The Crohn's Disease-Health Index: Development and Evaluation of a Novel Outcome Measure.

OBJECTIVE: We sought to develop and validate the Crohn's Disease-Health Index (CD-HI), a disease-specific, patient-reported outcome measure that serially measures Crohn's disease (CD) symptomatic burden in adults with CD. BACKGROUND: As therapeutic interventions are tested among patients with CD, responsive outcome measures are needed to track disease progression and therapeutic gain during clinical trials. PATIENTS AND METHODS: We conducted a national cross-sectional study of individuals with CD to identify the most prevalent and impactful symptoms of CD. The most relevant symptoms were included in the CD-HI. We used factor analysis, qualitative patient interviews, test-retest reliability evaluation, and known group validity testing to evaluate and optimize the CD-HI. RESULTS: The CD-HI contains 12 subscales that comprehensively measure CD burden using the patient's perspective. Fifteen adults with CD beta tested the CD-HI and found the instrument to be clear, easy to use, and relevant to them. Twenty-three adults with CD participated in an assessment of test-retest reliability, which indicated high reliability of individual questions, subscales, and the full instrument (intraclass correlation coefficient = 0.84 for the full instrument). The CD-HI and its subscales demonstrated a high internal consistency (Cronbach α = 0.98 for the full instrument). The CD-HI distinguished between groups of individuals with CD known to differ in disease severity. CONCLUSIONS: This research supports the use of the CD-HI as a valid, sensitive, reliable, and relevant patient-reported outcome to determine the multifactorial disease burden of those with CD, assess the relevance and merit of future CD therapies, and support drug labeling claims.

The Facioscapulohumeral Muscular Dystrophy-Health Index: Development and evaluation of a disease-specific outcome measure.

INTRODUCTION/AIMS: As promising therapeutic interventions are tested among patients with facioscapulohumeral muscular dystrophy (FSHD), there is a clear need for valid and reliable outcome tools to track disease progression and therapeutic gain in clinical trials and for clinical monitoring. Our aim was to develop and validate the Facioscapulohumeral Muscular Dystrophy-Health Index (FSHD-HI) as a multifaceted patient-reported outcome measure (PRO) designed to measure disease burden in adults with FSHD. METHODS: Through initial interviews with 20 individuals and a national cross-sectional study with 328 individuals with FSHD, we identified the most prevalent and impactful symptoms in FSHD. The most relevant symptoms were included in the FSHD-HI. We used patient interviews, test-retest reliability evaluation, known groups validity testing, and factor analysis to evaluate and optimize the FSHD-HI. RESULTS: The FSHD-HI contains 14 subscales that measure FSHD disease burden from the patient's perspective. Fourteen adults with FSHD participated in semistructured beta interviews and found the FSHD-HI to be clear, usable, and relevant to them. Thirty-two adults with FSHD participated in test-retest reliability assessments, which demonstrated the high reliability of the FSHD-HI total score (intraclass correlation coefficient = 0.924). The final FSHD-HI and its subscales also demonstrated a high internal consistency (Cronbach α = 0.988). DISCUSSION: The FSHD-HI provides researchers and clinicians with a reliable and valid mechanism to measure multifaceted disease burden in patients with FSHD. The FSHD-HI may facilitate quantification of therapeutic effectiveness, as demonstrated by its use as a secondary and exploratory measure in several clinical trials.

Patient-Reported Impact of Symptoms in Crohn's Disease.

INTRODUCTION: Patients with Crohn's disease (CD) experience a variety of symptoms that significantly affect their lives. In this study, we (i) ascertain the most prevalent and impactful symptoms in CD and (ii) identify modifying factors that are associated with a higher disease burden in CD. METHODS: We conducted semistructured interviews with adult participants with CD to determine what issues have the greatest impact on their lives. Next, we conducted a large cross-sectional study of individuals with CD to determine the prevalence and relative importance of those symptoms and themes and to identify the demographic features that are associated with a higher disease burden. RESULTS: Sixteen individuals with CD provided 792 direct quotes regarding their symptomatic burden. Four hundred three people with CD participated in our cross-sectional study. The symptomatic themes with the highest prevalence in CD were gastrointestinal issues (93.0%), fatigue (86.4%), dietary restrictions (77.9%), and impaired sleep or daytime sleepiness (75.6%). The symptomatic themes that had the greatest impact on patients' lives (0-4 scale) related to fatigue (1.82), impaired sleep or daytime sleepiness (1.71), gastrointestinal issues (1.66), and dietary restrictions (1.61). Symptomatic theme prevalence was strongly associated with a higher number of soft stools per day, greater number of bowel movements per day, missed work, employment and disability status, and having perianal disease. DISCUSSION: Patients with CD experience numerous symptoms that affect their daily life. These symptoms, some underrecognized, vary based on disease and demographic characteristics and represent potential targets for future therapeutic interventions.

