A LONGITUDINAL STUDY OF DISEASE PROGRESSION IN FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY (FSHD)

Abstract

Introduction/Aims:

In preparation for clinical trials, it is important to better understand how disease burden changes over time in facioscapulohumeral muscular dystrophy (FSHD) and to assess the capability of select metrics to detect these changes. This study aims to evaluate FSHD disease progression over 1 year and to examine the sensitivity of several outcome measures in detecting changes during this interval.

Methods:

We conducted a 12-month prospective observational study of 41 participants with FSHD. Participants were evaluated at baseline, 6 months, and 12 months with serial strength testing (manual muscle testing or MMT and maximum voluntary isometric contraction testing or MVICT), functional testing (FSHD-Composite Outcome Measure or FSHD-COM, FSHD Clinical Severity Score or CSS, and FSHD Evaluation Score or FES), sleep and fatigue assessments, lean body mass measurements, respiratory testing, and the FSHD-Health Index patient-reported outcome. Changes in these outcome measures were assessed over the 12-month period. Associations between changes in outcome measures and both age and sex were also examined.

Results:

In a 12-month period, FSHD participant function remained largely stable with a mild worsening of strength, measured by MMT and standardized MVICT scores, and a mild loss in lean body mass.

Discussion:

The abilities and disease burden of adults with FSHD are largely static over a 12-month period with participants demonstrating a mild average reduction in some measures of strength. Selection of patients, outcome measures, and trial duration should be carefully considered during the design and implementation of future clinical studies involving FSHD patients.

INTRODUCTION

In preparation for clinical trials involving promising FSHD therapeutics, it is important to have a solid understanding of FSHD disease progression. It is also necessary to identify the traditional and disease-specific clinical outcome assessments that are most capable of measuring changes in health and to determine how these metrics perform longitudinally. ^1–7

To address these needs, we aimed to conduct a study to serially follow a well-defined cohort of patients with a clinical diagnosis of FSHD. We sought to assess numerous metrics traditionally used to determine clinical change in neuromuscular populations as well as several FSHD-specific tools to appraise their responsiveness. In addition, we wanted to conduct exploratory analyses to determine if any demographic features, namely age or sex, are associated with faster or slower FSHD disease progression.

METHODS

Study Participants

Inclusion criteria: 1) clinical diagnosis of FSHD; 2) ages 18 to 75 years old; 3) symptomatic limb weakness; 4) facial muscle weakness; 5) weakness of scapular stabilizers or ankle dorsiflexors; and 6) ability to walk 30 feet without the assistance of another individual.

Exclusion criteria: 1) severe cardiac or respiratory dysfunction; 2) orthopedic conditions precluding safe testing of muscle function; 3) active malignancy; 4) use of muscle anabolic or catabolic agents such as corticosteroids, oral testosterone or derivatives, or oral beta agonists; and 5) ptosis or weakness of extraocular muscles or a muscle biopsy or EMG with features suggesting an alternative diagnosis to FSHD.

Participants were recruited from the neuromuscular subspecialty clinics at the University of Rochester Medical Center (URMC) and Ohio State University (OSU) Wexner Medical Center, and the National Registry for Myotonic Dystrophy (DM) & Facioscapulohumeral Dystrophy (FSHD). ⁸

Local institutional review board approval was obtained at both URMC and OSU Wexner Medical Center. All participants provided informed consent.

Study Design

This study was conducted between May 2013 and November 2016. Participants were evaluated at baseline, 6 months, and 12 months using the following assessments (details provided in the Supplemental Methods):

Strength Testing

Manual Muscle Testing (MMT)

Maximum Voluntary Isometric Contraction Testing (MVICT)

Functional Testing

FSHD-Composite Outcome Measure (FSHD-COM)

FSHD Clinical Severity Score (CSS)

FSHD Evaluation Score (FES)

Sleep and Fatigue Assessments

Epworth Sleepiness Scale (ESS)

Fatigue Severity Scale (FSS)

Patient-Reported Disease Burden

The Facioscapulohumeral Muscular Dystrophy-Health Index (FSHD-HI)

Pulmonary Function Testing

Forced Vital Capacity (FVC)

Assessment of Facial Involvement

Facial Strength Score

Facial Disability Index (FDI)

Statistical Analysis

Paired t-tests were used to assess mean changes in outcome measures from baseline to 6 months and from baseline to 12 months; associated 95% confidence intervals are also reported. Exploratory analyses using two-sample t-tests were performed, comparing male and female participants, and comparing participants equal to or below the mean age and above the mean age of the cohort. These comparisons were made with respect to mean 12-month changes in outcome measures. All analyses were exploratory; p-values are reported for descriptive purposes only and should not be interpreted as indicative of statistical significance.

