Remission of proliferative lupus nephritis following B cell depletion therapy is preceded by down‐regulation of the T cell costimulatory molecule CD40 ligand: An open‐label trial

Abstract

Objective. Autoreactive B cells play a key role in tissue injury in systemic autoimmune disease, and therefore a treatment resulting in B cell depletion could have benefit. This open-label study was undertaken to evaluate the efficacy of the anti-CD20 monoclonal antibody rituximab in the treatment of lupus nephritis.Methods. Lupus patients with active proliferative nephritis (4 with focal disease and 6 with diffuse disease) received rituximab (4 weekly infusions of 375 mg/m 2 ) combined with oral prednisolone. Clinical, laboratory, and immunologic responses, including peripheral lymphocyte subsets measured by flow cytometry, were prospectively assessed at monthly intervals for 12 months. Complete remission of nephritis was defined as normal serum creatinine and albumin levels, inactive urine sediment, and 24-hour urinary protein <500 mg. Partial remission was defined as >50% improvement in all renal parameters that were abnormal at baseline.Results. B cell depletion lasted from 1 month to 7 months and was well tolerated. Partial remission was achieved in 8 of 10 patients within a median of 2 months (range 1-4 months); in 5 of them, complete remission was subsequently established (at a median of 3 months from baseline), and it was sustained at 12 months in 4.As early as 1 month from baseline, the expression of the costimulatory molecule CD40 ligand on CD4؉ T cells was decreased by 4-fold, and it was almost blocked when partial remission was clinically evident. The expression of T cell activation markers CD69 and HLA-DR was significantly decreased at time points when partial remission was observed, and was further decreased during complete remission. In contrast, in patients who did not exhibit a response or when relapse was detected in patients in whom an initial remission had been achieved, such decreases were not prominent. Serum concentrations of double-stranded DNA autoantibodies were decreased in all patients, regardless of clinical outcome.Conclusion. Following B cell depletion, clinical remission of lupus nephritis is associated with a decrease in T helper cell activation, suggesting an additional role for B cells, independent of autoantibody production, in promoting disease. A controlled trial to confirm these promising clinical results is warranted.Systemic lupus erythematosus (SLE) is the prototypic autoimmune disease, characterized by multiorgan inflammation and the production of autoantibodies directed against various cellular components. Although many aspects of SLE pathogenesis remain unknown, a key role of B cells has been considered for years. Lupus B cells are characterized by certain alterations in phenotype and receptor levels and forms, abnormalities in protein phosphorylation, clonal expansion, and isotype switching, and somatic gene alterations (1-4). As suggested by the results of several studies, B cells from patients with SLE are hyperreactive due to intrinsic

Histopathologic and clinical outcome of rituximab treatment in patients with cyclophosphamide‐resistant proliferative lupus nephritis

“…The data on B cell depletion obtained in the present study show that patients who had the shortest duration of B cell depletion (2 months) showed a trend toward a less favorable histopathologic outcome (WHO classes V and IV/V) compared with patients who had more longstanding B cell depletion times. Since only 7 patients were studied, it is not possible to draw any firm conclusions from this finding, but similar observations of short B cell depletion times and unresponsiveness to treatment have been described by others (23). Interestingly, a correlation between short B cell depletion times and high numbers of circulating B cells before treatment has also been shown in a larger patient population (44).…”

“…In addition, a simultaneous reduction or disappearance of CD3ϩ and CD4ϩ lymphocyte subpopulations was noted in a majority of the patients. Interestingly, Sfikakis et al (23) recently reported a reduction in T cell subsets as well as T helper cell activation after rituximab treatment, thus demonstrating that B cell depletion not only affects B cell populations but may have other regulatory effects on mediators of inflammation and functions of the immune system. Serum levels of immunoglobulins are generally maintained after rituximab therapy, which further suggests that B lymphocytes in the central lymphoid organs are not eliminated completely and that long-lived plasma cells may maintain antibody production in the bone marrow.…”

“…Reports of the beneficial effects of rituximab in patients with proliferative lupus nephritis have also been published during the last few years (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24).…”

Rituximab and lupus: Good in real life, bad in controlled trials. comment on the article by Lu et al

“…Regarding ethnic factors, the 2 RCTs included American patients, predominantly from the US and Canada, but also from Mexico, Brazil, and Argentina. However, the majority of patients from recent uncontrolled studies were European (1,6,7,9,11,12). This ethnicity is important because some studies have suggested a variable therapeutic response to the main immunosuppressive agents in different ethnic groups (13).…”

B cell autonomous TLR signaling and autoimmunity

“…There is increasing evidence that B cells promote autoimmune disease not only by the production of auto-antibodies but also by serving as APCs for autoreactive T cells and by secretion of cytokines. Accordingly, remission of lupus nephritis after B cell depletion was associated with a decrease in T cell activation in blood (1). Most healthy individuals possess significant numbers of auto-reactive B cells (2) suggesting that additional events promoting alterations in B cell tolerance are required for initiation of autoimmune symptoms.…”