Idiopathic inflammatory myopathies (IIM) encompass a spectrum of autoimmune disorders characterized by muscle inflammation, frequently accompanied by extra-muscular manifestations that can affect the skin, lungs, heart, and joints. Patients can be categorised as having dermatomyositis (DM), immune-mediated necrotising myopathy (IMNM), anti-synthetase syndrome (ASS), inclusion body myositis (IBM), and controversial nomenclature subsets such as polymyositis (PM) and overlap myositis. These distinctions are made based on clinical, serological and pathological findings. A major barrier to advancements in the treatment of IIM is the poor understanding of disease pathogenesis. Although clinical and histological differences between subgroups are well recognised, the exact pathological mechanisms driving immune-mediated injury remain poorly defined. These limitations have hampered both the development of a more rigorous disease classification systems, outcome measures, and the development of targeted therapies (Connolly et al., 2024; Rose et al., 2015; Sangha et al., 2021). At present, treatment options are limited by the small number of available therapies, as well as a reliance on eminence-based decision making as opposed to a rigorous evidence base. Furthermore, available therapies are broad and non-specific. There are no validated tools to select treatments, nor biomarkers to predict treatment response (Connolly et al., 2024; Rose et al., 2015; Sangha et al., 2021).
IBM is notoriously distinct from the other forms of IIMs due to its characteristic clinical presentation and refractoriness to current pragmatic therapeutic strategies. Early clinical features of IBM on physical examination are the preferential involvement of finger flexion and knee extension muscle groups, with neck flexion and ankle dorsiflexion also being frequently affected. Dysphagia can be a presenting feature and frequently occurs during the disease course. The disease progresses slowly but relentlessly over time, interfering with all activities of daily living, leading to severe disability, loss of quality of life, and work impairment (Benveniste et al., 2011; Benveniste et al., 2021; Greenberg, 2019; Hanna et al., 2019; Machado et al., 2014; Sangha et al., 2021).
IBM is a rare disease and the epidemiology varies between and within countries, with an estimated overall prevalence of 46 per million (increasing to 97 per million in people older than 30 years, and 139 per million in people older than 50 years) (Callan et al., 2017; Shelly et al., 2021). Still, the prevalence is likely underestimated as the condition is often misdiagnosed and a mean diagnostic delay of around 5 years has been reported (Benveniste et al., 2011; Benveniste et al., 2021; Greenberg, 2019; Hanna et al., 2019; Machado et al., 2014; Sangha et al., 2021). The estimated annual US-cost of care for IBM is US$35000 (Keshishian et al., 2018). The pathophysiology is complex, remains poorly understood and is considered to involve an interaction between inflammatory and degenerative pathways (Machado et al., 2014; McLeish et al., 2022; Naddaf et al., 2018). The degenerative theory of IBM hypothesises that the disease is caused by ageing of muscle fibres associated with accumulation and aggregation of misfolded, ubiquitinated, multiple-protein aggregates in genetically susceptible people. Accumulation of these protein aggregates within muscle fibres is thought to trigger an inflammatory/immune response as a secondary outcome of muscle degeneration (Machado et al., 2014; Machado et al., 2023).
Treatment options in IBM have attempted to target inflammatory, degenerative, and atrophic features of IBM, with large clinical trials having been recently conducted (Benveniste et al., 2021; Hanna et al., 2019; Machado et al., 2023), but without success, which is partly due to the inconsistency and diversity of the patient-reported outcome measures (PROMs) used and problems with the quality of the evidence. There is a need to summarise and critically appraise the efficacy of treatment interventions in IBM.
Many challenges remain in the field of IIM. Better understanding of measurement properties of outcome measures in IIM, the identification of predictors of functional decline in patients with IIM, and the development of a comprehensive model of the impact of the disease are additional contributions that could help move the field forward.
Idiopathic inflammatory myopathies (IIM) are a group of rare autoimmune diseases with a broad spectrum of clinical manifestations, most frequently sharing the feature of immune-mediated muscle injury. Patients can be categorised as having dermatomyositis, immune-mediated necrotising myopathy, anti-synthetase syndrome, inclusion body myositis (IBM), polymyositis or overlap myositis based on characteristic clinical, serological, and pathological findings. IBM is unique among the IIM because of its degenerative component in addition to the inflammatory features. Our objectives and main contributions are: to identify the best evidence on the efficacy of treatment interventions for IBM and to describe their safety; to summarize the measurement properties of outcome measures in IIM; to develop an exploratory multifactorial model that explains the impact of IIM on people's lives; and to identify predictors of functional decline in patients with IIM.
The objectives of this post-Doc project are to:
1. To identify the best evidence on the efficacy of treatment interventions for inclusion body myositis and to describe their safety.
2. To summarize the measurement properties of outcome measures in idiopathic inflammatory myopathies.
3. To develop an exploratory multifactorial model that explains the impact of idiopathic inflammatory myopathies on people's lives.
4. To identify predictors of functional decline in patients with idiopathic inflammatory myopathies.
As the pathophysiology of idiopathic inflammatory myopathies (IIM) is complex and remains poorly understood (Machado et al., 2014; McLeish et al., 2022; Naddaf et al., 2018) and the several treatment options have attempted to target inflammatory, degenerative, and atrophic features (Benveniste et al., 2021; Hanna et al., 2019; Machado et al., 2023), further research is needed to investigate the efficacy and safety of treatment interventions.
