*2.3.5 Calcineurin inhibitors*

The use of calcineurin inhibitors tacrolimus and cyclosporin A in SLE is derived from the experience of these drugs gained in organ transplantation. These drugs suppress the production of cytokines, inhibit T- and B cell activation and preserve the renal podocyte actin cytoskeleton, thus reducing proteinuria [71]. In non-renal SLE cyclosporin A exhibits steroid-sparing effects, reduces disease activity and flares [72]. Cyclosporin A acts by modulating lymphocyte function [73, 74]. It forms 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].
