Maria G Tektonidou1, Laura Andreoli2, Marteen Limper3, Zahir Amoura4, Ricard Cervera5, Nathalie Costedoat-Chalumeau6, Maria Jose Cuadrado7, Thomas Dörner8, Raquel Ferrer-Oliveras9, Karen Hambly10, Munther A Khamashta11, Judith King12, Francesca Marchiori13, Pier Luigi Meroni14, Marta Mosca15, Vittorio Pengo16, Luigi Raio17, Guillermo Ruiz-Irastorza18, Yehuda Shoenfeld19, Ljudmila Stojanovich20, Elisabet Svenungsson21, Denis Wahl22, Angela Tincani2, Michael M Ward23
Abstract
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.
dx.doi.org/10.1136/annrheum...
Introduction
Antiphospholipid syndrome (APS) is a systemic autoimmune disorder with a wide range of vascular and obstetric manifestations associated with thrombotic and inflammatory mechanisms orchestrated by antiphospholipid (aPL) antibodies. Common APS clinical features include venous thromboembolism, stroke, recurrent early miscarriages and late pregnancy losses.1 According to current laboratory criteria for APS, aPL antibodies can be one of three types: lupus anticoagulant, anticardiolipin antibodies or antibeta2 glycoprotein I antibodies. Definite APS, fulfilling at least one clinical and one laboratory criteria of the updated Sapporo classification criteria, can occur in association with other autoimmune diseases, mainly systemic lupus erythematosus (SLE), or in its primary form (primary APS).1 2 Rarely, a life-threatening form of multiorgan thrombosis, known as catastrophic APS (CAPS), can occur. The presence of aPL in asymptomatic individuals or patients with SLE does not confirm the diagnosis of APS but can be associated with increased risk of thrombosis or pregnancy morbidity, depending on aPL characteristics and coexistence of other risk factors.3 4 The aPL type, the presence of multiple (double or triple) versus single aPL type, their titre (moderate-high titre vs low) and the persistence of aPL positivity in repeated measurements are defined as the ‘aPL profile’. The aPL profile is an important factor determining the risk of thrombotic and obstetric events, and consequently the intensity of treatment.3 4
Clinical practice in APS is highly variable, in part because it is a rare disorder, and because knowledge about its diagnosis/classification, clinical spectrum and management is continuously advancing. There is a great heterogeneity among studies on the laboratory and clinical criteria used to define APS and the treatment approaches used over the past four decades. These factors make it often difficult to know the best approach to apply in daily practice. In addition, there is a paucity of high-quality randomised controlled trials (RCTs) in APS because of the difficulties in conducting adequately sized trials in an uncommon disease and using randomised designs among patients with often devastating clinical presentations. The objective of this project was to develop evidence-based recommendations for the prevention and management of adult APS that will help guide practice and improve quality of care and patient outcomes.
Methods
We followed the updated European League Against Rheumatism (EULAR) standardised operating procedure5 and used the Appraisal of Guidelines for Research & Evaluation II tool.6 The steering committee included the convenor (MGT), co-convenor (AT), methodologist (MMW) and two physicians (LA, ML) responsible for the systematic literature reviews (SLRs) (both were members of the Emerging EULAR Network -(EMEUNET)). The task force included members from 11 European countries: 12 specialists in rheumatology or internal medicine, 2 obstetricians (RF-O, LR), 2 physicians from vascular medicine/thrombosis centres (VP, DW), 1 healthcare professional (KH), and 2 patient representatives (FM, JK).
The convenor prepared the first task force meeting and the first set of research questions on four major topics: risk stratification and risk modification in asymptomatic aPL-positive patients, primary and secondary thromboprophylaxis in APS, management of obstetric APS, and management of CAPS. The research questions were discussed among the task force members, and a set of 31 research questions was formulated using the PICO format (P, population; I, intervention; C, comparator; O, outcomes) and voted according to the Delphi method at a meeting in December 2017.
The data sources for the SLR were PubMed, Embase and the Cochrane Library, which were searched for relevant English-language published articles from their inceptions through 31 January 2018. We included one RCT published after this date because of the importance of its reported safety results (Trial on Rivaroxaban in Antiphospholipid Syndrome (TRAPS) trial).7 Search terms were developed with the aid of an experienced librarian, who performed the searches. All titles and abstracts of retrieved articles were first reviewed independently by the two literature reviewers. The full-text articles were then reviewed independently by three persons: one literature reviewer, convenor and methodologist. The data abstraction was performed by the two literature reviewers according to a written protocol and supervised by the methodologist. Data abstraction was then independently double-checked by the convenor and methodologist. Each included article was graded for its methodological quality and assigned to the relevant PICO question by the convenor and methodologist. Data were tabulated and summarised by the methodologist in an evidence report that included summary of findings tables with pooled estimates of effect sizes for studies that directly addressed the population, intervention and comparator of PICO questions. Based on this evidence, a first draft of recommendations on 12 topics was prepared by the convenor and co-convenor. The draft recommendations and evidence report were sent to all task force members for review prior to the second task force meeting.
The second task force meeting, held on 3 September 2018, included the presentation of SLR results, discussions of the first draft of recommendations in four working groups, working group presentations of the edited draft for each topic, and discussion and voting of the text. Incorporating additional discussions on wording changes, the final set of overarching principles and recommendations, including the level of evidence (LoE) and grade of recommendations (GoR) according to the Oxford Centre for Evidence-Based Medicine standards8 prepared by the methodologist in collaboration with convenors, was sent by the convenor to all task force members, who voted anonymously on the level of agreement (LoA). A rating scale of 0–10 (0: do not agree; 10: fully agree) was used for each recommendation. The manuscript was reviewed and approved by all task force members and the EULAR Executive Committee before submission.
Results
The SLR yielded 7534 articles and 15 hand-searched articles. After the titles and abstracts review, 670 articles were selected for full-text review. The full-text review yielded 249 articles for data abstraction; 61 were excluded and 188 articles were finally considered to be relevant. A detailed presentation of the results of the SLRs that informed the task force recommendations is published separately and should be reviewed together with this report.9 Based on the SLR results and expert opinion, 3 overarching principles and 12 recommendations were developed.
Source: ard.bmj.com/content/early/2...