A deeper understanding of the impact of the IIM on people's lives is also crucial, allowing therapeutic interventions to be targeted at the areas of most significant impact, making it necessary to create a comprehensive multifactorial model.
A review of all the measuring instruments applicable to outcome measures is necessary for clinical practice and research setting, given the diversity of instruments used and the lack of a gold standard.
Identifying predictors of functional decline in IIM) is vital for treatment planning and prognosis. These markers help clinicians intervene early, potentially halting disease progression and improving patient outcomes. Additionally, they offer insights into disease mechanisms, offering additional guidance to the development of targeted therapies, thereby enhancing patient care and advancing our understanding of IIM.
This project foresees the involvement of some international organizations/associations, as well as university institutions and research centres. Whenever possible, citizens will be involved in the planned research processes and in the planned productivity indicators (articles, abstracts, communications, etc.). It is planned to produce and publish evidence summaries aimed at the citizen as indicators of the project's productivity.
Benveniste, O., Guiguet, M., Freebody, J., Dubourg, O., Squier, W., Maisonobe, T., . . . Hilton-Jones, D. (2011). Long-term observational study of sporadic inclusion body myositis. Brain, 134(Pt 11), 3176-3184. https://doi.org/10.1093/brain/awr213
Benveniste, O., Hogrel, J.-Y., Belin, L., Annoussamy, M., Bachasson, D., Rigolet, A., . . . Allenbach, Y. (2021). Sirolimus for treatment of patients with inclusion body myositis: a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2b trial. The Lancet Rheumatology, 3(1), e40-e48. https://doi.org/10.1016/S2665-9913(20)30280-0
Callan, A., Capkun, G., Vasanthaprasad, V., Freitas, R., & Needham, M. (2017). A Systematic Review and Meta-Analysis of Prevalence Studies of Sporadic Inclusion Body Myositis. J Neuromuscul Dis, 4(2), 127-137. https://doi.org/10.3233/jnd-160198
Connolly, C. M., Gupta, L., Fujimoto, M., Machado, P. M., & Paik, J. J. (2024). Idiopathic inflammatory myopathies: current insights and future frontiers. Lancet Rheumatol, 6(2), e115-e127. https://doi.org/10.1016/S2665-9913(23)00322-3
Greenberg, S. A. (2019). Inclusion body myositis: clinical features and pathogenesis. Nat Rev Rheumatol, 15(5), 257-272. https://doi.org/10.1038/s41584-019-0186-x
Hanna, M. G., Badrising, U. A., Benveniste, O., Lloyd, T. E., Needham, M., Chinoy, H., . . . Amato, A. A. (2019). Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT): a randomised, double-blind, placebo-controlled phase 2b trial. Lancet Neurol, 18(9), 834-844. https://doi.org/10.1016/s1474-4422(19)30200-5
Keshishian, A., Greenberg, S. A., Agashivala, N., Baser, O., & Johnson, K. (2018). Health care costs and comorbidities for patients with inclusion body myositis. Curr Med Res Opin, 34(9), 1679-1685. https://doi.org/10.1080/03007995.2018.1486294
Machado, P. M., Ahmed, M., Brady, S., Gang, Q., Healy, E., Morrow, J. M., . . . Hanna, M. G. (2014). Ongoing developments in sporadic inclusion body myositis. Curr Rheumatol Rep, 16(12), 477. https://doi.org/10.1007/s11926-014-0477-9
Machado, P. M., McDermott, M. P., Blaettler, T., Sundgreen, C., Amato, A. A., Ciafaloni, E., . . . Dimachkie, M. M. (2023). Safety and efficacy of arimoclomol for inclusion body myositis: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol, 22(10), 900-911. https://doi.org/10.1016/s1474-4422(23)00275-2
McLeish, E., Slater, N., Sooda, A., Wilson, A., Coudert, J. D., Lloyd, T. E., & Needham, M. (2022). Inclusion body myositis: The interplay between ageing, muscle degeneration and autoimmunity. Best Pract Res Clin Rheumatol, 36(2), 101761. https://doi.org/10.1016/j.berh.2022.101761
Naddaf, E., Barohn, R. J., & Dimachkie, M. M. (2018). Inclusion Body Myositis: Update on Pathogenesis and Treatment. Neurotherapeutics, 15(4), 995-1005. https://doi.org/10.1007/s13311-018-0658-8
Rose, M. R., Jones, K., Leong, K., Walter, M. C., Miller, J., Dalakas, M. C., . . . Griggs, R. (2015). Treatment for inclusion body myositis. Cochrane Database Syst Rev, 7(6), Cd001555. https://doi.org/10.1002/14651858.CD001555.pub5
Sangha, G., Yao, B., Lunn, D., Skorupinska, I., Germain, L., Kozyra, D., . . . Machado, P. M. (2021). Longitudinal observational study investigating outcome measures for clinical trials in inclusion body myositis. J Neurol Neurosurg Psychiatry. https://doi.org/10.1136/jnnp-2020-325141
Shelly, S., Mielke, M. M., Mandrekar, J., Milone, M., Ernste, F. C., Naddaf, E., & Liewluck, T. (2021). Epidemiology and Natural History of Inclusion Body Myositis: A 40-Year Population-Based Study. Neurology, 96(21), e2653-e2661. https://doi.org/10.1212/WNL.0000000000012004
31/05/2024
31/05/2026
Self-care and health-disease