Treatment-induced downregulation of antiphospholipid antibodies: effect of rituximab alone on clinical and laboratory features of antiphospholipid syndrome

Sir, In 2000, a 20-year-old woman came to our attention with aphasia, transitory dysarthria, (CT scan compatible with stroke) and thrombocytopenia (platelet count 29 10/l). Laboratory tests revealed anticardiolipin antibodies (aCL) 328/ 15U/l (ELISA kit Phadia, Uppsala, Sweden, EliA Cardiolipin IgG/IgM, normal value <40 U/l), antibeta-2 glycoprotein I antibodies 104/9U/l (ELISA kit Phadia, Uppsala, Sweden, EliA ß2 Glycoprotein I IgG/IgM, normal value <40U/l), and positivity for lupus anticoagulant (LAC). LAC measurement included: dilute Russell’s viper venom time (dRVVT) (Hemosil, LA-screen/confirm, Instrumentation Laboratory, Lexington, USA), partial thromboplastin time-LA (PTT-LA) (Diagnostica Stago, Asnières, France), silica clotting time (SCT) (HemosIL, DiaPharma Group, Inc. Ohio, USA) and kaolin clotting time (KCT) (homemade, according to Exner). If PTT-LA was prolonged, the hexagonal phospholipid neutralization test was performed as confirmatory (STACLOT-LA, Diagnostica Stago, Asnières, France). A diagnosis of primary antiphospholipid syndrome (APS) was made when antiphospholipid antibody (aPL) positivity was confirmed 3 months later. Therapy with prednisone (50mg/day) and intravenous immunoglobulins (IVIG, 400mg/kg/ day for 5 days) was started, resulting in an increase in platelet count. Oral anticoagulation therapy (OAT) was started when the platelet count reached 60 10/l. Platelet levels increased up to 110 10/l within 4 weeks and remained stable between 130 and 140 10/l for 4 months, when they dropped again to 70 10/l. The patient was then treated with adjusted doses of prednisone (37.5mg/day) and IVIG (400mg/kg/day for five more days). Prednisone treatment was slowly tapered to a daily dose of 7.5mg and finally discontinued in May 2007, when platelet counts were between 120 and 150 10/l. In 2009, the patient presented with a worsening of thrombocytopenia (platelet count 40 10/l) and was treated with the same regime of IVIG, with partial response (platelet count up to 90 10/l). She relapsed within 3 weeks. Splenectomy was not performed due to the high risk of thromboembolic and/or haemorrhagic complications. After ruling out possible contraindications, treatment with rituximab (RTX) was started at the conventional weekly dose of 375mg/m (days 1, 8, 15 and 22). Two more monthly doses after the last infusion (day 22) were administered, based on the protocol we employ for mixed cryoglobulinaemia with good results on long-lasting disease remission. Prednisone treatment (daily dose of 10mg at day 1) was tapered and finally discontinued 4 weeks after first RTX infusion. No other immunosuppressive drugs were associated. Treatment was well tolerated and no side effects were observed. RTX administration led to an increase in the platelet count (Figure 1). In addition, aCL, antibeta2-GPI antibodies and LAC ratio were downregulated (Figure 1). In this case, RTX-induced downregulation of aPL was observed. It was associated with a significant improvement in thrombocytopenia, thus allowing OAT to be administered. Successful amelioration of thrombocytopenia in APS after treatment with immunosuppressive therapy has previously been reported. However, a non-negligible percentage of patients become resistant/non-responsive to immunosuppression, and sometimes splenectomy cannot be performed because of the high risk of bleeding and/or thrombotic events. Some authors have reported that RTX is effective in treating APS and reducing aPL, but drug-induced aPL downregulation remains a challenge. Notably, in a observational study in patients with systemic lupus erythematosus, RTX resulted in a significant reduction in levels of IgG aCL. To our knowledge, this is the first report showing downregulation of aPL after RTX alone in a patient with primary APS who was not treated with immunosuppressive drugs prior to anti-CD20 antibody therapy. Some authors reported a close correlation between aCL titre reduction and an improvement in platelet count in patients with primary APS who were treated with RTX Correspondence to: Dario Roccatello, Centro di Ricerche di Immunopatologia e Documentazione su Malattie Rare (CMID), Struttura Complessa a Direzione Universitaria di Immunologia Clinica, Ospedale Torino Nord Emergenza San G. Bosco ed Università di Torino, Piazza del Donatore di Sangue 3, 10154 Torino, Italy Email: dario.roccatello@unito.it Received 29 September 2010; accepted 17 January 2010