Milestones of progression in myotonic dystrophy type 1 and type 2.

INTRODUCTION/AIMS: Disease progression in myotonic dystrophy (DM) is marked by milestone events when functional thresholds are crossed. DM type 2 (DM2) is considered less severe than DM type 1 (DM1), but it is unknown whether this applies uniformly to all features. We compared the age-dependent risk for milestone events in DM1 and DM2 and tested for associations with age of onset and sex. METHODS: We studied a large cohort of adult participants in a national registry of DM1 and DM2. Using annual surveys from participants, we ascertained milestone events for motor involvement (use of cane, walker, ankle brace, wheelchair, or ventilatory device), systemic involvement (diabetes, pacemaker, cancer), loss of employment due to DM, and death. RESULTS: Mean follow-up of registry participants (929 DM1 and 222 DM2 patients) was 7 years. Disability and motor milestones occurred at earlier ages in DM1 than in DM2. In contrast, the risk of diabetes was higher and tended to occur earlier in DM2 (hazard ratio [HR], 0.56; P ≤ .001). In DM1, the milestone events tended to occur earlier, and life expectancy was reduced, when symptoms began at younger ages. In DM1, men were at greater risk for disability (HR, 1.34; P ≤ .01), use of ankle braces (HR, 1.41; P = .02), and diabetes (HR, 2.2; P ≤ .0001), whereas women were at greater risk for needing walkers (HR, 0.68; P = .001) or malignancy (HR, 0.66; P ≤ .01). DISCUSSION: Milestone events recorded through registries can be used to assess long-term impact of DM in large cohorts. Except for diabetes, the age-related risk of milestone events is greater in DM1 than in DM2.

The Spinal Muscular Atrophy Health Index: A novel outcome for measuring how a patient feels and functions.

INTRODUCTION: The Spinal Muscular Atrophy Health Index (SMA-HI) is a multifaceted, disease-specific, patient-reported outcome to measure an SMA patient's perception of their disease burden. In preparation for upcoming therapeutic trials, we examine the validity, reliability, and usability of the SMA-HI in adults, teenagers, and children with SMA. METHODS: Using data from a cross-sectional study of 359 international adult patients with SMA, we identified the most relevant symptoms to include in the SMA-HI. We utilized factor analysis, patient interviews with adults and minors (age 8-15 years), known-group validity testing, and test-retest reliability assessments to evaluate and refine the SMA-HI. RESULTS: The SMA-HI measures overall disease burden and 15 areas of SMA health. Fifteen adult patients and five patients, age 8 to 15 years, participated in semistructured qualitative interviews and found the SMA-HI to be comprehensive, easily completed, and to have clear meaning. The final SMA-HI and its subscales demonstrated good internal consistency (Cronbach α = 0.77-0.96), high test-retest reliability (intraclass correlation coefficient = 0.60-0.96), and an ability to differentiate between SMA groups with different disease severities affecting areas such as employment and ambulation (P < .0001 for both). DISCUSSION: This research provides evidence that the SMA-HI is a valid, relevant, and reliable outcome measure to assess multifaceted patient-reported disease burden in older children, teenagers, and adults with SMA. The SMA-HI provides an opportunity for researchers and clinicians to measure a SMA patient's perception of their health and determine relevant changes in response to therapeutic intervention or disease progression.

