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- antibodies, antiphospholipid
- biological therapy
- lupus erythematosus, systemic
- cardiovascular diseases
We read with interest the article by Chatzidionysiou et al,1 which reported a post-hoc analysis of two trials on intravenous belimumab in systemic lupus erythematosus (SLE), showing a significant reduction of antiphospholipid antibodies (aPL) only in patients cotreated with antimalarials.
However, this post-hoc analysis focused on anticardiolipin antibodies (aCL) only, with no data on anti-β2-glycoprotein I (antiβ2GPI) antibodies, which display the best diagnostic/prognostic value in antiphospholipid antibodies syndrome (APS). Moreover, although long-term use of antimalarials was reported to reduce aPL levels by itself,2 no information on the duration of antimalarials cotreatment was reported.1 Interestingly, treatment with belimumab was recently reported to induce aCL and antiβ2GPI disappearance in a small case series of patients with SLE-associated APS.3 We also reported a significant reduction in aCL and antiβ2GPI titres in 12 patients with SLE on belimumab, either alone or associated with antimalarials.4
This study aimed to assess the effect of subcutaneous belimumab (200 mg/week) versus placebo, in association with standard therapy +/- antimalarials, on aCL and antiβ2GPI titers in patients with SLE, using data from the randomised controlled trial "A study of belimumab administered subcutaneously in subjects with systemic lupus erythematosus (SLE)" (BLISS-SC).5
The median values and median per cent change from the baseline levels of IgG/IgM/IgA aCL and antiβ2GPI antibodies were evaluated at 24 and 52 weeks in the BLISS-SC trial5 and compared between treatment arms by the Mann-Whitney test. Analyses were stratified according to the antimalarials cotreatment and its duration.
A total of 249 patients with SLE from the BLISS-SC trial tested positive for aPL using different commercial ELISA kits; 174 received belimumab and 75 placebo; antimalarials were coadministered in 112 and 47 patients, respectively.
A significant reduction in antiβ2GPI IgA titres was observed in the belimumab group as compared with the placebo one (median per cent change of −22.0 vs −4.4, p=0.012) at 24 weeks. A significantly greater median per cent change in the belimumab group was confirmed for antiβ2GPI IgA (−25.6 vs −4.8, p=0.002), and for aCL IgM (−26.7 vs −7.1, p=0.017) at 52 weeks (data not shown). No aPL disappearance was found in the treatment arms. When stratifying the analysis according to antimalarials cotreatment, we found no significant difference in aPL titers reduction between the belimumab and the placebo groups in patients not receiving antimalarials, neither at 24 weeks (data not shown) or 52 weeks (figure 1A,B). Conversely, cotreatment with antimalarials significantly reduced median levels and was associated with a significantly greater change in antiβ2GPI IgA levels in the belimumab +antimalarials group as compared with the placebo +antimalarials group at both 24 weeks (median per cent change of −22.1 vs −2.2,p=0.010) and 52 weeks (−25.7 vs −0.0; p=0.002). Comparable results were found in aCL IgM levels at 52 weeks (−26.7 vs −12.5, p=0.026) as well. Notably, reduction in antiβ2GPI IgA and in aCL IgM titers in the belimumab +antimalarials group was statistically significant only for patients treated with antimalarials for >12 months (figure 1A).
This post-hoc analysis suggests a beneficial synergistic effect of subcutaneous belimumab and antimalarials in reducing not only aCL, but also antiβ2GPI antibody levels. Interestingly, this effect was significant in patients on long-term antimalarials treatment only.
The main limitations of this analysis are the relatively small sample size, and the fact that only data related to two follow-up time points were available, thus, despite the presence of a control group, spontaneous aPL fluctuations over time cannot be excluded.
Nevertheless, aPL are associated with an increased risk of cardiovascular events, which represent the leading cause of mortality in SLE. Since there is evidence that IgA aPL display a predictive value for thrombosis in patients with SLE6 the combined treatment with belimumab and antimalarials is a promising therapeutic tool that deserves further studies.
The authors would like to thank GlaxoSmithKline (Uxbridge, UK) for granting access to data through the Clinical Study Data Request (CSDR) consortium. GE has full access to the data of the study and takes responsibility for their integrity and accuracy of the results reported in this study.
AB and FP contributed equally.
Contributors Concept and design: AB, GE, PLM and SS. Data collection and analysis: FP. Interpretation of data: GE, PLM, DP and SS. Drafting of the manuscript: AB and GE. Critical revision of the manuscript for important intellectual content: all authors. AB and FP equally contributed. DP and PLM share senior contribution.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; internally peer reviewed.
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