Quality of life in patients with myositis is associated with functional capacity, body composition, and disease activity—Baseline data from a randomized controlled trial

To investigate the potential associations between functional capacity, muscle strength, body composition, and disease‐related measures and quality of life in patients with myositis.


| INTRODUC TI ON
Idiopathic inflammatory myopathies-in short myositis-comprise a group of rare autoimmune rheumatic diseases characterized by skeletal muscle inflammation, muscle weakness, high muscle fatiguability and low quality of life (QoL). 1,2The cornerstone treatment for myositis is immunosuppressive therapy except for inclusion body myositis, a treatment-resistant subgroup of myositis. 1,24][5] QoL is a complex measure, and it is unclear what factors might affect QoL in myositis.A candidate factor is disease-related muscle impairments which negatively affect the patients' ability to perform activities of daily living.In line with this, positive correlations between muscle strength (manual muscle testing 8; MMT8) and QoL for patients with myositis have been observed. 3,6,7However, only one study has investigated correlations between functional capacity (timed up & go; TUG, 2-minute walk test; 2MWT and 30-s sit-to-stand; 30-STS) and QoL in myositis and just in patients with sporadic inclusion body myositis. 8Given this scarce amount of available data on QoL and measures of muscle impairment, it is important to validate the previous findings as well as elaborate with additional and relevant tools for measuring muscle strength and functional capacity.Verification of a link between these parameters and QoL is an important step toward the development of strategies to increase QoL in people suffering from myositis.
Therefore, the present study aimed to investigate to which extent functional capacity, maximal muscle strength, body composition, and disease-related markers are associated with quality of life in patients with myositis.An in-depth analysis of relationships between these factors could provide a basis for optimizing future treatment regimens and monitoring tools in this patient population.

| Study design
This cross-sectional study comprised an extended analysis of previously unpublished baseline data obtained in a randomized controlled trial (RCT) that explored the effects of high-intensity strength training in patients with myositis (NCT04486261). 9The study was approved by the National Ethics Committee and adhered to the Helsinki Declaration and Danish GDPR regulations.Written and verbal information concerning the study procedures was provided to all participants.Written informed consent was obtained from all participating patients prior to the initiation of the study.

| Patient recruitment
Patients with myositis with an affiliation to The Capital Region of Denmark were identified for potential enrolment in the RCT study.
To be included in the study, patients had to be 18 years of age, fulfilling the ACR/EULAR criteria for myositis 10,11 with the date of diagnosis at least 6 months prior to inclusion and lastly, receive a dose of ≤5 mg prednisolone per day.Patients were excluded if they had inclusion body myositis, overlap myositis (except secondary Sjögrens syndrome), had co-morbidity preventing resistance training (severe heart/lung disease, uncontrolled hypertension (systolic >160 mmHg, diastolic >100 mmHg), severe knee/hip arthritis) or were deemed physically unable to exercise. 9All patients who completed the baseline testing for the RCT study were included in the present study.See Figure 1 for a flowchart depicting the inclusion process.

| Quality of life
QoL was assessed using the 36-item Short Form questionnaire (SF-36) comprising of eight subscales.The individual subscales rank from 0 to 100, with higher scores representing better health status.The subscales are grouped into two separate summary scores: physical component summary (PCS) and mental component summary (MCS).The four subscales of PCS consist of physical functioning, bodily pain, general health, and role physical.MCS consists of four subscales: vitality, social functioning, role emotional, and mental health. 12nclusion: All measures of functional capacity were positively related to the SF-36 physical component summary score, indicating higher functional capacity positively affects quality of life in patients with myositis.Health assessment questionnaire and patient global damage scores demonstrated the strongest correlations with SF-36 physical component summary scores, further supporting these patient-reported outcomes as viable monitoring tools in patients with myositis.

