Timothy Fairchild

Background. Inclusion body myositis (IBM) is the most common acquired skeletal muscle disease associated with ageing and involves both an autoimmune attack on muscle fibres as well as muscle degeneration with protein deposition. There have been multiple studies showing a relationship between exercise and improved outcomes in IBM, however only one prior trial showed a modest benefit of Oxandrolone in IBM. No studies have explored a combination of the two. We hypothesised that a combination of exercise training and testosterone treatment would improve muscle strength and physical activity in males affected by IBM, more than exercise alone.

Methods. This pilot study adopted a double-blinded, placebo-controlled, crossover design to assess whether testosterone combined with a prescribed exercise program would improve measures of muscle strength, physical activity and quality of life in men affected by IBM, over exercise alone. Treatment (exercise and placebo) and placebo (exercise only) arms were 12 weeks in duration, with a two-week wash-out period between arms. Primary outcome was quadriceps strength, measured by isokinetic dynamometer (Humac Norm). Secondary outcomes included lean body mass, functional tests and Patient Reported Outcomes (PROs). Outcome measures were collected at baseline, Week 12 and Week 26. In response to participant feedback, a 12-month Open Label Extension (OLE) was offered, with outcome measures collected at new baseline, 6-months and 12-months.

Results. The primary outcome, quadriceps extension strength the placebo and treatment arms, was non-significant. The DEXA assessment of lean body mass and other functional tests were also non-significant between the placebo and treatment arms. There was a significant reduction of peak torque extension at 60 degrees during the placebo period (p=0.04). Within the SF-36 questionnaire, the domain of ‘role limitations due to emotional problems’ demonstrated higher scores during the testosterone arm when compared to the placebo arm (p=0.044). All other domains, as well as the IBM-FRS, were non-significant. Within the OLE, the 2- minute walk test regular and fast were significant at 6 months (p=0.03 and p=0.032 respectively) but not at 12 months. The most common adverse event reported was falls which were considered a complication of IBM rather than the study. Within the OLE, 3 of the 12 participants withdrew from the study due to adverse events related to rising prostate specific antigen and haematocrit.

Conclusions. In this study comparing exercise alone to exercise in combination of testosterone supplementation, we were unable to detect a significant effect of the treatment on muscle strength, function or quality of life. However, peak torque extension at 60 degrees worsened significantly during the exercise-only arm, which could indicate that testosterone conferred some stabilisation effect during the treatment period. Individuals on testosterone also felt that their daily activities were not as limited due to the emotional problems compared with placebo, perhaps indicating that testosterone contributes to improved mood and mental health. Individuals who participated in the OLE had improved walk tests at 6 months which then declined at 12 months. This warrants further investigation in future studies, where the benefit of testosterone on walking strength may decline after a prolonged period. Finally, we note that 12 men requested the OLE due to perceived positive effects and lack of adverse effects, so potentially the benefits of testosterone require a longer period of intervention to manifest than that applied during the crossover phase.

Background. Idiopathic Inflammatory Myopathies (myositis) are a group of rare neuromuscular diseases. Conditions within this group include Dermatomyositis (DM), Necrotising Myositis (NAM), Polymyositis (PM), Overlap Myositis and the currently untreatable Inclusion Body Myositis (IBM). It is well established that patients within research-active clinical environments have better outcomes and development of effective disease-modifying treatments is dependent on translational, patient-centered research.

Aim: Establishment of a translational research programme within specialist myositis outpatient clinics at Perron Institute for Neurological and Translational Science and Murdoch University (Perth, Australia).

Methods. Facilitated through a significant patient bequest towards myositis re¬search, a laboratory and clinical research programme was founded in 2017 by Professor Merrilee Needham. Appointment of laboratory and clinical research leads supported new workflows where during clinic visits, patients meet with research nurses/coordinators and are provided the opportunity to take part in myositis research, including donating blood and urine samples that are taken directly to the on-site laboratories for analysis. Consented patients are also enrolled in the team’s emerging observational Myositis Registry, and natural history data is collected via questionnaires and outcome measures through our team physiotherapist. At their clinic visit, patients are kept up to date with clinical trial opportunities and research news. For those actively taking part in clinical trials, re¬search visits are often aligned with clinic appointments, increasing convenience and ease of participation. Within our laboratory programme, Lead Scientist Dr Jerome Coudert and his team are characterising the immune profiles, underlying pathways and mechanisms, genetic and metabolic changes of patients over time, as well as performing detailed analyses on blood, urine and muscle samples. A critical element of the research clinic model is keeping patients actively engaged with the research programme. Our patients are kept up to date with current and upcoming projects, advise us of what is important to study next, and are actively participating in project design and review. In recent years, our group has been complimented by an increasing number of higher degree students as well as medical students, across both the clinical and laboratory arms of the programme.

