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 a proof-of-concept study of
the human anti-IL-6 monoclonal antibody sirukumab
failed to demonstrate superiority of the drug to
placebo in patients with active nephritis. 73 A Phase
I trial of the IL-6 receptor antagonist tocilizumab
showed improved SLE disease activity and decreased
autoantibody production, but the observed dose-
related decreases in absolute neutrophil counts
raised concerns. 74
The importance of the type I IFN pathway in the
pathogenesis of SLE has prompted the investigation
of anti-IFN antibodies as potential drugs. 75 The first
data supporting the efficacy of IFN-α inhibition came
from a Phase IIb trial of sifalimumab; 76 the results
were modest but in favour of sifalimumab. However,
another phase II study of the monoclonal anti-IFN-α
antibody rontalizumab demonstrated superiority
to placebo in patients with low IFN-regulated
gene expression, but not in patients with high IFN
gene signature, 77 contrary to what was expected
considering the biologic mechanism of the drug.
A Phase II trial of the type I IFN receptor antagonist
anifrolumab has been successful, meriting further
development of this agent. Anifrolumab was more
efficacious than placebo, especially in patients
with a high IFN gene signature; however, no dose
response was displayed. 78 Results from ongoing
trials, including a trial in lupus nephritis, are awaited.
Abatacept, a soluble fusion protein comprising
the extracellular domain of the human cytotoxic
T lymphocyte-associated protein 4 (CTLA-4) and
a fragment of the Fc portion of human IgG1, has
also been investigated as a potential treatment
for SLE. T cell activation relies on co-stimulatory
interactions. The interaction of CD80/86 on antigen-
presenting cells with CD28 on T cells is one of
the most important co-stimulatory pathways. The
CLTA-4 molecule is homologous to CD28, but binds
to CD80 and CD86 with higher affinity, resulting
in competitive inhibition of the binding of CD28
to CD80/CD86. Abatacept is approved for use in
rheumatoid arthritis and has also been studied in
other autoimmune diseases. Two randomised clinical
trials in SLE patients have been conducted. Patients
with a current mucocutaneous, musculoskeletal
or serositis flare were included in the first trial; 79
unfortunately, abatacept did not prove more
efficient than placebo. Later discussions raised the
concern whether the choice of the primary endpoint
in this trial concealed the inferiority of abatacept
to placebo.80 The second trial of abatacept in SLE
was a Phase II/III trial comprising 298 patients with
active biopsy-proven proliferative lupus nephritis. 81
The patients were randomised to receive abatacept
or placebo in addition to glucocorticoids and
mycophenolate mofetil. The time to attain complete
response did not differ between the treatment
arms, but greater improvements were seen in
favour of abatacept regarding serologic markers
and proteinuria. Later, a reanalysis with different
definitions of renal response unveiled inferiority of
abatacept to placebo, 82 highlighting that the choice
of outcomes in clinical trials might be determinant
of their success.
Conclusions
The heterogeneity of SLE makes the design of
clinical trials and the choice of adequate outcome
measures challenging. Moreover, sufficient numbers
of SLE patients in clinical trials can only be
guaranteed by joint efforts, for example, within the
frame of international multicentre collaborations.
For these reasons, it is not surprising that drug
development in SLE has not been as expeditious as
in more common and less heterogeneous rheumatic
diseases, such as rheumatoid arthritis.
Towards optimisation of the management of
SLE, it is important that research focuses on: (i) a
better understanding of autoimmunity underlying
clinical phenotypes in order to identify adequate
drug targets; (ii) in depth investigation of the
effects of currently available therapies in order
to improve their use; and (iii) better trial designs,
including the choice of coherent outcome measures.
In order to achieve these goals, it is important to
remain receptive to new classification concepts. For
example, studying new drugs in patients showing
specific clinical patterns rather than in SLE at large
might conceivably result in more homogeneous
study populations. Another example might be
stratification of SLE patients into subsets based
on distinct immunological profiles such as
interferon signature genes or autoantibody
expression patterns.
Last, but not least, the patients’ perspective
should be taken into consideration when studying
drug effects. Self-perceptions of HRQoL, fatigue,
pain and functional disability should be an integral
part of the clinical assessment. A new drug cannot
be considered effective if it does not significantly
improve the patients’ HRQoL.
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