K E Y W O R D S
IMACS core set measures, muscle strength, patient-reported outcomes, physical function, quality of life

| Functional capacity
All tests of functional capacity and muscle strength and power were performed on the same day, except for functional index 3 (FI3) and 5 repetitions maximum (RM) testing in selected strength exercises, which were performed on two separate days.The order of testing was leg extensor muscle power, 2MWT, balance test (data not included), TUG, handgrip strength, and 30-STS.The participants were instructed not to exercise or drink excessive amounts of alcohol (≥2 units) 24 h before all tests.No restrictions were made on sleep, caffeine, or food intake.

| Functional index 3
FI3 is a validated tool for myositis patients to measure muscle endurance. 13It consists of three tasks; shoulder flexion, neck flexion, and hip flexion.Shoulder and hip flexion were performed for both the dominant and non-dominant sides, starting with the dominant side.
The pace of the repetitions was standardized using a digital metronome at 40 beats per minute (equal to 20 repetitions/min).Each of the tasks started with five familiarization repetitions; thereafter, the participants continued to perform as many repetitions as possible or until 60 successive repetitions were completed.

| 2-minute walk test
The 2MWT was used as a measure of gait function 14 and short-term endurance capacity.The test was performed on a 20-m long indoor track with turns marked cones on the floor and with the participants instructed to cover the longest distance possible in 2 min.

| Timed up and go test
TUG was used as a measure of functional mobility. 15From a seated position in a chair (45-cm vertical seat position), the participants were asked to stand up with no assistance (incl.the armrest), walk three meters forward, turn around a cone, walk back, and sit down.
The instruction was to do this as fast as possible, in a controlled manner.Three attempts were performed, and the fastest performance was selected for statistical analysis.

| The 30-s sit-to-stand test
As a measure of lower extremity muscle performance and dynamic postural stability, the 30-STS test was performed. 16Sitting on a chair (45-cm vertical seat position), the participants were asked to stand up and sit down as many times as possible in a 30-second time interval, with their arms crossed over the chest.Knees and hips were required to be fully extended before sitting down.

| Leg extensor muscle power
Unilateral maximal leg extensor muscle power was assessed in the dominant leg using the Nottingham power rig. 17The participants were seated to ensure a knee joint angle of 15 degrees (0-degree full extension) when the footplate was fully pushed down.The participants performed at least five attempts with a pause of 15-20 s between successive attempts.Additional attempts were performed until no further increase in peak power output could be measured.
The best attempt (highest peak power) was selected for statistical analysis.

| Muscle strength-five repetitions maximum
Upper and lower body muscle strength was assessed in the following strength exercises: leg press, bench press, knee extension, cable row, and sitting bicep curls by a 5-RM test. 18Following a light warm-up, the participants were familiarized with the exercises by performing 10 repetitions at weight corresponding to their self-estimated 15-RM load.Thereafter, the participants gradually increased the weight until reaching the maximum weight that they were able to lift in 5 repetitions.There was a 2-minute rest period between each attempt.All exercises, except for the biceps curl (dumbbells), were performed in adjustable machines (Cybex, Massachusetts, USA).

| Handgrip strength
Maximal handgrip strength was measured by a static hand dynamometer (Jamar, JLW Instruments, USA).Three successive trials were performed for the dominant hand, each separated by a pause of 60 s.The participants were seated in an upright position with the arm bent at 90° at the elbow and were not allowed to use legs to support the arm. 19The handle of the dynamometer was adjusted to fit the size of the hand, and the best of the three trials (highest peak force) was selected for statistical analysis.

| Body composition
Whole body DEXA scans were performed using an iDXA fan-beam densitometer (GE Lunar, Madison, Wisconsin, USA), using Encore software version 16.0 for analyses.Adjusted appendicular lean mass (AALM) was defined as the sum of lean tissue from the arms and legs and adjusted to height 2 (kg/m 2 ). 20e total fat percentage was analyzed without adjustments.
Adjusted total fat mass (ATFM) was defined as a total sum of fat tissue and adjusted to the appendicular lean mass (ALM), to account for inter-subject variations in size and muscle mass.Scans were performed prior to the physical testing, with the same restrictions as mentioned in reference to functional capacity testing.

