renal prognosis in patients with lupus nephritis. 11
Based on their atheroprotective effects, antimalarial
agents are expected to be beneficial in SLE patients
at high risk for thrombotic events; for example,
patients with the antiphospholipid syndrome
or high titres of antiphospholipid antibodies.
It is recommended that all SLE patients receive
adequate doses of antimalarial agents unless it is
contraindicated due to, for example, retinopathy.
Glucocorticoids have rapid and powerful anti-
inflammatory and immunosuppressive effects, 12
and are used for most SLE manifestations, from
mild cutaneous disease to life-threatening
conditions, often in combination with other drugs.
Pulse methylprednisolone therapy is commonly used
during severe exacerbations to induce remission,
followed by high doses of oral corticosteroids with
a gradual taper. Low-dose oral corticosteroids are
used in the vast majority of SLE patients as a long-
term remission maintenance therapy. Fortunately,
the glucocorticoid-induced harm has received
increasing recognition in recent years. Apart from
complications, recent indications of harmful effects
of glucocorticoids on SLE itself have contributed to
a scepticism towards the acceptance of long-term
use, and a need for a paradigm shift has emerged. 13
Moderate to severe flares in major organs are
usually managed with an initial induction therapy
using methylprednisolone, cyclophosphamide,
mycophenolate mofetil, or combinations thereof. 14–16
In lupus nephritis, the low-dose regimen proposed
in the Euro-Lupus Nephritis Trial 17 is the most
commonly used cyclophosphamide regimen, and
comprises six pulses of 0.5g cyclophosphamide,
one every second week for a total of three months,
followed by maintenance therapy with azathioprine.
Together with mycophenolate mofetil, this
regimen has replaced the initial high dose NIH
cyclophosphamide protocol, 18–20 mainly because of
severe infections and toxicity concerns, for example,
associations with premature gonadal failure. 21 In
patients with nephritis who have not responded
to this management, the anti-CD20 monoclonal
antibody rituximab may be an alternative. 22
Calcineurin inhibitors have received growing
attention as potential therapeutic agents in
SLE, especially in lupus nephritis. 23 Low doses
of tacrolimus are effective and well tolerated in
patients with renal SLE who have failed treatment
with cyclophosphamide, 24 and an open-label
prospective study showed non-inferiority of
tacrolimus as an induction therapy of active biopsy-
proven nephritis compared with mycophenolate
mofetil and cyclophosphamide. 25 Later, a meta-
analysis of nine studies demonstrated that
tacrolimus was superior to cyclophosphamide but
not to mycophenolate mofetil in inducing complete
renal remission in lupus nephritis. 26 Results from
recent studies of voclosporine are awaited.
In recent years, more targeted therapies have
been investigated, and biological agents have
been used either following approval or as off-
label therapies. Future strategies that may prove
promising include small molecules modifying
intracellular signal pathways, for example, through
targeting Lyn, Syk, PI3Ks and Btk. The proteasome
inhibitor bortezomib, approved for the treatment of
multiple myeloma, was recently shown to improve
the disease activity and reduce the numbers of
peripheral blood and bone marrow plasma cells
in twelve refractory SLE patients. 27 Lupuzor, also
known as P140 peptide and IPP-201101, is a 21-mer
linear peptide originating from the small nuclear
ribonucleoprotein U1-70K, phosphorylated at the
34 | Issue 90 | 2018 | hospitalpharmacyeurope.com
Ser140 position. The mechanism of action of lupuzor
is not fully elucidated, but studies in lupus-prone
mice have shown promising immunomodulatory
effects, 28–33 and a Phase IIb trial evaluating 149 SLE
patients documented greater response rates in patients
receiving lupuzor than in patients receiving placebo. 34
The management
of SLE and the
development of
new therapies
have been
challenging
because of the
prominent
heterogeneity of
the disease and
underlying
immunopathology
Biologics in SLE
Biologic agents have been the focus of research
towards the development of modern therapies. Due
to its important role in B cell homeostasis, BAFF has
been of central interest as a target molecule.
Belimumab is the first drug to be licensed for use
in SLE in more than 50 years, and the first biologic
agent approved for the disease. The efficacy of
belimumab in reducing SLE activity has been shown
in Phase III randomised placebo-controlled clinical
trials. 35,36 Belimumab is a recombinant human IgG1-λ
monoclonal antibody that specifically binds to the
soluble 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