BAFF fragment , and prevents the binding of BAFF to its receptors on the surface of B cells . Normally , the binding of BAFF to B cells prolongs their survival and promotes their maturation and differentiation towards immunoglobulin production . 37 BAFF signalling also leads to increases in anti-apoptotic proteins . As defective clearance of apoptotic cells is implicated in the pathogenesis of SLE and the stimulation of autoantibody production , the reductions in anti-apoptotic proteins as a result of BAFF inhibition is expected to hamper this B cell-driven component in the pathogenesis of the disease .
Rituximab is a chimeric anti-CD20 monoclonal antibody , widely used for the treatment of non-Hodgkin lymphoma , rheumatoid arthritis , vasculitis and other autoimmune diseases , and also as an off-label therapy in refractory SLE ,
38 , 39
mostly for therapy-resistant lupus nephritis . Several centres have reported uncontrolled experiences with rituximab for the treatment of severe and refractory SLE , including cohorts of lupus nephritis . 22 , 40 – 50 Studies of refractory renal SLE treated with rituximab combined with cyclophosphamide reported beneficial effects on various outcomes . 22 , 41 , 42 , 51 – 53 However , randomised controlled trials of rituximab treatment in
54 , 55
patients with SLE failed to show efficacy . Despite the negative results of the clinical trials , rituximab has been included in European and American recommendations for the management of renal SLE . 56 , 57 Apart from refractory renal SLE , the use of rituximab has also been documented in other organ manifestations , such as severe arthritis , haematological abnormalities , and
neuropsychiatric SLE when conventional
38 , 58 – 60
treatments have failed .
Atacicept , another biologic agent , which blocks the effects of both BAFF and its homologous molecule APRIL ( a proliferation-inducing ligand ), 61 has also been studied as a candidate drug for SLE . A clinical trial of atacicept in lupus nephritis was terminated prematurely , due to adverse events , that is , hypogammaglobulinaemia and infections . 62 Blisibimod is a fusion protein consisting of four high-affinity BAFF-binding domains and the Fc domain of human IgG1 , targeting both soluble and membrane-bound BAFF . A dose-ranging Phase IIb clinical trial of blisibimob 63 determined a safe and effective dose to further be studied in a Phase III trial , which unfortunately was not successful . Only one of the two Phase III trials of tabalumab , a fully human monoclonal antibody targeting soluble and membrane-bound BAFF , met its primary endpoint , 64 , 65 being the reason why no further development of the drug was planned for SLE . However , no dose-ranging Phase II studies had preceded the Phase III trials , and several outcomes in both trials justify the rationale
66 , 67
of targeting BAFF in SLE .
Phase II 68 and Phase IIb 69 clinical trials of epratuzumab , a humanised monoclonal antibody against CD22 , demonstrated favourable effects on SLE disease activity , prompting the initiation of two Phase III trials , which unfortunately failed to meet their primary clinical efficacy endpoints . 70 Experimental inhibition of IL-6 in murine lupus impedes autoreactive B cell activity and ameliorate nephritis features , 71 , 72 but
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