Exploring hand and upper limb function in patients with inclusion body myositis (IBM).

Inclusion body myositis (IBM) is an inflammatory myopathy characterized by progressive weakness of knee extensors and finger flexors. Many patients lose independence with fine motor tasks; however, a gap remains as to how these deficits correlate with performance on functional outcome measures. We describe functional hand impairments as measured by performance-based outcome measures in a cross-sectional sample of 74 patients with IBM. Subjects completed a series of outcome measures (Functional Dexterity Test (FDT), Performance of the Upper Limb (PUL), and Sollerman Hand Function Test (SHFT)) alongside a collection of patient reported outcomes (PROs). Assessments were compared to standard IBM measurements, including grip strength and IBM Functional Rating Scale (IBMFRS). FDT and SHFT demonstrated significant correlations to grip (p<0.001; Spearman correlations r=0.48-0.70). Significant correlation was found between all functional outcome measures and IBMFRS (p<0.001; Spearman correlations r=0.51-0.77), as well as PRO Upper Extremity Scale for IBM (IBM-PRO) (p<0.05; Spearman correlations r=0.55-0.73). Non-ambulatory patients demonstrated significantly weaker grip (p<0.001), resulting in lower PUL scores and increased FDT completion times (p<0.001). Collectively, these assessments may provide insight to understanding functional limitations of the hands and potentially allow for more inclusive clinical trials with future validation of hand assessments in IBM.

LGMDD1 natural history and phenotypic spectrum: Implications for clinical trials.

OBJECTIVE: To delineate the full phenotypic spectrum and characterize the natural history of limb girdle muscular dystrophy type D1 (LGMDD1). METHODS: We extracted age at clinical events of interest contributing to LGMDD1 disease burden via a systematic literature and chart review. Manual muscle testing and quantitative dynamometry data were used to estimate annualized rates of change. We also conducted a cross-sectional observational study using previously validated patient-reported outcome assessments (ACTIVLIM, PROMIS-57) and a new LGMDD1 questionnaire. Some individuals underwent repeat ACTIVLIM and LGMDD1 questionnaire assessments at 1.5 and 2.5 years. RESULTS: A total of 122 LGMDD1 patients were included from 14 different countries. We identified two new variants (p.E54K, p.V99A). In vitro assays and segregation support their pathogenicity. The mean onset age was 29.7 years. Genotype appears to impact onset age, weakness pattern, and median time to loss of ambulation (34 years). Dysphagia was the most frequent abnormality (51.4%). Deltoids, biceps, grip, iliopsoas, and hamstrings strength decreased by (0.5-1 lb/year). Cross-sectional ACTIVLIM and LGMDD1 questionnaire scores correlated with years from disease onset. Longitudinally, only the LGMDD1 questionnaire detected significant progression at both 1.5 and 2.5 years. Treatment trials would require 62 (1.5 years) or 30 (2.5 years) patients to detect a 70% reduction in the progression of the LGMDD1 questionnaire. INTERPRETATION: This study is the largest description of LGMDD1 patients to date and highlights potential genotype-dependent differences that need to be verified prospectively. Future clinical trials will need to account for variability in these key phenotypic features when selecting outcome measures and enrolling patients.

Phenotypic diversity in an international Cure VCP Disease registry.

BACKGROUND: Dominant mutations in valosin-containing protein (VCP) gene cause an adult onset inclusion body myopathy, Paget's disease of bone, and frontotemporal dementia also termed multisystem proteinopathy (MSP). The genotype-phenotype relationships in VCP-related MSP are still being defined; in order to understand this better, we investigated the phenotypic diversity and patterns of weakness in the Cure VCP Disease Patient Registry. METHODS: Cure VCP Disease, Inc. was founded in 2018 for the purpose of connecting patients with VCP gene mutations and researchers to help advance treatments and cures. Cure VCP Disease Patient Registry is maintained by Coordination of Rare Diseases at Sanford. The results of two questionnaires with a 5-point Likert scale questions regarding to patients' disease onset, symptoms, and daily life were obtained from 59 participants (28 males and 31 females) between June 2018 and May 2020. Independent of the registry, 22 patients were examined at the Cure VCP Disease annual patient conference in 2019. RESULTS: In the questionnaires of the registry, fifty-three patients (90%) reported that they were with inclusion body myopathy, 17 patients (29%) with Paget's disease of bone, eight patients (14%) with dementia, two patients (3%) with amyotrophic lateral sclerosis, and a patient with parkinsonism. Thirteen patients (22%) reported dysphagia and 25 patients (42%) reported dyspnea on exertion. A self-reported functional rating scale for motor function identified challenges with sit to stand (72%), walking (67%), and climbing stairs (85%). Thirty-five (59%) patients in the registry answered that their quality of life is more than good. As for the weakness pattern of the 22 patients who were evaluated at the Cure VCP Disease annual conference, 50% of patients had facial weakness, 55% had scapular winging, 68% had upper proximal weakness, 41% had upper distal weakness, 77% had lower proximal, and 64% had lower distal weakness. CONCLUSIONS: The Cure VCP Disease Patient Registry is useful for deepening the understanding of patient daily life, which would be a basis to develop appropriate clinical outcome measures. The registry data is consistent with previous studies evaluating VCP patients in the clinical setting. Patient advocacy groups are essential in developing and maintaining disease registries.

Optimizing hand-function patient outcome measures for inclusion body myositis.

Inclusion body myositis is the most commonly acquired myopathy after the age of 45. The slowly progressive and heterogeneous disorder is a challenge for measuring clinical trial efficacy. One current method for measuring progression utilizes the Inclusion Body Myositis-Functional Rating Scale. We have found that the upper extremity domain scores in the Inclusion Body Myositis-Functional Rating Scale do not consistently change until there is extreme loss of grip and finger flexor strength. Therefore, we performed a cross-sectional observational study of 83 inclusion body myositis patients and 38 controls recruited at the 2019 Annual Patient Conference of The Myositis Association. We evaluated new Inclusion Body Myositis Patient-Reported Outcome measures for upper extremity function modified from the NIH Patient-Reported Outcomes Measurement Information System as well as pinch and grip strength. We found that Patient-Reported Outcome measures hand-function have a higher correlation with pinch and grip strength than the Inclusion Body Myositis-Functional Rating Scale.