Four-year longitudinal study of clinical and functional endpoints in sporadic inclusion body myositis: Implications for therapeutic trials
Introduction
Sporadic inclusion body myositis (sIBM) is the most common acquired inflammatory muscle disease in adulthood after the age of 50 years [1]. The pathological analysis shows the co-existence of auto-immune and degenerative mechanisms within the muscle yet the underlying etiology remains obscure [2] and to date there is no approved treatment [3]. Now several molecules are in sIBM clinical trials to assess safety and efficacy. Designing an efficient clinical trial requires the identification of a reliable outcome measures appropriate to the studied disease. These outcomes should be specific to sIBM since its features differ from the other myositides based on a unique muscular deficit phenotype with slow progression, usually asymmetry, and the absence of extra-muscular involvement. In addition outcome measures must be reliable, clinically meaningful, and sensitive to change.
Precise longitudinal data are of primary importance to construct the statistical analysis plan, including sample size estimation based on expected size of effect relative to precision of endpoints and duration of study. In sIBM, these key data are critically lacking. Recently, three independent studies have demonstrated that knee extension strength is a sensitive marker of disease progression in sIBM on a short term period ranging from 6 to 12 months [4], [5], [6]. The longest reported follow-up was achieved in eight patients in a 4-year-lasting study using manual muscle testing (MMT) [7]. However MMT has limitations in that it produces ordinal data that is not continuous nor scaled. In this study, MMT upper and lower composite scores decreased by 3.5 and 3.6%/year, respectively. Grip strength, as measured by dynamometry, decreased by 10.7%/year. Using the same methods, shorter studies demonstrated slower rate of decline [8], [9]. Clinically meaningfulness of strength, either measured on individual muscles, either averaged from different muscles into composite scores, is not straightforward. The relationships between strength and motor abilities, and their consequences on functional outcome such as the 6-minute walking distance, or activities of daily living have not received much attention. Before starting any therapeutic clinical trial in sIBM, there is thus a critical need to identify and quantify adequate outcome measures through longitudinal natural history studies.
A few years ago, we initiated a study of 22 patients with sIBM. First results were published after a 9-month follow-up [4]. In order to demonstrate that short term changes could be extended in long-term follow-up, we conducted a 48 months evaluation of the same patients. A secondary objective of the study was to validate an inexpensive, portable, fast and simple measure of isometric quantitative knee extension strength, since this outcome measure was reported by our group and others to be a promising indicator of disease progression.
Section snippets
Patients
Twenty-two patients with definite sIBM (based on muscle biopsies) were initially recruited in the first 9-month follow-up study [4] and 20 could be contacted to take part in the study. Thirteen accepted to come back 4 years after initial assessment for an additional comprehensive evaluation. None of them was treated by immunosuppressants nor immunumodulators for their IBM. The protocol was approved by the local Ethics Committee (CPP-Ile de France VI - ID RCB: 2012-A01634-39) and French
Changes over four years
Thirteen patients (6 men, 7 women) accepted a four-year evaluation visit at a mean age of 71.7 ± 7.9 years. Seven patients refused to participate for personal or organizational reasons. Two of them felt depressed and two others felt it was too complicated to organize their travel owing to the fact that they were non-ambulant. Among the participants, one man was non-ambulant and a zero value was assigned to his 6MWD. Except wrist extension and MMT composite score, all the measurements significantly
Discussion
The present study provides the natural history of sporadic inclusion body myositis over 4 years in 13 patients. We demonstrated that almost all the functional measurements (strength and walking ability), along with the clinical scores and scales declined significantly over 4 years in the whole population. When analyzed individually, one patient improved. The different outcomes were highly correlated, linearly or not, but were not equally affected across the different clinical conditions. All the
Conflict of interest
JYH is the inventor of some of the devices used in this study (MyoGrip for which a patent is pending, MyoWrist, MyoAnkle and fixed dynamometer).
Other authors have declared no conflicts of interest.
Acknowledgements
This study was supported by Novartis and the Association Française contre les Myopathies (AFM). The authors would like to thank Amélie Moraux for all fruitful discussions.
References (18)
- et al.
Quadriceps strength is a sensitive marker of disease progression in sporadic inclusion body myositis
Neuromuscul Disord
(2012) - et al.
Longitudinal observational study of sporadic inclusion body myositis: implications for clinical trials
Neuromuscul Disord
(2013) - et al.
Innovative methods to assess upper limb strength and function in non-ambulant Duchenne patients
Neuromuscul Disord
(2013) - et al.
The 2-min walk test is sufficient for evaluating walking abilities in sporadic inclusion body myositis
Neuromuscul Disord
(2014) Epidemiology of neuroimmunological diseases
J Neurol
(2006)- et al.
Inclusion body myositis: a degenerative muscle disease associated with intra-muscle fiber multi-protein aggregates, proteasome inhibition, endoplasmic reticulum stress and decreased lysosomal degradation
Brain Pathol
(2009) - et al.
Long-term observational study of sporadic inclusion body myositis
Brain
(2011) - et al.
Knee extensor strength exhibits potential to predict function in sporadic inclusion-body myositis
Muscle Nerve
(2012) - et al.
Inclusion body myositis in Connecticut: observations in 35 patients during an 8-year period
Medicine (Baltimore)
(2001)
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2022, Neuromuscular DisordersCitation Excerpt :demonstrated a strong correlation between muscle strength by dynamometry (whole body composite score) and IBMFRS (r = 0.883) [7]. Similarly, Hogrel et al. reported a strong correlation between IBMFRS and composite QMT score (r == 0.926) in 13 IBM subjects [9], while Cortese et al. found a moderate correlation between IBMFRS and MMT (r == 0.6) in 51 IBM subjects [8]. The largest study to date (up to 181 IBM patients) by Sangha and colleagues, found strong correlations between IBMFRS and MMT (r == 0.70) and moderate correlations between IBMFRS and MVICT (r == 0.54) [10].
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2021, The Lancet RheumatologyCitation Excerpt :We planned to enrol 44 participants (22 per group). The assumptions used for sample size calculations were based on observational data.23,28 We assumed that the relative change in knee extension strength (expressed as % of the predicted values) at month 12 would be −17% (SD 16%) in the placebo group.
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