RESULTS

The cohort of 41 enrolled individuals consisted of predominantly older men with baseline weakness and functional limitations. All individuals had clinical symptoms of FSHD; seventeen individuals were also genetically confirmed, and five individuals had genetically confirmed relatives. All individuals were White and Non-Hispanic. Demographic information, is provided in Table 1. All 41 participants completed the baseline visit, 40 participants completed their 6-month visit, and 39 participants completed their 12-month visit.

Table 1.

Baseline Characteristics of Study Participants

No. of participants	41
Sex, no. (%)
Male	26 (63.4)
Female	15 (36.6)
Age in years
Mean ± SD	53.1 ± 11.6
Years since symptom onset
Mean ± SD	25.7 ± 13.6
Age at diagnosis in years
Mean ± SD	37.7 ± 13.4
Employment status, no. (%)
Employed	25 (61.0)
Retired	9 (22.0)
Disabled	7 (17.0)
Education level, no. (%)
High school	9 (22.0)
Technical school	2 (4.9)
College	19 (46.3)
Graduate school	8 (19.5)
Other	3 (7.3)
Genetic Diagnostics: DNA test, no. (%)
DNA test positive: one allele < 35 kb	14 (34.1)
DNA test indeterminate: one allele > 35–50 kb*	2 (4.9)
DNA test negative: all alleles > 50 kb & methylation test not done*	1 (2.4)
Genetic testing not done (clinical diagnosis)	24 (58.5)
Family history, no. (%)
Affected family members	28 (68.3)
No affected family members	13 (31.7)
Patient-reported initial symptoms, no. (%)
Facial involvement	12 (29.3)
Proximal upper extremity involvement	34 (82.9)
Distal upper extremity involvement	4 (9.8)
Proximal lower extremity involvement	8 (19.5)
Distal lower extremity involvement	8 (19.5)
Someone other than patient noticed problem	1 (2.4)
Lower back	1 (2.4)
Omitted	1 (2.4)

Notes

^*Participant diagnosed with FSHD type 2

Baseline results of all evaluations are described in Supplemental Table 1. Changes from baseline values at 6 months and 12 months are reported in Supplemental Tables 2 and 3, respectively. The average study visit window ± 1 standard deviation was 188 ± 14 days between baseline and 6-month visits and 184 ± 19 days between 6-month and 12-month visits.

Table 2 shows changes in strength, lean body mass, functional, and patient-reported outcomes from baseline to 12 months. Average MMT, average standardized MVICT (total), average standardized MVICT (upper body), and average standardized MVICT (lower body) appeared to worsen slightly for the overall study cohort. DEXA lean body mass also worsened slightly. Figure 1 visually represents the changes in select outcome measures over the study duration.

Table 2.

Changes in Strength, Lean Body Mass, Functional, and Patient-Reported Outcomes from Baseline to 12 Months

Outcome Measure	Mean ± SD change	95% confidence interval	p-value
Average MMT Score	−0.03 ± 0.11	(−0.06, 0.01)	0.11
Average Standardized MVICT Score	−0.43 ± 1.11	(−0.80, −0.06)	0.02
Average Standardized MVICT Score (Upper)	−0.53 ± 1.38	(−0.99, −0.07)	0.03
Average Standardized MVICT Score (Lower)	−0.28 ± 0.90	(−0.59, 0.02)	0.06
DEXA Lean Body Mass	−0.33 ± 1.04	(−0.76, 0.10)	0.12
FSHD-COM	0.27 ± 3.45	(−0.94, 1.47)	0.66
FSHD Clinical Severity Score (CSS)	0.13 ± 1.04	(−0.21, 0.48)	0.44
FSHD Evaluation Score (FES)	0.32 ± 1.21	(−0.08, 0.71)	0.12
FSHD-HI Total Score	−3.03 ± 9.96	(−6.26, 0.20)	0.07

Figure 1.

A) Average MMT Scores and B) Average Standardized MVICT Scores Over 12 Months

Results of age and sex subgroup analyses are provided in Supplemental Tables 4 and 5, respectively. There were no differences based on age in the change of average MMT score over 12 months; however, participants above the mean age of 53.1 years tended to display a greater worsening in average standardized MVICT scores (total, upper, and lower) than individuals below the mean age. There were no differences in average MMT score between 0–12 months based on sex; nonetheless, male participants tended to exhibit a worsening in average standardized MVICT scores (total, upper, and lower body) while female participants were relatively stable in these measures.

