Rituximab therapy for recurrent thromboembolic disease in antiphospholipid syndrome

Sir, Antiphospholipid Syndrome (APS) is an autoimmune disorder characterized clinically by recurrent fetal loss and arterial and venous thrombosis and serologically by persistently positive serum antiphospholipid antibodies (aPL). Recurrent thromboembolic disease due to APS can be a therapeutic challenge. In patients with aPL, recurrent thromboembolic events are common, with recurrence rates as high as 69% over 6 years follow-up. The presence of persistently high titres of anticardiolipin antibodies (IgG> 40 GPLU) and a history of previous thrombosis were independent predictors of thrombotic effects. There have been case reports of the efficacy of rituximab on the clinical manifestations of APS and on reducing the levels of aPL. We describe a case of its use in a patient with APS with recurrent pulmonary embolism (PE) due to poor compliance with anticoagulation. A 19-year-old female, with no past medical history, presented acutely with exertional breathlessness and pleuritic chest pain 4 weeks after an elective termination of pregnancy. D-dimers were raised at 2483 ug/l (0–500). CT pulmonary angiography demonstrated large bilateral proximal pulmonary arterial emboli. A standard thrombophilia screen was unremarkable, except for positive aPL antibodies. She was positive for IgG anticardiolipin antibodies (ACA), to a titre of 87 GPLU (normal range (NR) < 10) and for IgG anti-beta2glycoprotein-1 (anti-ß2-GP-1) antibodies, 49 u/ml (NR < 8). Levels of ACA and anti-ß2-GP-1 antibodies rose to >120 GPLU and >100 u/ml, respectively, on repeat testing 4 months later. Lupus anticoagulant testing was not performed. Anti-nuclear antibody (ANA) screening was positive, 1 : 80 (speckled) and anti-dsDNA antibodies titres were mildly raised (51 u/ml, NR 0–22), but complement levels were normal and there were no clinical features of systemic lupus. Anti-ENA screening against a standard diagnostic panel was negative. She was treated acutely with heparin and was then started on warfarin (target international normalized ratio of 2.5–3.5). Due to poor compliance with treatment and monitoring, she went on to suffer two further episodes of PE over the next 6 months. She was unwilling to undergo long-term heparinization, so was switched to dabigatran (a direct thrombin inhibitor) at a dose of 150mg b.d. , subsequently reduced because of recurrent haemoptysis and menorrhagia. Four months later she suffered a fourth PE, requiring re-admission and a further period of heparinization, which left her with significant breathlessness on mild exertion. Echocardiography demonstrated moderate dilatation of the right atrium and proximal pulmonary arteries. Pulmonary arterial systolic pressure was estimated at 82mmHg. She was restarted on dabigatran and a decision to treat with two infusions of rituximab 1 g, 2 weeks apart, was made. Two months post infusion her ACA titre had fallen to 67 GPLU, and anti-ß2GP-I antibodies to 33 u/ml. Levels of both had fallen to normal by 8 months (Figure 1). A year after rituximab treatment, she has not had any further PEs and her ACA and anti-ß2-GP-I antibodies remain suppressed. She has recently safely negotiated open pulmonary endarterectomy, which has markedly improved her exertional breathlessness. Only a handful of case reports have been published on the use of rituximab in patients with APS. Not all aspects of the pathogenesis of the APS are fully understood, but it seems clear that aPL antibodies, particularly anti-ß2-GP-I, are central to its thromboembolic manifestations through their proinflammatory and pro-coagulant effects on protein C, annexin V, platelets, serum proteases, toll-like receptors and tissue factor, and via impaired fibrinolysis. Current therapies for APS do not target disease-specific antibodies but aim at reducing recurrent thromboembolic events. B cells are likely to be central to the generation of the aPLinduced clinical manifestations of the disease, so could constitute a therapeutic target in APS. A reduction in aPL titres following rituximab has been reported, as has a reduced rate of recurrent thrombotic events in APS patients followed for 10–36 months postrituximab. Lasting reduction in aPL titres has not been consistently observed which may reflect Correspondence to: Jyoti Bakshi, High Wycombe Hospital, Queen Alexandra Road, High Wycombe, Buckinghamshire, HP11 2TT, UK. Email: jb101@doctors.org. uk Received 16 January 2013; accepted 29 April 2013