To determine whether serum BAFF levels correlate with relapse or remission in patients with systemic lupus erythematosus (SLE) following B cell depletion therapy (BCDT) and to assess the relationship between serum BAFF levels, B cell numbers, and immunoglobulin and autoantibody levels during active disease, both before and after BCDT.

Thirty‐five patients with active SLE underwent BCDT with rituximab and were monitored for a minimum of 18 months, using clinical and serologic measures of disease activity. Serum BAFF was measured sequentially by enzyme‐linked immunosorbent assay before BCDT and during disease relapse or remission after B cell repopulation.

Serum BAFF levels prior to BCDT correlated positively with the numbers of CD19+ B cells and with the levels of IgG and IgA. Following BCDT and subsequent B cell repopulation, BAFF levels were significantly higher during relapse, as compared with disease remission, and were significantly greater than at disease flare prior to BCDT. At the time of relapse after BCDT, serum BAFF levels were inversely correlated with B cell numbers, with flare at lower B cell numbers being associated with the highest BAFF levels. The correlations between serum BAFF levels and levels of IgG and IgA were lost following BCDT, but changes in serum BAFF levels correlated positively with changes in anti–double‐stranded DNA (anti‐dsDNA) antibody levels during relapse or remission after BCDT.

The present findings suggest a significant role of BAFF in driving disease flare after B cell repopulation following BCDT. Sequential BCDT may promote ever‐increasing levels of BAFF, accompanied by rising anti‐dsDNA antibody levels and disease flare even at low B cell numbers. Therefore, our data justify the judicious use of BAFF blockade in a subgroup of lupus patients after BCDT.