*2.4.2 Belimumab*

*Lupus - Need to Know*

*2.3.6 Plasmapheresis*

**2.4 Biologics**

*2.4.1 Rituximab*

*2.3.7 Intravenous immunoglobulin*

subgroups of SLE patients [97].

a complex with cyclophilin to block the phosphatase activity of calcineurin. Thus, it decreases the production of inflammatory cytokines by T lymphocytes [75]. Tacrolimus is preferentially used for lupus nephritis as it exhibits fewer side effects and is characterized by better long-term outcome [76]. Tacrolimus is a macrolide antibiotic with immunosuppressive properties. It has a mode of action similar to that of cyclosporin A, although the two drugs are structurally unrelated. It exerts its effects principally through impairment of gene expression in target cells [77]. Tacrolimus bonds to an immunophilin and this complex inhibits calcineurin phosphatase. Tacrolimus inhibits calcium-dependent events, such as interleukin-2 gene transcription, nitric oxide synthase activation, cell degranulation, and apoptosis. It also potentiates the actions of glucocorticoids. It may enhance expression of the transforming growth factor beta-1 gene [78]. T cell proliferation, especially type 1 T helper cell, in response to ligation of the T cell receptor is inhibited by tacrolimus. Tacrolimus has been successfully applied in combination with low-dose MMF and corticosteroids as induction therapy in lupus nephritis [76, 79, 80]. Tacrolimus (0.075 mg/kg/day) has been used in refractory lupus nephritis with good results [81], however severe drug adverse events were observed, such as a high rate of infections and diabetic ketoacidosis. Cyclosporin A (2.6-3.7 mg/kg/day) has also been used in refractory lupus nephritis with good results, however drug adverse events such as tremor and hypertension have been noted [81]. Voclosporin, a novel calcineurin inhibitor is now used in lupus nephritis and is showing promising results [82].

Plasmapheresis has been used successfully in refractory cases of neuropsychiatric lupus [83]. Plasmapheresis has also been applied in pregnant women with active lupus or antiphospholipid syndrome or in cases of lupus nephritis [84]. Immunoadsorption,

Therapeutic intravenous immunoglobulin (IV IG) mostly consists of human polyspecific immunoglobulin G. IV IG has been used in patients with systemic lupus erythematosus and was shown to reduce the activity of the disease [85]. IV IG may be used in cases of refractory neuropsychiatric lupus [83] and in lupus myocarditis [86].

Biologic drugs currently incorporated in SLE treatment are rituximab [87–89] and belimumab [90–93] (**Figure 1**). The sequential use of rituximab and belimumab is also under investigation [94, 95]. Other biologic agents targeting the B lymphocyte have also been applied [96]. Various biologic drugs have been used in treatment regimens for SLE patients with poor response or side effects to standard treatment [97]. The original goal of biologics was to induce disease remission and establish self-tolerance [98, 99]. This goal has not been achieved. It may be that the heterogeneity of disease mechanisms inherent in SLE may guide the introduction of cell- and cytokine- or pathway specific therapies which will be effective in various

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

is replacing plasmapheresis and appears to have good results [84].

**116**

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.
