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 placebocontrolled 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, doubleblinded, 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 steroidsparing 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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