BAFF Levels After Cyclophosphamide and Mycophenolate Use in Patients With Systemic Lupus Erythematosus

1.3. Research question Flares of lupus nephritis are related to the behavior of BAFF levels before, during, and after induction therapy.

2. Theoretical framework B-cell activating factor (BAFF), also known as B lymphocyte stimulator (BLyS) serves as a vital survival and differentiation factor for normal B-cell development. There is an inverse relationship between BAFF circulating levels and the percentage and number of circulating B cells. APRIL (a proliferation-inducing ligand) shares substantial homology with BAFF and binds to two of the three BAFF receptors (BCMA and TACI) but not to BR3. Like BAFF, APRIL has little role in the maintenance of memory B cells but does promote plasma cell survival better than does BAFF. Both BAFF and APRIL levels behave differently after B cell depletion in SLE and rheumatoid arthritis. BAFF levels have been associated with the development of systemic lupus erythematosus (SLE) in murine models and with clinical activity of SLE in humans. BAFF plays a pathogenic role in SLE in part through T cell-dependent B cell autoantibody production. Treatment strategies involving BAFF blockade haven been studied in patients with SLE inducing overall improvement in disease activity, mainly in musculoskeletal and mucocutaneous domains leading to the approval of Belimumab for the treatment of patients with systemic lupus erythematosus without severe renal or neurological involvement.

Anti-CD20 antibodies (Rituximab), cyclophosphamide (CYC), and mycophenolate (MMF) have all been used for the treatment of systemic lupus erythematosus, and both moderate and severe activity. Both MMF and CYC show a significant effect on disease activity and circulating B, T, Natural Killer cells (NK), and Natural Killer T cells (NKT) cell subsets. Baseline C4 level, early normalization of complement, and reduction in proteinuria have been shown to predict renal response to therapy with MMF or CYC in lupus nephritis. With Rituximab (RTX), B cell depletion has been associated with response to treatment and relapses. The elevation of serum BAFF levels after B cell depletion with RTX in SLE are associated with anti-double-stranded DNA antibody levels and disease flare. The rise of BAFF is probably due to the decrease in its receptors leading to a release of BAFF and a delayed regulation of BAFF messenger-RNA (mRNA) transcription, both of which could favor the re-emergence of autoreactive B cells.

It has been suggested that the rise in BAFF levels after anti-CD20 therapy might be related to flares of the disease and that repeated rituximab infusions can result in a feedback loop characterized by ever-rising BAFF levels, surges in autoantibody production and worsening of the disease. Additionally, the combination of antiCD20 with anti-BAFF or anti-CD4 antibody greatly reduces the number of splenic plasma cells in mouse models and anti-CD20 plus anti-BAFF has been proven to have a lasting benefit both in lupus-prone mice and in mice with established disease.

B-cell depletion therapy (BCDT) has been used in patients with refractory disease with failure to standard therapy through a combination of RTX and CYC, which showed an improvement in clinical and serological disease activity. Serological findings suggest that B cell clones committed to producing antinucleosome antibodies and anti-dsDNA have a relatively rapid turnover compared with cell clones producing other autoantibodies(30). BAFF levels rose in most patients at 3 months post BCDT. Those patients with an expanded autoantibody profile and raised BAFF levels at baseline had shorter responses to BCDT. Retreatment with BCDT may produce a more sustained clinical response.