Diminished muscle integrity in patients with fibrodysplasia ossificans progressiva assessed with at-home electrical impedance myography

Diminished muscle integrity in patients with fibrodysplasia ossificans progressiva assessed with at-home electrical impedance myography

The current results demonstrate that EIM is an efficient and accessible method capable of detecting aberrant bioelectric properties of muscle tissue in patients with FOP. Whole-body and regional EIM endpoints (θ and X) at 50 kHz and 100 kHz were found to be lower in patients with FOP compared to healthy subjects. Equally interesting was the observation that EIM data at the single-patient level indicated regional variability, where some muscle groups of patients with FOP fell within a normal range for θ (see left upper for FOP Patient 12, Fig. 2) and other muscles were more affected as indicated by lower θ values. The heterogeneity in EIM measures, whether from an inter- or intra-patient perspective, suggests that EIM may be sensitive to anatomically localized pathological processes (e.g., regional HO growth). However, factors such as widespread HO within a FOP patient may underpin less variability in EIM data.

The pathobiological basis for the current set of EIM findings (i.e., changes in whole-body and regional θ, X, and R values) in patients with FOP is likely multifactorial. We hypothesize that myopathic processes and perhaps relatedly, inflammatory mechanisms, present at a regional or systemic level would ultimately alter the conduction of electrical currents29,30. More specifically, lower X values may be attributed to changes in cell membranes or muscle atrophy as damaged cell membranes yield a decrease in tissue capacitance. The presence of extensive HO may contribute to the low X values as bone is a poor conductor as a result of low levels of fluid or electrolytes. Additionally, R, a measure of difficulty for electrical currents passing through tissue, was in contrast elevated in the FOP cohort. This finding was in accord with the current understanding that HO or calcification in soft tissue would ultimately increase the resistance for a passing electrical current. Thus, the lower θ values observed in patients with FOP are hypothesized to reflect a combination of myofiber structural alterations and HO. A focus for future EIM studies in FOP patients would be a determination of how θ, X, or R regionally vary during a flare-up, while a finer dissection of pathophysiological mechanisms of FOP underpinning changes in EIM properties warrants further investigation and perhaps is best suited using preclinical models of FOP5.

We also sought to evaluate whether and how EIM parameters relate to a benchmark functional measure of FOP, CAJIS26. Here, strong negative correlations were found between CAJIS scores and θ and X at both 50 and 100 kHz, on a whole-body and regional scale (i.e., left-lower). As a progressive condition, FOP disease burden, as indicated by more extensive HO and more severe loss of functional mobility as captured by CAJIS, frequently worsens with age. In line with this trend, EIM-based endpoints also significantly associated well with age among our FOP patient population, a finding not replicated in healthy control subjects. To further evaluate the ability of EIM to reflect patients’ functional status, we utilized a PROMIS-based questionnaire to evaluate physical activity level. We found positive correlation between θ and X values with level of physical activity, while R was negatively correlated with this same measure. As our other analyses have demonstrated, R is negatively correlated with disease affliction. With more extensive disease, as expected, PROMIS data indicated decreased engagement in physical activity. In turn, the reported correlations between EIM endpoints and physical activity level are consistent with correlations between EIM endpoints and disease affliction.

The negative association between EIM endpoints and CAJIS scores suggest that abnormal EIM metrics reflect muscle dysfunction secondary to chronic immobilization, yet the possibility that aberrant bioelectric properties of muscle as a causal factor precipitating HO cannot be ruled out without further investigation. Nonetheless, these data point to the utility of EIM as a biomarker method to objectively evaluate a FOP patient’s functional status and possibly after further investigation, a tool to monitor disease over time.

Prior to the current investigation, EIM has been established as a flexible tool to assess muscle in healthy subjects as well as neuromuscular and musculoskeletal conditions21,22,23,24,29,30,31,32. Yet, the implementation of EIM in a virtual setting is unique to this study. Importantly, despite virtual data collection by an individual other than a study staff member, we observed that healthy control subject EIM data are well within the range of what has been reported for θ, X, and R at 50 and 100 kHz. For instance, in separate studies, the mean θ at 50 kHz across multiple muscle groups in healthy male children and healthy adults was approximately ~ 11° degrees and ~ 14°, respectively31,32. In this study’s virtual healthy control cohort involving pediatric and adult participants, the mean θ at 50 kHz across multiple muscle groups was similarly ~ 11°. Inter-study differences in mean θ values may have risen from variability in in age, gender, and BMI distribution as well as measures such as physical activity levels. Nonetheless, the alignment and consistency between in-person and virtual EIM evaluations provides support for using EIM in a virtual manner, whether it is in healthy controls or in patients with FOP.

