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,
mostly for therapy-resistant lupus nephritis. 38,39
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
patients with SLE failed to show efficacy. 54,55
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
treatments have failed. 38,58–60
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
of targeting BAFF in SLE. 66,67
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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