Sporadic inclusion body myositis (sIBM) is the commonest severe myopathy in patients over age 50. Previous therapeutic trials have targeted the inflammatory features of sIBM, but all have failed. Since protein dyshomeostasis may also play a role in sIBM, we tested the effects of targeting this feature of the disease. Using rat myoblast cultures, we found that up-regulation of the heat shock response with Arimoclomol reduced key pathological markers of sIBM in vitro. Furthermore, in mutant valosin-containing protein VCP mice, which develop an inclusion body myopathy (IBM), treatment with Arimoclomol ameliorated disease pathology and improved muscle function. We therefore evaluated the safety and tolerability of Arimoclomol in an investigator-lead, randomised, double-blind, placebo-controlled, proof-of-concept patient trial and gathered exploratory efficacy data which showed that Arimoclomol was safe and well tolerated. Although Arimoclomol improved some IBM-like pathology in vitro and in vivo in the mutant VCP mouse, we did not see statistically significant evidence of efficacy in this proof of concept patient trial.

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The aim of the study was to evaluate the levels of physical activity in individuals with primary Sjögren’s syndrome (PSS) and its relationship to the clinical features of PSS. To this cross-sectional study, self-reported levels of physical activity from 273 PSS patients were measured using the International Physical Activity Questionnaire-short form (IPAQ-SF) and were compared with healthy controls matched for age, sex and body mass index. Fatigue and other clinical aspects of PSS including disease status, dryness, daytime sleepiness, dysautonomia, anxiety and depression were assessed using validated tools. Individuals with PSS had significantly reduced levels of physical activity [median (interquartile range, IQR) 1572 (594–3158) versus 3708 (1732–8255) metabolic equivalent of task (MET) × min/week, p < 0.001], but similar levels of sedentary activity [median (IQR) min 300 (135–375) versus 343 (223–433) (MET) × min/week, p = 0.532] compared to healthy individuals. Differences in physical activity between PSS and controls increased at moderate [median (IQR) 0 (0–480) versus 1560 (570–3900) MET × min/week, p < 0.001] and vigorous intensities [median (IQR) 0 (0–480) versus 480 (0–1920) MET × min/week, p < 0.001]. Correlation analysis revealed a significant association between physical activity and fatigue, orthostatic intolerance, depressive symptoms and quality of life. Sedentary activity did not correlate with fatigue. Stepwise linear regression analysis identified symptoms of depression and daytime sleepiness as independent predictors of levels of physical activity. Physical activity is reduced in people with PSS and is associated with symptoms of depression and daytime sleepiness. Sedentary activity is not increased in PSS. Clinical care teams should explore the clinical utility of targeting low levels of physical activity in PSS.Electronic supplementary materialThe online version of this article (doi:10.1007/s00296-016-3637-6) contains supplementary material, which is available to authorized users.

Background Sporadic inclusion body myositis (IBM) is the commonest idiopathic inflammatory myopathy occurring in patients over the age of 50 years. IBM muscle displays inflammatory and degenerative features. Previous trials have only involved agents directed purely at the inflammatory component of IBM pathology and all were ineffective. Modulating the cytoprotective “heat shock response” (HSR) represents a therapeutic strategy through which the detrimental aspects of both inflammation and degeneration could be dampened. Arimoclomol is an orally administered pharmacological agent that can up-regulate the HSR by amplifying heat shock protein (HSP) expression. Objectives To evaluate the safety and tolerability of arimoclomol in IBM and to gather exploratory efficacy data of arimoclomol in IBM. Methods In this double-blind, placebo-controlled, two-centre (London, UK and Kansas, USA), phase IIa study, 24 patients with IBM were randomised to arimoclomol 100mg TID or placebo (2:1 ratio) over 4 months (as mandated by the FDA), followed by an 8 month follow up period. The primary outcome was adverse event reporting (safety and tolerability). Measures of physical function (IBM functional rating scale (IBMFRS)), muscle strength (manual muscle testing (MMT) and maximum isometric contraction testing (MVICT)) and fat-free mass percentage (measured by dual-energy X-ray absorptiometry (DEXA)) were included as secondary outcome measures. HSP70 levels in muscle biopsy tissue (adjusted to myosin content) before and after the treatment phase were also measured. Mann-Whitney U test was used to compare changes in the arimoclomol and placebo groups at 4 months (IBMFRS, MMT, MVICT, DEXA and HSP70), 8 months (IBMFRS, MMT and MVICT) and 12 months (IBMFRS, MMT, MVICT and DEXA). Results We enrolled 17 men and 7women with a mean age of 66.8±7.5 years and mean disease duration of 8.4±4.3 years. All patients fulfilled the Griggs criteria for definite (42%) or probable (58%) IBM. One serious adverse event was observed in the arimoclomol group (hypertension requiring prolonged hospitalization on the day of the first biopsy). One arimoclomol recipient developed transient hyponatremia. Ophthalmologic examination did not reveal any significant ocular morbidity. Overall, the safety and tolerability profiles were similar between groups. At 8 months, we detected a trend of slower decline in the IBMFRS (-0.68±1.58 vs -2.50±3.31, p=0.055), average MMT (-0.12±0.22 vs -0.26±0.27, p=0.147) and MVICT of right hand grip (1.26±2.63 vs -0.54±1.86, p=0.064) of the arimoclomol group but no differences were seen for changes in the other MVICT scores (left hand grip, left and right quadriceps, and total sum score), DEXA fat free mass percentage and HSP70 levels in the muscle tissue. Conclusions Arimoclomol was safe and well tolerated and demonstrated a preliminary signal for potential therapeutic benefit in patients with IBM. These data support further research of arimoclomol in IBM. Acknowledgements This investigator-initiated trial was funded by Arthr...

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BackgroundInclusion body myopathy with dementia and Paget disease of bone (IBMPFD) and myofibrillar myopathies (MFM) are genetically determined myopathies that can mimic sporadic Inclusion Body Myositis (sIBM), especially if the disease phenotype is incomplete (eg, skeletal muscle involvement only), if there is no family history (either because a mutation arises in the germ line or because the disease in the parents was unrecognised) and if the histological features overlap with those of sIBM. It is therefore possible that some sIBM cases may be caused by undetected mutations in the IBMPFD and MFM causative genes.ObjectiveTo investigate the association of sIBM with mutations in the IBMPFD and MFM causative genes.MethodsTwenty-nine patients with sIBM (meeting diagnostic criteria for definite or probable sIBM according to Griggs) were screened for mutations in the following genes: valosin containing protein (VCP), Desmin (DES), Myotilin (MYOT) and Crystallin alpha-B (CRYAB).ResultsNo pathogenic mutations in the VCP, DES, MYOT and CRYAB genes were detected in this group of sIBM patients.ConclusionThis study provides evidence that common mutations in the VCP, DES, MYOT and CRYAB genes are not associated with the development of sIBM. Our results support current clinical practice in patients with sIBM, which are not usually screened for mutations in these genes, unless there the history or biopsy findings suggest a genetically determined myopathy.

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