There are a number of challenges associated with identifying much needed novel and sensitive biomarkers in FOP. Aside from patient availability, given the ultra-rare status of FOP, logistical hurdles and contraindications towards employing normally routine procedures (i.e., biopsy or MRI) can further limit biomarker development in this condition. Imaging techniques such as PET, SPECT, CT, or X-Ray can provide critical information on FOP disease activity and burden, yet the frequency of implementation may be limited, particularly in the pediatric FOP population. Nonetheless, validation of non-invasive and objective biomarkers capable of monitoring musculoskeletal health in FOP would be advantageous in clinical and research settings alike. Thus, the current study aimed to test the utility of EIM in FOP, and determined that EIM-based endpoints that inform on muscle health, particularly θ and X at 50 kHz, can differentiate between patients with FOP and matched, healthy controls. These measures also significantly associate with CAJIS, a functional measure of mobility validated in FOP populations26, as well as with reported physical activity levels, another measure of functionality. Moreover, the COVID-19 pandemic imposed further limitations and hurdles in performing clinical research in patients with FOP. Ultimately, the pandemic drove a creative adaptation (i.e., transitioning to a virtual platform) of an already-flexible tool in EIM, and allowed for execution of an at-home clinical biomarker research study, which likely has implications for future studies carried out beyond the COVID-19 pandemic.

By adapting the in-person EIM study visit for a virtual platform, a number of insights have been garnered. Firstly, study participants and the individual who collected EIM data have consistently reported that appropriate operation and handling of the EIM device was easy to learn. FOP patients and families have similarly expressed how valuable they feel at-home modalities that inform on their disease status or overall health can be given the logistical difficulties with travel many individuals face. Relatedly and from a research perspective, moving our acquisition paradigm to a virtual platform has significantly decreased the burden on our participants. Additionally, a virtual scanning modality allows for wider reach, which is particularly important given the ultra-rare status of FOP. From a clinical standpoint for FOP, the painful flare-ups that often precede an episode of HO induction and growth are difficult to predict. Patients have repeatedly emphasized the need to accurately detect flare-up states and thus potential HO lesions. While further research is necessary to determine the ability of EIM to detect the underlying soft tissue changes associated with a flare-up, the findings of this study serve as a good foundation that demonstrates the ability of EIM to detect disease-related changes in FOP in general.

There are several limitations in this study that warrant discussion. First, our study analyzed muscle groups, which were in large part evaluated in prior EIM investigations. On one hand, this approach provided guidance in terms of the expected range for EIM values, which was important considering the novel use of EIM in patients with FOP as well as in a virtual study setting. Yet, limiting the muscle groups evaluated also led to the exclusion of certain anatomical regions where HO lesions notably form in FOP (e.g., neck, upper back or jaw). Examination with EIM of small muscle groups such as those in the facial area with current EIM equipment is challenging. Second, in patients with widespread presence of HO and who use specialized wheelchairs, paraspinal muscles were particularly difficult to access with the EIM device, yet all other muscle groups were evaluated. Third, this study was cross-sectional and can only inform on the value of EIM as a tool to assess an acute state of muscle health in FOP patients. We propose that future work in FOP populations should incorporate EIM within a multidisciplinary clinical research framework that monitors patients longitudinally. Such study designs are critical in order to determine how EIM measures track with other benchmark measures over time, as well as to ascertain the value of EIM as a method that can identify acute versus chronic changes, predict disease progression, and relatedly, detect episodic events such as HO expansion or flare-ups. Integrating non-contrast MRI or MR spectroscopy, when possible to employ in a FOP patient, may provide important insights into how altered muscle tissue properties may relate to EIM-based measures. Fourth, as no FOP patient was in a confirmed flare-up state, the utility of EIM to detect and monitor flare-ups could not be established. Finally, we can only speculate about the possible pathophysiological mechanisms driving abnormal EIM measurements in FOP patients. Localized or systemic myopathy, chronic inflammation, atrophy, HO, prolonged immobilization or combination of factors could modulate the bioelectric properties of muscle tissue. An opportunity for further research may entail evaluation of EIM with other objective and more established methods such as imaging (18F-NaF PET/CT, CT, X-Ray, and MRI) or quantification of circulating markers18,33,34,35.

In conclusion, EIM has tremendous potential as an objective, non-invasive, and convenient clinical research tool that can be utilized to detect diseased muscle in pediatric and adult patients with FOP. Given EIM’s inherit flexibility and ease of operation, this method can be incorporated as a standalone measure or in combination with current approaches standardized in clinical or research settings. The results presented herein, provide a necessary foundation for further determining the utility of EIM as a biomarker method that can be used to track disease progression, monitor patients in flare-up states, and, possibly inform on treatment effects in FOP.


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