Response to: Disentangling Facioscapulohumeral Muscular Dystrophy Disability From Age and Comorbidities: A Call for Refined Stratification

We thank Dr. Messina for his interest in our study on longitudinal changes in the facioscapulohumeral muscular dystrophy Rasch‐built overall disability scale (FSHD‐RODS) over 6.5 years [1]. We appreciate his thoughtful comments regarding potential influences of age and comorbidities on patient‐reported outcomes (PROs). These aspects are indeed relevant for understanding disability in FSHD and for optimizing future study designs. However, several of the raised concerns do not substantially affect the interpretation of our findings.

Dr. Messina points out that our cohort covered a wide age range (18–72 years) and suggests that age‐related functional decline might confound FSHD‐RODS results. We wish to emphasize that the FSHD‐RODS was specifically developed using Rasch analysis to ensure one‐dimensionality and the absence of differential item functioning (DIF) for key demographic variables, including age and sex [2]. Importantly, the development cohort itself covered the full adult age range (18–87 years), ensuring that the scale is valid and age‐independent across adulthood. This means that a given level of functional limitation yields the same score regardless of age. The scale therefore captures disease‐related disability rather than age‐dependent effects. This property is one of the main strengths of the Rasch‐built approach and allows valid comparisons across individuals and time, independent of demographic variability.

We agree that comorbidities may influence physical functioning in FSHD. In our cohort, however, severe comorbidities such as respiratory disease (n = 2) or malignancy (n = 3) were uncommon, and none of the participants were acutely ill during follow‐up. One participant was diagnosed with a malignancy, and one participant was diagnosed with asthma during follow‐up. Pulmonary function was within normal limits for most participants and remained stable over time; only 15 individuals had mildly reduced forced vital capacity (FVC; 70%–80% predicted), without respiratory symptoms. One participant had a severely impaired FVC of 46% predicted. While additional stratification by comorbidity might be informative, it is not standard practice to perform or report such subgroup analyses in brief correspondence. More importantly, the FSHD‐RODS is designed to reflect the real‐life impact of FSHD in a representative patient population. Attempting to exclude or correct for every possible health factor would detract from its clinical validity and applicability to everyday functioning.

In any long‐term observational study, it is neither feasible nor desirable to correct for all conceivable influences, including psychiatric, cognitive, metabolic, or oncological conditions. Such corrections are rarely implemented even in interventional trials. Instead, careful consideration is required to determine which factors are most relevant to capture and report. Consensus within the field will be essential to harmonize future approaches to stratification and adjustment in FSHD outcome research.

We also note that the main results of our study showed no decline in FSHD‐RODS or SIP68 scores over 6.5 years, while disease severity scores revealed only minimal progression. This argues against a significant confounding effect of age‐related decline or comorbidity. If such factors had strongly influenced functional outcomes, one would expect a measurable decrease in PROs, which was not observed. Moreover, one participant became wheelchair dependent during follow‐up, a transition that we interpret as part of the disease's natural course rather than an unrelated comorbidity effect—precisely the type of change that sensitive PROs are intended to detect.

We appreciate the opportunity to clarify these aspects. The FSHD‐RODS provides a robust, age‐independent measure of functional ability in FSHD and remains a valuable instrument for longitudinal and interventional studies. We agree that refined stratification and systematic consideration of comorbidities will further improve interpretability in future trials, and our ongoing work aims to contribute to this field‐wide harmonization.

Funding

This work was supported by Prinses Beatrix Spierfonds (W.OR18‐07, W.OR12‐22) and FSHD Stichting (WP35, WP36).

Conflicts of Interest

The authors declare no conflicts of interest.

Teeselink S. and Mul K., “Response to: Disentangling Facioscapulohumeral Muscular Dystrophy Disability From Age and Comorbidities: A Call for Refined Stratification,” European Journal of Neurology 32, no. 11 (2025): e70448, 10.1111/ene.70448.

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.