DISCUSSION

Our study showed limited progression in FSHD disease burden over a 12-month period, with only mild decrements in strength, which confirms prior understanding of clinical continuation in a year time span in FSHD. ^9,10 Although progressive weakness was detected through MMT and MVICT it could not be consistently ascertained through functional tests, lean body mass, patient-reported disease burden, sleep and fatigue measures, pulmonary function, or facial involvement measures. This highlights the challenge of conducting a clinical trial in a slowly progressive chronic disease.

Prior studies have shown a variable level of progression in FSHD. In a previous natural history study with a well-defined cohort of 81 FSHD patients, decline was noted in composite MMT and MVICT scores, though not in lean body mass, at 12 months. ⁹ In a 6-year retrospective cohort analysis of 313 participants in the NIH-funded National Registry of FSHD Patients and Family Members, patients’ 6-year risk of progression was generally low: 11.9% risk for job modification due to FSHD, 12.4% risk for difficulty swallowing, 15.5% risk for difficulty using arms, and 23.4% risk for disability due to FSHD. ¹⁰ In terms of ambulation, 16.1% of patients progressed to using a cane, 14.4% progressed to using a walker, and 24.0% progressed to using a wheelchair over a 6-year period. ¹⁰ Because of the slow progression of FSHD, future clinical trials may have to demonstrate an improvement with treatment beyond decelerating disease progression or evaluate participants for an extended period of time in order to differentiate treatment from placebo.

Longitudinal studies in FSHD to date have been planned with variable durations; 48 weeks or shorter is common for interventional trials while 1–5 years is common for observational studies. Our assessment falls within this timeframe, and our results provide information that will inform the planning of future clinical studies in FSHD in relation to sample size determination and the need for extended follow-up duration if the goal is only to reduce the rate of disease progression (and not provide a reversal of disease).

Our results should be interpreted with the realization that patients often experience clinical gains through participation in clinical studies, even with no therapeutic intervention. ^11–13 Additionally, learning effects in clinical measures and simple chance with the relatively small sample size may explain some of the variation seen in 0–6 month and 0–12 month measures.

There are certain limitations to this study. Many of our patients (58.5%) were not individually genetically confirmed to have FSHD. Although the majority of participants were referred from a tertiary center with subspecialty expertise in FSHD, misdiagnosis based on FSHD phenotype is not uncommon ¹⁴, and it is, therefore, possible that some participants had clinical but not genetic characteristics consistent with FSHD. Overall, our patients were highly educated and motivated to travel to tertiary medical centers to participate in clinical research, and they satisfied relatively stringent inclusion/exclusion criteria for this study. Furthermore, our study cohort was relatively small, consisting primarily of older, White, non-Hispanic men. Thus, the full spectrum of disease manifestations was likely not fully captured by this sample. The mild decrease in strength observed over 12 months in the overall sample and subgroup differences will require validation in a broader sample of the FSHD population. Nevertheless, our study cohort might be reflective of the subset of the FSHD community that is likely to participate in forthcoming research and clinical trials. Moreover, our investigation importantly demonstrated low attrition despite not having any therapeutic intervention.

This research provides longitudinal data for the FSHD patient and research community. These data can be considered in performing sample size estimations when planning studies in FSHD over a 12-month period. Future studies with larger cohorts are needed to further evaluate how FSHD progresses over a longer time course and in diverse demographic cohorts, in preparation for upcoming clinical trials.

ABBREVIATIONS

CSS

FSHD Clinical Severity Score

DEXA

Dual-energy X-ray absorptiometry

ESS

Epworth Sleepiness Scale

FDI

Facial Disability Index

FES

FSHD Evaluation Score

FVC

Forced Vital Capacity

FSHD

Facioscapulohumeral Muscular Dystrophy

FSHD-COM

FSHD-Composite Outcome Measure

FSHD-HI

FSHD-Health Index

FSS

Fatigue Severity Scale

LBM

Lean Body Mass

MMT

Manual Muscle Testing

MVICT

Maximum Voluntary Isometric Contraction Testing; synonymous with QMT

DATA AVAILABILITY

Any anonymized data not included in the manuscript or supplemental figures will be shared, according to good clinical practice, with qualified investigators upon request.