HHE Rheumatology and musculoskeletal supplement 2018 | Page 26

A persistent
challenge to
treatment of
IIMs relies on the
elucidation of
their pathogenic
mechanisms,
particularly IBM.
IBM has failed
to respond to
several drugs
currently used
for the treatment
of PM, DM
and IMNM
the transforming growth factor-β (TGF-b)
superfamily including myostatin and activin–
inhibin complex. 25,26 The follistatin role in
regulating various members of the TGF-b family
suggests follistatin as a potential gene therapy for
muscle diseases including muscular dystrophy 24
and IBM. 27 A Phase I clinical trial of follistatin
gene transfer to patients with IBM (NCT01519349)
was recently published. In this ‘proof-of-principle’
trial, six male IBM patients received bilateral
intramuscular quadriceps injections of AAV1
vectors carrying an isoform of follistatin
(FS344). 27 This study observed an improvement
in the 6MWD test and all post-treatment
biopsies showed an increased number of muscle
fibres. However, there were methodological
concerns regarding the use of steroids and an
exercise protocol that may have influenced
study results.
Rapamycin is an mTOR inhibitor that can
deplete T effector cells, preserve T regulatory
cells and induce autophagy, 28 potentially restoring
abnormal protein degradation pathways that are
evident in IBM .29 A randomised, double-blinded
trial of rapamycin for the treatment of IBM
(NCT02481453) was published in abstract
format. 30 At 12 months, the study did not meet
its primary endpoint (quadriceps strength using
quantitative muscle testing), however differences
were observed for several secondary endpoints
namely the 6MWD and MRI fat muscle
replacement. An open phase continuation of this
study is ongoing.
Arimoclomol is an agent that increases heat
shock protein (HSP) expression by prolonging
the main transcription factor of HSP, the heat
shock factor 1 (HSF-1), 31 and showed no effect
in the non-stressed cells. 32 In a small placebo-
controlled pilot safety trial, arimoclomol was
found to be safe and well tolerated in patients
with sIBM. There were trends observed in some
of the secondary clinical outcome measures but
no statistically significant morphological
changes in the repeat muscle biopsies from
arimoclomol-treated patients as compared with
placebo, however, studies in an in vitro cellular
model and mouse model showed improvement
in the pathological and functional deficits
associated with sIBM. 4 A randomised, double-
blinded, Phase II clinical trial of arimoclomol
for the treatment of sporadic IBM is ongoing
(NCT02753530).
Conclusions
A persistent challenge to treatment of IIMs
relies on the elucidation of their pathogenic
mechanisms, particularly IBM. PM, DM and
IMNM reasonably respond to immunosuppressive
therapy with high-dose steroids and steroid-
sparing agents. The new agents currently
being studied in clinical trials target specific
pathogenic mechanisms and are promising for
the treatment of patients with diseases resistant
to the conventional immunosuppressant
treatment. By contrast, IBM has failed
to respond to several drugs currently used for
the treatment of PM, DM and IMNM. The
progress in understanding the pathogenicity
of IBM has allowed promising clinical trials of
drugs involved in the pathogenic mechanism
of IBM.
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