New Therapies for Systemic Lupus Erythematosus: Cellular Targets

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B cells in systemic lupus erythematosus

Although multiple immunologic abnormalities are important for the development and clinical expression of SLE, increasing evidence strongly points to the B cell as a central player in the immunopathogenesis of this disease [1]. In addition to secretion of autoantibodies, B cells are major antigen-presenting cells that may activate and polarize T cells through cognate interactions, and help regulate and organize inflammatory responses through cytokine and chemokine secretion and regulation of

Rituximab

CD20 is a member of the tetraspan family of integral membrane protein; its precise function in B cells is unknown [34], [35]. CD20 is only produced by B cells and is expressed on immature B cells, naïve B cells, memory B cells, and GC B cells, but not on early pre–B cells or plasma cells. Thus, treatment with an anti-CD20 antibody has the potential to deplete all subsets of B cells except early pre–B cells and plasma cells. Because CD20 expression is restricted to B cells, the clinical and

Efficacy in systemic lupus erythematosus

Leandro and colleagues [39], [40] at University College in London treated over 20 patients who had SLE with rituximab (500–1000 mg × 2) in combination with cyclophosphamide (750 mg × 2) and a brief course of high-dose steroids. These patients were refractory to conventional therapy, which for many included conventional cyclophosphamide therapy or mycophenolate. This regimen was originally proposed and used by Edwards and Cambridge [41] as a means to deplete B cells for the treatment of RA. B

Potential toxicity

Although rituximab has been generally well tolerated, infusion reactions have occurred in patients treated for autoimmune disease and these can be severe [49]. These reactions are similar to the infusion reactions that occur with intravenous immunoglobulin (IVIG), which were best described in 1962 by Brandon and colleagues from the Swiss Red Cross [50]. Their experience with IVIG indicated that although some patients were more sensitive to infusion, sensitivity and nonsensitivity were relative

Effects on B cells

Anolik and colleagues [67] reported the effect of rituximab treatment on the B-cell subsets in SLE. Compared with normal controls, patients who had SLE displayed several abnormalities in peripheral B-cell homeostasis at baseline, including naïve lymphopenia, expansion of a CD27 memory population [68], and expansion of circulating plasmablasts. The investigators found naïve IgD+ CD27 B-cell (naïve B cell) lymphopenia (35% ± 17% SLE versus 68% ± 6% normal controls, P=.008), CD27 memory cell

Mechanism of B-cell depletion

In vitro studies have demonstrated that rituximab can induce antibody-dependant cell-mediated cytotoxicity (ADCC) and complement-mediated cytotoxicity (CMC) [74], [75]. In addition, cross-linking rituximab can induce cell death by apoptosis [76]. It is critical to know which of these three mechanisms of cell killing is important in vivo because alterations of specific amino acids in the Fc region can be used to modify interaction between monoclonal antibodies and Fc receptors and complement.

Other anti-CD20 antibodies

A humanized anti-CD20 monoclonal antibody has been used in a single patient who had SLE [88]. This patient had initially been treated successfully with rituximab, but retreatment failed to deplete B cells and was clinically ineffective. The patient had high levels of HACA (43,500 ng/mL). When severe cytopenias developed (hemoglobin 2.9 and platelets 2000), the patient was treated with hA20, a humanized anti-CD20, steroids, and a single bolus of cyclophosphamide with a good clinical response.

Anti-CD22 antibodies

CD22 is a 135-kDa B-cell–specific sialoglycoprotein. Expression of CD22 is fairly similar to expression of CD20 (ie, CD22 is expressed on B-cell precursors, immature B cells, mature B, and GC B cells, but not on plasma cells). CD22 is phosphorylated after B-cell receptor activation and may modulate signaling and B-cell survival [89], [90]. Epratuzumab is a humanized IgG1 antihuman CD22 monoclonal antibody that has been used in phase 1/2 trials for non-Hodgkin's lymphoma [91]. A pilot study of

Summary

Use of rituximab for the treatment of human SLE appears to be reasonably safe. However, there is evidence that antibody responses to immunization or infection and the normal increase in serum immunoglobulins in very young children may be inhibited. Moreover, the development of late-onset neutropenia after rituximab treatment of lymphoma should alert investigators to be vigilant for similar problems in patients who have autoimmune diseases. Immunoglobulin levels should be monitored and treatment

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