*2.4.1 Rituximab*

Rituximab is a humanized anti-CD20 monoclonal antibody used for B cell depletion therapy. Rituximab can induce killing of CD20+ cells via various mechanisms.

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*2.4.2 Belimumab*

*Novel Therapeutic Interventions in Systemic Lupus Erythematosus*

The effects of rituximab include complement-mediated cytotoxicity and antibodydependent cell-mediated cytotoxicity [100]. Targeting the B cell has been proposed by many research studies in SLE [101]. Results from various registries have shown a favorable benefit-risk ratio in treatment refractory SLE [102, 103]. Rituximab has been shown to be safe and effective in the treatment of non-renal SLE [103]. Namely, it decreases disease activity, immunologic parameters and has a steroid-sparing effect. It can be recommended for organ-specific manifestations, such as arthritis and thrombocytopenia. Rituximab has been shown to be effective for certain refractory SLE patients, in particular refractory neuropsychiatric SLE [104]. Thus, it can be administered in this patient group. The therapeutic effect of rituximab has been compared with that of MMF and with that of cyclophosphamide in a trial of 54 lupus nephritis patients and was shown to be equally effective [105]. B cell depletion is observed but it is not complete, because early B cells and plasma cells do not express CD20 [106]. Normalization of B cell subsets has been observed in rituximab-treated SLE patients [101]. In the initial introduction of rituximab, it was suggested that complete B cell depletion might confer a better outcome for SLE [101]. However, SLE flares were observed after repeated rituximab infusions. These flares were thought to be a result of elevated circulating CD257 (BLyS) levels and high anti-dsDNA levels [107, 108]. Thus, it was proposed that B cell depletion with rituximab induced a surge in CD257 levels that may have exacerbated disease in some SLE patients [106]. In these individuals, rituximab depletion was followed by rapid peripheral B cell reconstitution, with increased circulating plasmablasts. It has been suggested that these plasmablasts might stimulate autoreactive T helper cells, which promote autoantibody production and may drive a positive feedback loop promoting disease activity [106]. Consequently, rituximab is considered in lupus nephritis only after cyclophosphamide and MMF have failed or in relapses [109]. Despite that, an analysis of the LUNAR study showed complete response with rituximab in cases of lupus nephritis [110].

Belimumab, the anti-CD257 monoclonal antibody, acts as a soluble CD257 antagonist and was the first drug approved in more than 50 years by the FDA for SLE [111–118]. The recognition of B cells as central in the pathogenesis of SLE led to the development of drugs that block B cells, including antibodies to B-cell surface antigens, B-cell tolerogens, blockers of co-stimulatory molecules and inhibitors of cytokines with direct effect on B cells [119]. The BAFF/APRIL axis has been thoroughly investigated as these cytokines are vital to B-cell maturation and survival [115, 120, 121]. Belimumab is an anti-BAFF antibody. Belimumab should be considered in extrarenal lupus in patients with inadequate response to hydrochloroquine and corticosteroids and immunosuppressive drugs [122]. Patients with cutaneous and musculoskeletal manifestations are expected to respond better. Belimumab was tested in a study in which it was administered in lupus patients after rituximab [123]. The effects of belimumab on proteinuria and neuropsychiatric SLE were examined in a recent study. It was found that belimumab decreased proteinuria and improved neuropsychiatric symptoms in neuropsychiatric SLE [124]. The US Food and Drug Administration (FDA) has expanded the indication for belimumab to adults with active lupus nephritis who are receiving standard therapy. The expanded indication for belimumab for patients with LN is based on findings from the BLISS-LN phase 3 trial. In this randomized placebo controlled clinical trial on the effect of belimumab on lupus nephritis it was shown that belimumab led more patients to a primary efficacy renal response than placebo and also led to a complete renal response more patients than the placebo [125]. The risk of a renal related

event or death was lower among patients receiving belimumab.

*DOI: http://dx.doi.org/10.5772/intechopen.97168*

#### *Novel Therapeutic Interventions in Systemic Lupus Erythematosus DOI: http://dx.doi.org/10.5772/intechopen.97168*

The effects of rituximab include complement-mediated cytotoxicity and antibodydependent cell-mediated cytotoxicity [100]. Targeting the B cell has been proposed by many research studies in SLE [101]. Results from various registries have shown a favorable benefit-risk ratio in treatment refractory SLE [102, 103]. Rituximab has been shown to be safe and effective in the treatment of non-renal SLE [103]. Namely, it decreases disease activity, immunologic parameters and has a steroid-sparing effect. It can be recommended for organ-specific manifestations, such as arthritis and thrombocytopenia. Rituximab has been shown to be effective for certain refractory SLE patients, in particular refractory neuropsychiatric SLE [104]. Thus, it can be administered in this patient group. The therapeutic effect of rituximab has been compared with that of MMF and with that of cyclophosphamide in a trial of 54 lupus nephritis patients and was shown to be equally effective [105]. B cell depletion is observed but it is not complete, because early B cells and plasma cells do not express CD20 [106]. Normalization of B cell subsets has been observed in rituximab-treated SLE patients [101]. In the initial introduction of rituximab, it was suggested that complete B cell depletion might confer a better outcome for SLE [101]. However, SLE flares were observed after repeated rituximab infusions. These flares were thought to be a result of elevated circulating CD257 (BLyS) levels and high anti-dsDNA levels [107, 108]. Thus, it was proposed that B cell depletion with rituximab induced a surge in CD257 levels that may have exacerbated disease in some SLE patients [106]. In these individuals, rituximab depletion was followed by rapid peripheral B cell reconstitution, with increased circulating plasmablasts. It has been suggested that these plasmablasts might stimulate autoreactive T helper cells, which promote autoantibody production and may drive a positive feedback loop promoting disease activity [106]. Consequently, rituximab is considered in lupus nephritis only after cyclophosphamide and MMF have failed or in relapses [109]. Despite that, an analysis of the LUNAR study showed complete response with rituximab in cases of lupus nephritis [110].
