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The current management of antiphospholipid syndrome (APS) centres on attenuating the procoagulant state while balancing the haemorrhagic risks.1 This approach relies mainly on a thromboprophylaxis strategy rather than targeting pathogenic antiphospholipid antibodies (aPL)-mediated pathways.
Herewith, we report the aPL disappearance in three patients with APS associated to systemic lupus erythematous (SLE) while on treatment with belimumab, potentially paving the way for development of new targeted therapies for APS. Belimumab is a monoclonal antibody that works by blocking the B-lymphocyte stimulator and avoiding B-cell activation.2 It is the first biological drug approved for the treatment of autoantibody positive SLE in active phase and it has shown its capability to reduce the antibodies levels, including anti-double stranded-DNA.3 Intriguingly, in murine models of APS in the setting of SLE, belimumab proved its ability to stop disease progression and to reduce mortality rate.4 However, its use in patients with APS needs further investigation.
After chart-reviewing all the aPL-positive patients with SLE treated in our centre with belimumab, investigating the changes in the aPL profile, we identified three patients with diagnosis of SLE5 and APS (fulfilling Sydney classification criteria)6 and persistent aPL positivity (confirmed in more than six occasions over the previous 5 years before starting belimumab) in whom we observed aPL disappearance. Clinical characteristics are detailed in table 1 and aPL testing methodology is detailed in online supplementary material S1. All patients received belimumab for active SLE (intravenous 10 mg/kg at 2-week intervals for the first three doses and at 4-week intervals thereafter). After 8 months since belimumab was started, Patient #1 became persistently negative for anti-β2-glycoprotein I antibodies (anti-β2GPI), while anticardiolipin antibodies (aCL) titre significantly decreased. While on treatment, anti-β2GPI and aCL levels both turned negative in Patient #2. Interestingly, after being on belimumab for 1 year, she planned a pregnancy and preferred to suspend the treatment, after 8 months since suspension, antiβ2GPI antibodies were detectable again. Patient #3 was persistently negative for aCL while being on belimumab (28 months). When he discontinued the therapy for lack of response, aCL antibodies returned positive after 2 months. Figure 1 illustrates aPL titres of the three patients in relationship with belimumab therapy. Two patients (#1 and #3) persistently tested positive for lupus anticoagulant despite belimumab treatment. No patients experienced hypogammaglobulinaemia while on belimumab and IgG/IgM levels were constantly within normal range. Of note, none of the patients was started on a concomitant immunosuppressive treatment when belimumab was begun. However, a synergic role of hydroxychloroquine in the aCL and anti-β2GPI disappearance cannot be excluded.
Persistent aPL disappearance is a hot topic of discussion in the field of APS, but the clinical significance of sero-negativisation is still to be elucidated.7 8 To the best of our knowledge, despite its limitations (eg, sample size and retrospective design), this pilot study is the first report of aPL negativisation after starting therapy with belimumab. Even more interesting, after stopping the treatment (mean time of 2 months), patients turned to be positive tested for IgG aPL again. The clinical relevance of these findings should be investigated in prospective multicentre studies, but if confirmed, they might modify the therapeutic management of patients with APS . Potentially, the current ‘antithrombotic’ approach to patients with APS will be at least combined in the future with an ‘immunomodulatory’ approach.
SS and ER contributed equally.
Handling editor Josef S Smolen
Contributors ER and SS designed the study, performed data analysis and drafted the manuscript. ER, IC, DR1, MR, DR2 and SS gave a substantial contribution to concept and study design and participated in the interpretation of data. All the authors gave the final approval of the version to be published.
Competing interests None declared.
Patient consent Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
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