Results. At time of submission, we have over 400 active patients and disease-control participants, with over 2,000 samples collected and biobanked. Our ethical approvals support invitation of participants to take part in future studies based on genotype or phenotype of interest. Our programme has supported five Investigator-Initiated clinical trials over the last 3 years and four commercial clinical trials in myositis. Our highly collaborative approach sees growing national and international collaborative projects and grant applications. In 2020 we received a $1.8M grant from the Australian Government to lead an international, multi-site, Phase 3 trial of Sirolimus in IBM.

Conclusions. Research allows us to offer our patients hope and to partner with them on the journey to finding new treatments and improving quality of life. Our translational programme features a direct and bi-directional pipeline between laboratory and clinical research, built on a solid foundation of observational research projects designed to facilitate future research and treatment trials in myositis.

Background. Sporadic Inclusion body myositis (IBM) is an inflammatory disease that affects skeletal muscles in individuals over the age of 45. It leads to progressive muscle wasting and progressive disability and loss of independence for patients. Histologically, inflammation is characterised by myofibers displaying upregulated expression of major histocompatibility complex (MHC) class I molecules and invasion by immune cells comprising abundant CD8+ T cells. There is currently no cure, and regular exercise is the only recommended treatment recognised to be effective at limiting muscle inflammation and hindering the dis¬ease progression. In healthy men, physical exercise along with administration of testosterone was shown to increase skeletal muscle mass and performance in an additive fashion. Previous studies report that androgens are anti-inflammatory, inhibiting CD4+ T cell differentiation into inflammatory Th1 cells and promoting regulatory T cells. We hypothesised that combining testosterone supplementation with exercise training will reduce the level of autoimmune inflammation better than exercise alone, in men affected by IBM.

Methodology. We conducted a double-blind, placebo-controlled, cross-over randomised controlled trial (RCT) in fourteen men with IBM, to assess whether a period of exercise training using a personalised regime combined with topical application of testosterone, reduced the inflammatory immune response associated with this disease over and above just exercise alone. To assess the intervention efficacy, we analysed the phenotype of immune cells in the blood by flow cytometry, and measured the serum cytokine and chemokine content by Luminex immunoassay.

Results. The testosterone supplementation resulted only in a significant reduction of eosinophil numbers. However, we found additional immunoregulatory effects of the exercise training program over study that were testosterone-independent, including altered proportions of subsets within monocytes, T and B cells, and reduced circulating concentration of several pro-inflammatory cytokines such as IL-12, IL-17, TNF-alpha, MIP-1beta and sICAM-1.

Conclusions. Overall, our findings indicate that regular exercise training impacts the immune response in IBM and provides anti-inflammatory benefits to IBM patients; concomitant testosterone supplementation over a 12-week period provided essentially no anti-inflammatory effect over exercise alone. This work further emphasizes that maintaining a regular level of exercise helps in controlling inflammation in IBM, and also possibly, the pace of progression of the disease toward severe stages. We cannot exclude that incorporating testosterone supple-mentation to exercise training may provide a synergistic anti-inflammatory in IBM, but the optimal duration of intervention and the stage of disease progression when the intervention provides most benefits will need to be further characterised and refined to achieve optimal outcomes.

Diabetes results in hyperglycaemia, due to decreased/absent insulin production or decreased insulin sensitivity. The lack of cellular glucose absorption induces compensatory mechanisms involving carbohydrate and nitrogen metabolism and oxidative stress mechanisms. Metabolomics can provide comprehensive characterisation of molecular pathways and may contribute to understanding me tabolic changes in diabetes. The present study aims to combine experimental design optimisation with multivariate statistical analysis to validate a liver metabolite extraction protocol for the assessment of biomarkers of streptozotocin (STZ)-induced diabetes. Metabolic profiles of livers from STZ-induced diabetic rats and controls (n=8) were investigated with gas chromatography mass spectrometry (GC-MS). The data was further analysed by Principal Component Analysis to compare the metabolite profiles of diabetic and control rats. The analysis revealed an average of 143 ± 12.5 metabolites from the analysed livers. Of these 78 metabolites were positively identified. The two groups showed significant differences in metabolite profiles, including carbohydrates, amino acids, and organic acids. We have identified several relevant metabolites significantly altered in STZ-induced diabetes. These represent metabolites from key metabolic pathways, including gluconeogenesis and the tricarboxylic acid cycle. Metabolites that display significant and specific up or down regulation correspond well to existing data on diabetic metabolism. We have shown that GC-MS is a useful tool for characterising metabolic changes in diabetes. Understanding the biochemical changes occurring in diabetes will aid in the discovery and evaluation of possible treatments and provide a mechanism for further study of the disease itself.