Background Elevated levels of the B-cell activating cytokine BAFF (also known as BLyS) have been associated with active systemic lupus erythematosus (SLE), and methotrexate use has been shown to increase soluble BAFF levels. The anti-BAFF monoclonal antibody belimumab has been approved as an add-on to standard-of-care SLE treatment, mainly comprising glucocorticoids, antimalarial agents (AMA) and other immosuppressants. We aimed at investigating the effect of AMA and three other commonly used immunosuppressants in SLE (methotrexate, azathioprine, mycophenolic acid) on serum BAFF levels.
Methods We analysed data from two phase III clinical trials of belimumab, the BLISS-52 (n=865; NCT00424476) and BLISS-76 (n=819; NCT00410384) trials. Access to data was granted by GlaxoSmithKline. Baseline serum samples (before belimumab initiation) were obtained from the patients and stored at −80°C until BAFF level determination using ELISA. The Mann-Whitney U test was used to compare BAFF level distributions between treatment groups. Subsequently, linear regression models were applied to determine independence.
Results BAFF levels were higher in patients receiving methotrexate (mean, SD: 1835, 1617 pg/mL; n=212; p=0.001), azathioprine (mean, SD: 1901, 1472 pg/mL; n=364; p<0.001) and mycophenolic acid (mean, SD: 1994, 1544 pg/mL; n=175; p<0.001) and no immunosuppressant other than the one investigated (AMA allowed) compared with patients receiving no immunosuppressive treatment other than AMA (mean, SD: 1593±1929; n=860). In contrast, patients on AMA displayed lower BAFF levels (mean, SD: 1654, 1318 pg/mL; n=1085) compared with patients who did not use AMA (mean, SD: 1942, 2408 pg/mL; n=580; p=0.002). In linear regression, AMA use showed a consistent and independent association with lower BAFF levels in all models, whereas use of each one of methotrexate, azathioprine and mycophenolic acid showed associations with higher BAFF levels. Each one of the models were adjusted for the use of immunosuppressants other than the one investigated.
Conclusions We observed a differential effect of antimalarial agents and other immunosuppressants on BAFF levels, reflecting the different mechanisms of action of these drugs. Considering the importance of BAFF levels in B-cell homeostasis and the pathogenesis of SLE, these findings should be taken into account in the therapeutic management of SLE and the concomitant administration of different treatments, including BAFF inhibitors.
Funding Source(s): The study was supported by grants from the Swedish Research Council, Professor Nanna Svartz Foundation (2017–00213), Swedish Rheumatism Association, King Gustaf Vs 80 year Foundation, Ingegerd Johanssons Fund, Stockholm County Council and Karolinska Institutet Foundations.
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