on new therapies for APSReferencesTektonidou MG, Andreoli L, Limper M, et al. EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann Rheum Dis 2019:annrheumdis-2019-215213.Rodríguez-Pintó I, Espinosa G, Erkan D, et al. The effect of triple therapy on the mortality of catastrophic anti-phospholipid syndrome patients. Rheumatology (Oxford) 2018;57(7):1264–70.
PDF