Mexiletine in Myotonic Dystrophy Type 1: A Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: To assess mexiletine's long-term safety and effect on 6-minute walk distance in a well-defined cohort of patients with myotonic dystrophy type 1 (DM1). METHODS: We performed a randomized, double-blind, placebo-controlled trial of mexiletine (150 mg 3 times daily) to evaluate its efficacy and safety in a homogenous cohort of adult ambulatory patients with DM1. The primary outcome was change in 6-minute walk distance at 6 months. Secondary outcomes included changes in hand grip myotonia, strength, swallowing, forced vital capacity, lean muscle mass, Myotonic Dystrophy Health Index scores, and 24-hour Holter and ECG results at 3 and 6 months. RESULTS: Forty-two participants were randomized and 40 completed the 6-month follow-up (n = 20 in both groups). No significant effects of mexiletine were observed on 6-minute walk distance, but hand grip myotonia was improved with mexiletine treatment. There were no differences between the mexiletine and placebo groups with respect to the frequency or type of adverse events. Changes in PR, QRS, and QTc intervals were similar in mexiletine- and placebo-treated participants. CONCLUSIONS: There was no benefit of mexiletine on 6-minute walk distance at 6 months. Although mexiletine had a sustained positive effect on objectively measured hand grip myotonia, this was not seen in measures reflecting participants' perceptions of their myotonia. No effects of mexiletine on cardiac conduction measures were seen over the 6-month follow-up period. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for ambulatory patients with DM1, mexiletine does not significantly change 6-minute walk distance at 6 months.

Patient-reported impact of symptoms in Huntington disease: PRISM-HD.

OBJECTIVE: To determine the frequency and relative importance of symptoms experienced by adults with Huntington disease (HD) and to identify factors associated with a higher disease burden. METHODS: We performed 40 qualitative interviews (n = 20 with HD, n = 20 caregivers) and analyzed 2,082 quotes regarding the symptomatic burden of HD. We subsequently performed a cross-sectional study with 389 participants (n = 156 with HD [60 of whom were prodromal], n = 233 caregivers) to assess the prevalence and relative importance (scale 0-4) of 216 symptoms and 15 symptomatic themes in HD. Cross-correlation analysis was performed based on sex, disease duration, age, number of CAG repeats, disease burden, Total Functional Capacity score, employment status, disease status, and ambulatory status. RESULTS: The symptomatic themes with the highest prevalence in HD were emotional issues (83.0%), fatigue (82.5%), and difficulty thinking (77.0%). The symptomatic themes with the highest relative importance to participants were difficulty thinking (1.91), impaired sleep or daytime sleepiness (1.90), and emotional issues (1.81). High Total Functional Capacity scores, being employed, and having prodromal HD were associated with a lower prevalence of symptomatic themes. Despite reporting no clinical features of the disease, prodromal individuals demonstrated high rates of emotional issues (71.2%) and fatigue (69.5%). There was concordance between the prevalence of symptoms reported by manifest individuals and caregivers. CONCLUSIONS: Many symptomatic themes affect the lives of those with HD. These themes have a variable level of importance to the HD population and are identified both by those with HD and by their caregivers.

Correction to: Eight years after an international workshop on myotonic dystrophy patient registries: case study of a global collaboration for a rare disease.

The original version of this article [1] unfortunately included an error to an author's name. Author Jordi Díaz-Manera was erroneously presented as Jorge Alberto Diaz Manera. The correct author name has been included in the author list of this Correction article.

Patient-reported study of the impact of pediatric-onset myotonic dystrophy.

INTRODUCTION: The prevalence and impact of symptoms affecting individuals with pediatric forms of myotonic dystrophy type-1 (DM1) are not well understood. METHODS: Patients from the United States, Canada, and Sweden completed a survey that investigated 20 themes associated with pediatric-onset DM1. Participants reported the prevalence and importance of each theme affecting their lives. Surveys from participants were matched with surveys from their caregivers for additional analysis. RESULTS: The most prevalent symptomatic themes included problems with hands or fingers (79%) and gastrointestinal issues (75%). Problems with urinary/bowel control and gastrointestinal issues were reported to have the greatest impact on patients' lives. Responses from participants and their caregivers had varying levels of agreement among symptomatic themes. DISCUSSION: Many symptoms have meaningful impact on disease burden. The highest levels of agreement between caregivers and individuals with pediatric forms of myotonic dystrophy were found for physical activity themes.

Eight years after an international workshop on myotonic dystrophy patient registries: case study of a global collaboration for a rare disease.

