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Assessing disease progression

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DMD disease course

Duchenne muscular dystrophy (DMD) is characterised by rapidly weakening muscles and wasting muscle tissue, causing noticeable development and motor function issues as early as 2 years of age. Although there is substantial variability in rates of progression depending on genotype, most patients by the age of 12 develop muscle tightening, and walking may no longer be possible due to spine curvature. In the following years, cardiomyopathy develops and respiratory muscles including the diaphragm are affected and assisted ventilation is needed.1-3 Four common stages may characterise DMD progression: the early and late ambulatory stages (estimated mean age 5.5 years to 7.8 years), and the early and late non-ambulatory stages, which generally occurs after 12 years.4 Age of loss of ambulation, a critical disease milestone, also demonstrates considerable variability across both non-treated (range: 8.6–10.3 years) and corticosteroid-treated patients (range:10.0–13.4 years).5 Cardiac events such as heart failure and arrhythmia are the main causes of death, followed by respiratory failure and infections.6 Reported life expectancy vary across countries, sources, and time periods. A recent meta-analysis reported a median life expectancy of 22.0 years. However, patients born after 1990 had an increased life expectancy of 28.1 years, demonstrating the beneficial effects of corticosteroid therapy.7
Duchenne Disease Progression

Patients with DMD have progressive loss of function 1,8-18

Duchenne Loss of Function

Importance of accurate measurement of progression and treatment outcomes

In DMD, clinicians rely on various tests for assessing disease progression. The progressive nature and the wide phenotype variability that characterise DMD requires sensitive, relevant, valid and reliable tools to assess disease manifestations and predict disease course. Recent advances of care and therapy in DMD underscore a need to identify appropriate outcome measures in ambulant and non-ambulant DMD patients across clinical and research settings.19

Three types of tests are used in DMD to assess physical disease progression across clinical and research settings, including: motor function tests, magnetic resonance spectroscopy (MRS) and muscle strength tests.

Tests assessing motor function

4SC

Four-stair climb (4SC)

The 4SC measures the time taken for the participant to climb four standard stairs. The timed 4SC is considered a valid, reliable, and easily managed measure of motor function. It is useful to assess dynamic balance, functional abilities and falling risk in ambulant children with DMD.19

Slower 4SC correlates with reduced ability to perform activities of daily living and is predictive of declining health related quality of life measures and loss of ambulation (LoA). A > 6-second 4SC is predictive of a greater likelihood of 10% worsening in 6MWD. In addition, a > 8-second 4SC predicts greater likelihood of LoA over 12 months and a treatment effect of 4.7 +/- 7.5 seconds for corticosteroid-treated patients 7 years of age has been demonstrated.20 A 12-month decline in stair-climbing speed of -0.035 tasks/second (where the “task” is all four stairs) results in a clinically meaningful change.21

NSAA

total score

North star ambulatory assessment (NSAA)

The NSAA is a functional motor outcome measure, widely used in clinical practice as well as clinical trials. It is a validated and reliable DMD-specific assessment scale, recognised as a reference outcome measure for assessing the course of the disease from 3-5 years of age until Loss of ambulation (LoA).22 The NSAA is a physiotherapist assessment of lower limb motor function in ambulant children with DMD, consisting of 17 items scored on a scale of 0-2. In the natural course of the disease, the score improves up to the age of six years, followed by an average decline of approximately 3.7 points per year after seven years of age.23,24 The loss of 2.0 NSAA items predicts clinically meaningful disease progression.25 Moreover, complete loss of function in one NSAA item, or decline in 1-2 items, is considered as an important change by patients and parents.23 Higher NSAA scores at baseline are also associated with LoA at an older age and lower scores are directly correlated with increased risk of LoA.23,24

6MWT

6-minute walk test (6MWT)

The 6MWT measures the distance achieved along a 60-metre level course over 6 minutes. It is a well-established outcome measure in a variety of diseases. Although it is a general walk test and not a DMD-specific test, it assesses motor function and endurance, which are key aspects of disease status. The MCID of the 6MWT, assessed in 174 DMD patients, was 28.5 and 31.7 meters based on two statistical distribution methods.21 The 6MWT has demonstrated validity, sensitivity, and reliability for monitoring DMD patients. Moreover, 6MWT correlates with disease progression, and skeletal muscle strength as measured by quantitative knee extension, endurance, and gross motor skills. The test can be used from 5 years of age until loss of ambulation (LoA).27 However, the 6MWT has several limitations including challenges with statistical power due cross-patient variability, impact of age at baseline (improved performance in young patients versus a decline in older patients), and a learning effect i.e., patients tend to get better with practice.22,28,29

TTR

Time to rise/time to stand/supine to stand (TTR/TTS/STS)

TTR measures the time taken to stand up straight from a lying position on the floor. It is a clinically meaningful test of progression and a prognostic factor for time to loss of ambulation (LoA). It has been shown that faster TTR at baseline is significantly associated with an older age at LoA (p < 0.001).24 In addition, a hazard increase of 10% of LoA over the same time for every second increase in the recorded baseline TTR was reported.24 TTR has also been identified as an important prognostic factor of disease progression.26

Test assessing muscle morphology

MRS

Magnetic resonance spectroscopy (MRS) vastus lateralis

Skeletal muscle magnetic resonance spectroscopy (MRS) measures are non-invasive biomarkers sensitive to pathologic changes in dystrophic muscles. The use of imaging techniques has been increasingly explored to detect and track early muscle-related alterations. Skeletal muscle MRS fat fraction analysis measures the shift from muscle tissue to adipose tissue.

Muscle fat fraction, measured by MRS, quantifies the level of fat infiltration, which in turn is inversely correlated with muscle function. Quantitative magnetic resonance (MR) biomarkers have the potential to track disease progression in DMD and serve as clinical trial endpoints. It has been shown that MR measures correlate to functional results over time. Vastus lateralis fat fraction (VLFF) measured by MRS was inversely correlated to muscle function, as determined by ambulation status, 4SC and TTR. 33

Tests assessing muscle strength

Knee extension

Quantitative muscle testing (QMT) can be used longitudinally for assessment of DMD disease status. Measure of knee extension strength is done in a seated position with the knee joint in 90 degrees position, and the maximum extension strength is measured. The average one-year changes are significantly different in DMD patients than those experienced in healthy controls. Correlation between strength tests and other assessments have been shown.34

Elbow extension

Quantitative muscle testing (QMT) of elbow extension can be used in non-ambulant patients. The patient is seated on a chair of a dynamometer with the elbow joint positioned at 90 degrees, and maximum extension strength is measured. Performance of the upper limb (PUL) has shown reliability and correlation with the 6-minute walk test (6MWT) when used in ambulant patients.34

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