| Activity levels
The International Physical Activity Questionnaire (IPAQ) was used to assess self-reported physical activity.Active hours and sedentary hours per week were calculated and analyzed. 21To also obtain objective measures of habitual physical activity levels, accelerometers (Actigraph -wGT3X-BT) were worn by the participants for 5-7 consecutive days.The accelerometers were placed on the hip of the dominant leg.
For the analysis of sedentary/light, moderate, and vigorously physical activity the GGIR-package in R was used. 22,23Included in the GGIR-package are features of data cleaning (i.e., non-wear time) and user-defined cut-off points for physical activity levels measured in milli-gravitational units (mg). 23In the present study, cut-off points were set at <69.1 mg (sedentary/light), 69.1-258.7 mg (moderate), and > 258.7 mg (vigorously), as previously presented by Hildebrandt et al., 2014 for adults. 22eps per day were calculated based on the Actilife software algorithm (Actigraph LLC, Pensacola, FL, USA) for calculating steps, with the first and last day of wearing the Actigraph excluded. 24rther, patients who ended up being excluded from the physical activity in the GGIR analysis, due to excessive non-wear time, were also excluded in the "steps per day" analysis.

| Disease-related outcomes
The International Myositis Assessment and Clinical Studies Group (IMACS) disease core set was used to quantify disease activity and disease damage 25 : Physician global activity (PhGA), patient global activity (PtGA), as well as extramuscular global assessment (EMGA) were evaluated using a Visual Analogue Scale (VAS, 0-100 mm; lower values represent less disease activity). 25The manual muscle testing 8 (MMT8) was used to estimate muscle strength in eight predefined muscles. 25Muscle strength grading is from 0 to 10 with a higher score being stronger (score 0-80).Perceived physical function was reported by using the health assessment questionnaire (HAQ) (0-3; lower scores representing higher self-perceived function). 25Plasma creatine kinase (CK) was measured by blood sampling.Disease damage was evaluated by physician global damage (PhGD) and patient global damage (PtGD) using VAS (0-100 mm; lower values represent less disease damage). 25

| Statistical analysis
Following visual inspection and subsequent statistical testing of the data, it was noted that an assumption of linearity could not be reasonably verified and therefore data were analyzed using Spearman rank correlation, as it assesses the monotonic relationship between variables without the assumptions of linearity. 26ditionally, a post hoc analysis between HAQ and measures of functional capacity as well as HAQ and the measures of muscle strength was conducted.
The significance level was set at p < .05using 2-tailed testing.All investigated variables are presented as means with standard deviation unless otherwise stated.All statistical analyses were performed using R via RStudio (v.2022.07.1).

| Body composition and activity levels
Height-normalized appendicular lean mass did not correlate with PCS (Table 2).In contrast, both total fat percentage (r s = −.63,For visualization of correlations, see Appendix S1 (Figures A12-A19).
b Three patients who received bDMARD also received sDMARD (two also received prednisolone).
No correlations to the SF-36 MCS were observed for any of the above outcome variables.For visualization of correlations, see Appendix S2 (Figures B1-B27).

| DISCUSS ION
The present study examined the potential associations between quality of life (SF-36 physical/mental component summary scores) and selected measures of functional capacity, muscle strength and power, body composition, habitual physical activity levels, and disease markers in patients with myositis.
The main findings were that functional index as maximal leg extensor power has been shown to be negatively associated with mobility limitations in the general population. 30r upper extremity strength, handgrip strength and bench press strength showed a correlation with physical SF-36, which could indicate that strength measures for the upper extremities should be chosen with care, as it may not be relevant monitoring outcomes for physical function in patients with myositis.Handgrip strength has been recognized as a strong predictor of limitations in activity of daily living 31,32 and overall health 32,33 and is, therefore, an monitoring tool with great potential for patients with myositis.
Strong positive correlations are typically observed between muscle mass and muscle strength 34 and therefore an improved performance in activities of daily living might also be expected with increasing muscle mass in patients with myositis.However, no correlations between lean mass assessed by DEXA and physical or mental SF-36 could be observed in the present study.It is possible, however, that correlations might be expected with more advanced stages of the disease, as muscle quality, 1,2 and muscle function are strongly negatively affected by disease progression over time. 5terestingly, the present study revealed negative correlations between total fat percentage, adjusted fat mass, and physical quality of life, which has also been observed in patients with long-term juvenile dermatomyositis. 35Thus, it may be useful to monitor this parameter in patients with myositis.6][37]  to strong positive between habitual physical activity levels measured by accelerometers and longitudinal changes in clinical outcomes for patients with myositis, as improvements in the habitual physical activity levels coincided with improvements in MMT8, HAQ, and PhGD. 24,38,39lf-perceived physical function assessed by HAQ appeared to be among the most influential factors (strongest predictors) on physical quality of life in the present study.Similar findings have been observed previously 40 and reaffirm that HAQ is a vital measure in the monitoring of patients with myositis. 25 Some strengths of the present study may also be mentioned.