BACKGROUND: Myotonic Dystrophy is the most common form of muscular dystrophy in adults, affecting an estimated 10 per 100,000 people. It is a multisystemic disorder affecting multiple generations with increasing severity. There are currently no licenced therapies to reverse, slow down or cure its symptoms. In 2009 TREAT-NMD (a global alliance with the mission of improving trial readiness for neuromuscular diseases) and the Marigold Foundation held a workshop of key opinion leaders to agree a minimal dataset for patient registries in myotonic dystrophy. Eight years after this workshop, we surveyed 22 registries collecting information on myotonic dystrophy patients to assess the proliferation and utility the dataset agreed in 2009. These registries represent over 10,000 myotonic dystrophy patients worldwide (Europe, North America, Asia and Oceania). RESULTS: The registries use a variety of data collection methods (e.g. online patient surveys or clinician led) and have a variety of budgets (from being run by volunteers to annual budgets over €200,000). All registries collect at least some of the originally agreed data items, and a number of additional items have been suggested in particular items on cognitive impact. CONCLUSIONS: The community should consider how to maximise this collective resource in future therapeutic programmes.

Patient Reported Impact of Symptoms in Spinal Muscular Atrophy (PRISM-SMA).

OBJECTIVE: To determine the frequency and relative importance of symptoms experienced by adults with spinal muscular atrophy (SMA) and to identify factors that are associated with a higher burden of disease in this population. METHODS: We conducted a cross-sectional study of 359 adults with SMA using the International SMA Patient Registry. Participants provided input regarding 20 symptomatic themes and 207 symptoms that potentially affect adults with SMA. Participants were asked about the relative importance of each symptom, and analysis was conducted to determine how age, sex, SMA type, education, mobility, and employment status relate to symptom prevalence. RESULTS: Limitations with mobility or walking (98.6%) and the inability to do activities (98.6%) were the 2 themes with the highest prevalence in the study sample. Limitation with mobility or walking was the theme that was identified as having the greatest effect on the lives of adults with SMA. Employment status was associated with the prevalence of 4 of 20 themes and a reliance on an assistive device was associated with 7 of 20 themes. The prevalence of breathing difficulties, choking or swallowing difficulties, and communication difficulties differed among those with different SMA types. CONCLUSIONS: There are many symptomatic themes that affect the lives of adults with SMA. These themes vary in prevalence and relative importance in the adult SMA population.

Myotonic dystrophy patient preferences in patient-reported outcome measures.

INTRODUCTION: When preparing for clinical trials in myotonic dystrophy type-1 (DM1), it is important that researchers develop and identify patient-reported outcome measures with good measurement properties. METHODS: Fifty-two DM1 patients enrolled in 2 clinical studies completed the Myotonic Dystrophy Health Index (MDHI), 36-Item Short Form Health Survey (version 2; SF-36v2), Individualized Neuromuscular Quality of Life questionnaire (INQoL), and a questionnaire comparing the relevance, usability, overall preference, and perceived responsiveness of each measure. The associations between instrument scores and physical function, genetic test results, and employment status were examined. RESULTS: The MDHI was preferred over the INQoL in 13 of 13 areas and was preferred over the SF-36v2 in 9 of 13 areas. The MDHI was the only score that was associated with participant employment status, CTG repeat length, and the 3 measurements of clinical function. DISCUSSION: The MDHI correlates well with physical function and is viewed favorably by participants in DM1 clinical studies. Muscle Nerve, 2018.

High frequency of gastrointestinal manifestations in myotonic dystrophy type 1 and type 2.

OBJECTIVE: To analyze gastrointestinal (GI) manifestations, their progression over time, and medications being used to treat GI symptoms in a large cohort of patients with myotonic dystrophy types 1 (DM1) and 2 (DM2). METHODS: We analyzed patient-reported data and medical records in a national registry cohort at baseline and 5 years. RESULTS: At baseline, the majority of patients reported trouble swallowing in DM1 (55%; n = 499 of 913) and constipation in DM2 (53%; n = 96 of 180). Cholecystectomy occurred in 16.5% of patients with DM1 and 12.8% of patients with DM2, on average before 45 years of age. The use of medications indicated for gastroesophageal reflux disease was reported by 22.5% of DM1 and 18.9% of patients with DM2. Greater risk of a GI manifestation was associated with higher body mass index and longer disease duration in DM1 and female sex in DM2. At the 5-year follow-up, the most common new manifestations were trouble swallowing in patients with DM1 and constipation in patients with DM2. CONCLUSIONS: GI manifestations were common in both DM1 and DM2, with a relatively high frequency of gallbladder removal in DM1 and DM2 occurring at a younger age compared to normative data in the literature. Studies are needed to determine the pathomechanism of how sex, weight gain, and duration of disease contribute to GI manifestations and how these manifestations affect quality of life and clinical care for patients with DM1 and DM2.

