HHE Rheumatology and musculoskeletal supplement 2018 | Page 21

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.
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
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HHE 2018 | hospitalhealthcare.com
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.