Belimumab has therapeutic benefit in active systemic lupus erythematosus (SLE), especially in patients with high-titer anti-dsDNA antibodies. We asked whether the profound B cell loss in belimumab-treated SLE patients is accompanied by shifts in the immunoglobulin repertoire. We enrolled 15 patients who had been continuously treated with belimumab for more than 7 years, 17 matched controls, and 5 patients who were studied before and after drug initiation. VH genes of sort-purified mature B cells and plasmablasts were subjected to next-generation sequencing. We found that B cell-activating factor (BAFF) regulates the transitional B cell checkpoint, with conservation of transitional 1 (T1) cells and approximately 90% loss of T3 and naive B cells after chronic belimumab treatment. Class-switched memory B cells, B1 B cells, and plasmablasts were also substantially depleted. Next-generation sequencing revealed no redistribution of VH, DH, or JH family usage and no effect of belimumab on representation of the autoreactive VH4-34 gene or CDR3 composition in unmutated IgM sequences, suggesting a minimal effect on selection of the naive B cell repertoire. Interestingly, a significantly greater loss of VH4-34 was observed among mutated IgM and plasmablast sequences in chronic belimumab-treated subjects than in controls, suggesting that belimumab promotes negative selection of activated autoreactive B cells.
Interstitial lung disease is one of the most common and severe extra-articular manifestations associated with rheumatoid arthritis. Previous to the biologic treatment era, methotrexate was the medication known to cause acute lung disease mostly in patients with preexisting rheumatoid lung disease. However, recent case reports of patients treated with biologic therapies show an increased incidence of acute lung disease caused by tumor necrosis factor alpha inhibitors. This case will illustrate acute lung disease caused by adalimumab, a recombinant IgG1 monoclonal antibody. The rheumatology community must be aware of this adverse effect described so far with all 3 major tumor necrosis factor alpha inhibitors, before starting but also during maintenance therapy.
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