What Matters Most: A Perspective From Adult Spinal Muscular Atrophy Patients.

There are multiple symptoms that affect adults with spinal muscular atrophy (SMA). The extent of these symptoms and their impact on individuals' lives is not fully known. We interviewed 15 adults with genetically confirmed SMA. Participants were asked to identify issues that have significant impact on their lives. Interviews were recorded, transcribed, coded, and analyzed. Participants provided 1045 direct quotes. 177 potential symptoms of importance were identified. Symptoms were grouped by like topics into fourteen symptomatic themes. The symptoms and issues identified by SMA patients alter their physical, mental, and social health and may be amendable to therapeutic intervention.

Medication adherence in patients with myotonic dystrophy and facioscapulohumeral muscular dystrophy.

Myotonic dystrophy (DM) and facioscapulohumeral muscular dystrophy (FSHD) are the two most common adult muscular dystrophies and have progressive and often disabling manifestations. Higher levels of medication adherence lead to better health outcomes, especially important to patients with DM and FSHD because of their multisystem manifestations and complexity of care. However, medication adherence has not previously been studied in a large cohort of DM type 1 (DM1), DM type 2 (DM2), and FSHD patients. The purpose of our study was to survey medication adherence and disease manifestations in patients enrolled in the NIH-supported National DM and FSHD Registry. The study was completed by 110 DM1, 49 DM2, and 193 FSHD patients. Notable comorbidities were hypertension in FSHD (44 %) and DM2 (37 %), gastroesophageal reflux disease in DM1 (24 %) and DM2 (31 %) and arrhythmias (29 %) and thyroid disease (20 %) in DM1. Each group reported high levels of adherence based on regimen complexity, medication costs, health literacy, side effect profile, and their beliefs about treatment. Only dysphagia in DM1 was reported to significantly impact medication adherence. Approximately 35 % of study patients reported polypharmacy (taking 6 or more medications). Of the patients with polypharmacy, the DM1 cohort was significantly younger (mean 55.0 years) compared to DM2 (59.0 years) and FSHD (63.2 years), and had shorter disease duration (mean 26 years) compared to FSHD (26.8 years) and DM2 (34.8 years). Future research is needed to assess techniques to ease pill swallowing in DM1 and to monitor polypharmacy and potential drug interactions in DM and FSHD.

Parent-reported multi-national study of the impact of congenital and childhood onset myotonic dystrophy.

AIM: The frequency and impact of symptoms experienced by patients with congenital, childhood, and juvenile-onset myotonic dystrophy (CDM/ChDM/JDM) is not documented. This report identifies symptomatic areas with the greatest disease burden in an international population of patients with early-onset myotonic dystrophy type-1 (DM1). METHOD: We distributed surveys to parents of patients with CDM/ChDM/JDM. Patients with CDM/ChDM/JDM were members of the US National Registry of DM1 Patients and Family Members, the Canadian Neuromuscular Disease Registry, or the Swedish Health System. Surveys inquired about 325 symptoms and 20 themes associated with CDM/ChDM/JDM. Parents identified the importance of each symptom and theme to their affected child. The prevalence of each symptom and theme were compared across subgroups of patients. The statistical analysis was performed using Fisher's exact and Kruskal-Wallis tests. RESULTS: One hundred and fifty parents returned surveys. The most frequently reported symptomatic themes in children were issues involving communication (81.7%) and problems with hands or fingers (79.6%). Problems with communication and fatigue were the issues that were reported to have the greatest impact on childrens' lives, while 24.1% of children reported cardiac disorders and 15.8% had problems with anesthesia. INTERPRETATION: A range of symptoms contribute to the burden of disease faced by children with DM1. Many of these symptoms are under-recognized.