CO N FLI C T O F I NTER E S T S TATEM ENT
The authors declare that they have no competing interests.

First, the
single-center study design enabled individual tests in all participants to be performed by the same assessor, which reduced inter-individual bias.Second, all participants were tested within 6 weeks, thereby limiting any potential bias caused by seasonal changes.Measures of functional capacity appeared to uniformly influence physical quality of life (PCS) in patients with myositis.Likewise, muscle strength and power were positively correlated with physical quality of life.These observed relationships suggest that exerciseinduced gains in functional capacity and muscle strength may be expected to translate into corresponding improvements in quality of life.Therefore, introducing exercise to improve functional capacity and muscle strength might be beneficial for patients with myositis.The Health Assessment Questionnaire (HAQ) and IMACS patient global damage (PtGD) score obtained in the present study demonstrated a marked influence (strongest correlations) on physical quality of life (PCS) compared to all other outcome parameters.Consequently, these functional capacity, muscle, and patient-reported outcomes are deemed to be highly relevant in the clinical monitoring as well as in the setting of clinical trials of patients with myositis.In contrast, no correlations with any outcome were observed to mental quality of life (MCS), which suggests that more sensitive tools should be developed to monitor and evaluate mental health in patients with myositis.AUTH O R CO NTR I B UTI O N S KYJ, PAA, CHS and LPD have made substantial contributions to the conceptualisation of the study.KYJ, CG and LPD participated in data collection.KYJ conducted the statistical analyses, in cooperation with JLN and CAS.KYJ drafted the manuscript with the supervision of LPD and support of HDS.All authors critically reviewed and revised the manuscript.All authors have reviewed and approved the final manuscript.ACK N OWLED G M ENTS We thank Professor Ingrid Lundberg (Karolinska Institute), Associate Professor Helene Alexanderson (Karolinska Institute), PhD Anders Jørgensen, and the patient advisory board for their valuable input to the design of the current Randomized controlled trial protocol.FU N D I N G I N FO R M ATI O N This work was supported by The Danish Rheumatism Association-Grant number R185-A6606, Helsefonden-Grant number 21-B-0125; The A.P. Moller Foundation-Grant number 20-L-0031; IKM, University of Copenhagen-Grant number N/A; Eva Merete Falck Crones Fond-Grant number 10-100071; Direktør Emil C. Hertz og Hustru Inger Hertz' Fond-Grant number KJR 13016; Copenhagen University Hospital, Rigshospitalet-Grant number N/A. 27

Table 1 .
A total of 32 patients with myositis were included, 21 were

TA B L E 1
Baseline demographics and disease characteristics.
Functional capacity, muscle strength, body composition, and activity level vs. quality of life (Short Form 36 questionnaire, physical component score, and mental component score).
3, 2-minute walk distance, 30-s sit-to-stand performance, timed up & go capacity, 5-RM leg press, 5-RM bench press, handgrip strength, and maximal TA B L E 2 Note: Data are presented as means and standard deviation in parentheses.Bold font means significant.Abbreviations: 2MWT, 2-minute walk test; 30 STS, 30-second sit to stand; 5RM, five repetitions maximum strength test; ad., adjusted; App., appendicular; FI3, functional index 3; IPAQ, International Physical Activity Questionnaire; MCS, mental component summary; PCS, physical component summary; TUG, timed up and go. a n = 30, two patients did not perform the 5RM test.bn = 25, seven patients were excluded due to excessive non-wear time.leg extensor muscle power were positively associated with physical quality of life (SF-36 physical component summary score).In contrast, no associations were observed with mental quality of life (SF-36 mental component summary score).Notably also, while all disease-related measures were unrelated to mental quality of life, a number of these measures (i.e., extramuscular global assessment, patient-reported physical function, patient-and physician-reported disease severity) were found to be correlated with physical quality of life.press strength, leg extension muscle power) were statistically correlated with physical SF-36.This could indicate that lower extremity strength and power are parameters that positively affect quality of life in patients with myositis, probably by affecting general mobility,