Myotonic dystrophy health index: Correlations with clinical tests and patient function.

INTRODUCTION: The Myotonic Dystrophy Health Index (MDHI) is a disease-specific patient-reported outcome measure. Here, we examine the associations between the MDHI and other measures of disease burden in a cohort of individuals with myotonic dystrophy type-1 (DM1). METHODS: We conducted a cross-sectional study of 70 patients with DM1. We examined the associations between MDHI total and subscale scores and scores from other clinical tests. Participants completed assessments of strength, myotonia, motor and respiratory function, ambulation, and body composition. Participants also provided blood samples, underwent physician evaluations, and completed other patient-reported outcome measures. RESULTS: MDHI total and subscale scores were strongly associated with muscle strength, myotonia, motor function, and other clinical measures. CONCLUSIONS: Patient-reported health status, as measured by the MDHI, is associated with alternative measures of clinical health. These results support the use of the MDHI as a valid tool to measure disease burden in DM1 patients.

Patient-Reported Impact of Symptoms in Myotonic Dystrophy Type 2 (PRISM-2).

OBJECTIVE: To determine the frequency and relative importance of the most life-affecting symptoms in myotonic dystrophy type 2 (DM2) and to identify the factors that have the strongest association with these symptoms. METHODS: We conducted a cross-sectional study of adult patients with DM2 from a National Registry of DM2 Patients to assess the prevalence and relative importance of 310 symptoms and 21 symptomatic themes. Participant responses were compared by age categories, sex, educational attainment, employment status, and duration of symptoms. RESULTS: The symptomatic themes with the highest prevalence in DM2 were the inability to do activities (94.4%), limitations with mobility or walking (89.2%), hip, thigh, or knee weakness (89.2%), fatigue (89.2%), and myotonia (82.6%). Participants identified the inability to do activities and fatigue as the symptomatic themes that have the greatest overall effect on their lives. Unemployment, a longer duration of symptoms, and less education were associated with a higher average prevalence of all symptomatic themes (p < 0.01). Unemployment, a longer duration of symptoms, sex, and increased age were associated with a higher average effect of all symptomatic themes among patients with DM2 (p < 0.01). CONCLUSIONS: The lives of patients with DM2 are affected by a variety of symptoms. These symptoms have different levels of significance and prevalence in this population and vary across DM2 subgroups in different demographic categories.

The impact of congenital and childhood myotonic dystrophy on quality of life: a qualitative study of associated symptoms.

This study systematically evaluated the symptoms associated with congenital and childhood myotonic dystrophy, and how these symptoms affect health related quality of life. We conducted interviews with patients affected by congenital or childhood myotonic dystrophy and their affected parent to identify which symptoms have the greatest effect on their lives. Each interview was recorded, coded, and analyzed using a qualitative framework technique. In 34 interviews with 13 parents and 21 patients, we identified 189 symptoms, representing 22 themes in physical, emotional, social, and disease-specific quality of life. Communication difficulties, cognitive impairment, and social role limitations were the most frequently identified themes. These interviews identified multiple themes and symptoms, some previously under-recognized, which play a key role in the disease burden associated with congenital and childhood myotonic dystrophy.

Myotonic Dystrophy Health Index: initial evaluation of a disease-specific outcome measure.

INTRODUCTION: In preparation for clinical trials we examine the validity, reliability, and patient understanding of the Myotonic Dystrophy Health Index (MDHI). METHODS: Initially we partnered with 278 myotonic dystrophy type-1 (DM1) patients and identified the most relevant questions for the MDHI. Next, we used factor analysis, patient interviews, and test-retest reliability assessments to refine and evaluate the instrument. Lastly, we determined the capability of the MDHI to differentiate between known groups of DM1 participants. RESULTS: Questions in the final MDHI represent 17 areas of DM1 health. The internal consistency was acceptable in all subscales. The MDHI had a high test-retest reliability (ICC = 0.95) and differentiated between DM1 patient groups with different disease severities. CONCLUSIONS: Initial evaluation of the MDHI provides evidence that it is valid and reliable as an outcome measure for assessing patient-reported health. These results suggest that important aspects of DM1 health may be measured effectively using the MDHI.