Sarcopenia in patients with rheumatic musculoskeletal diseases

To investigate the impact of high‐dose glucocorticoid therapy on sarcopenia in hospitalized patients with rheumatic musculoskeletal diseases (RMDs).

RMDs are chronic multisystem autoimmune diseases, 6 and chronic inflammation is considered a relevant factor in sarcopenia.
Additionally, most RMD patients with systemic organ manifestations require hospitalization for high-dose glucocorticoid treatment. 7ucocorticoids are known to cause muscle volume loss caused by proteolysis through the activation of catabolic pathways, and bed rest during hospitalization leading to low physical activity is another factor that induces skeletal muscle loss. 8As sarcopenia is associated with infection, resulting in an increased risk of morbidity and mortality, 9 it is important to recognize the prevalence of sarcopenia and the risk factors for sarcopenia in patients with RMDs who need highdose glucocorticoid treatment in hospital.
This study aimed to investigate the prevalence of sarcopenia, sarcopenia progression, and its relevant factors in patients with RMDs during 1-month hospitalization with high-dose glucocorticoid therapy.

| Patients and data collection
We retrospectively reviewed all patients with RMDs who were hospitalized for at least 1 month at Keio University Hospital between 2020 and 2022 to undergo remission induction therapy with high-dose glucocorticoids.1][12][13][14][15][16] We included patients whose skeletal mass index (SMI) was available before the initiation of high-dose glucocorticoid therapy and 1 month later in the analysis.We collected the following clinical characteristics from the patients' charts: underlying diseases, height, body weight, body mass index (BMI), SMI, laboratory data, treatment regimen, and frequency of infection that required antibiotics or antiviral drugs.This study was approved by the Ethics Committee of the Keio University School of Medicine (approval number: 20130506) and performed in accordance with the principles of the Declaration of Helsinki.The requirement for written informed consent was waived in accordance with Japanese regulations.

| Skeletal mass index measurement and definition of sarcopenia
The SMI was measured using dual-energy X-ray absorptiometry.
Sarcopenia was defined as <5.4 kg/m 2 of SMI for women and <7.0 kg/m 2 of SMI for men according to the definition of the Asian Working Group for Sarcopenia. 17The progression of sarcopenia was defined as a >10% decrease in SMI. 18

| Statistical analysis
Continuous variables are shown as means and standard deviations.Differences between the 2 groups were analyzed using the Mann-Whitney U test for nonparametric data and the Chi-squared or Fisher's exact test for categorical data.To identify independent parameters for sarcopenia progression, binary logistic regression analysis was used for variables with a P < 0.05 in a previous univariate analysis as covariates.A cut-off value to discriminate the sarcopenia progression from the sarcopenia non-progression was calculated using the receiver operating characteristic (ROC) curve.
Statistical significance was set at P < 0.05.All statistical analyses were performed using GraphPad Prism version 8 (GraphPad Software).

| Clinical characteristics before high-dose glucocorticoid therapy
We included 49 patients who underwent dual-energy X-ray absorptiometry before and 1 month after high-dose glucocorticoid treatment.There were no patients who had to keep bed rest due to cardiopulmonary dysfunction.Clinical features before high-dose glucocorticoid treatment are shown in the Table 1.The mean age was 53.3 years, and 36 (73.5%) were female.The most frequent underlying disease was SLE in 21 patients (42.9%), followed by systemic vasculitis syndrome in 9 (18.4%) and idiopathic inflammatory myopathy in 7 (14.3%).Eighteen patients (36.7%) were treated with glucocorticoids before admission.

| Presence of sarcopenia and sarcopenia progression
The mean SMI was 5.7 ± 1.1 kg/m 2 , and 41 (83.7%) patients were already categorized as having sarcopenia (<5.4 kg/m 2 for woman and <7.0 kg/m 2 for men, Figure 1A) before high-dose glucocorticoid therapy.All patients had undergone routine specialist-regulated rehabilitation to prevent disuse syndrome during hospitalization.After 1 month of high-dose glucocorticoid therapy with the mean dose of 0.91 mg/kg/d, the mean SMI was decreased to 5.1 ± 1.0 kg/m 2 (mean change from baseline to 1 month, −0.67 mg/m 2 , P < 0.0001), and 2 more patients were diagnosed as sarcopenia, resulting in 43 (87.8%)patients being sarcopenic at 1 month.Furthermore, sarcopenia progression (>10.0%decrease in SMI from baseline) was observed in 28 (57.1%)patients.
On the other hand, among the patients who were already treated with glucocorticoid mean dose of 0.14 mg/kg/d, 17 (94.4%)were sarcopenic at both baseline and 1 month; however, the mean TA B L E 1 Clinical characteristics of the patients at baseline and after remission induction treatment.
The proportion of patients who had been treated with glucocorticoid tended to be greater among those with sarcopenia at baseline (41.4% vs 14.3%, P = 0.229) with a higher glucocorticoid dose (0.17 ± 0.31 vs 0.01 ± 0.03 mg/kg/d, P = 0.126), but these were not statistically significant.
Among the 8 patients who were not categorized as having sarcopenia at baseline, sarcopenia progression was observed in 3 (37.5%).

| Changes in physique after high-dose glucocorticoid treatment during 1-month hospitalization
We examined changes in physique, including body weight, muscle volume, and fat volume over 1 month.Body weight was significantly decreased in patients with sarcopenia progression compared to those without (−5.1 ± 3.6 vs −1.9 ± 0.6 kg, P = 0.008), and the decrease was mainly because of the decrease in skeletal muscle mass, not because of the fat volume mass (Figure 1C).We further investigated serial body weight change (Figure 1D), which was significantly reduced from baseline to week 1 (−2.
Our study demonstrated that more than 80% of patients with RMDs had sarcopenia before high-dose glucocorticoid treatment, and that muscle volume decreased even after 1-month hospitalization with high-dose glucocorticoid treatment.Rapid reduction in body weight can predict muscle volume loss, which can lead to a predisposition to infection.
Sarcopenia is a growing global health concern because reduced muscle strength leads to loss of function and is a major cause of adverse health outcomes. 19Sarcopenia usually occurs in older people because it affects 5%-50% of persons aged >60 years; 20 however, patients with RMDs are also predisposed to developing sarcopenia. 21This is partly due to the underlying proinflammatory state, because muscle loss results from a combination of diminishing anabolic signals and promotion of catabolic signals mediated by proinflammatory cytokines. 22Decreased muscle use due to pain and fatigue caused by these diseases may be another cause of sarcopenia; our study results showed that more than 80% of patients with RMDs already had sarcopenia before treatment, which supports this idea.
Glucocorticoid use is another significant cause of sarcopenia in patients with RMDs.Glucocorticoids are one of the most widely prescribed drugs that have many clinical applications; 23 they upregulate anti-inflammatory pathways and downregulate proinflammatory pathways. 24Although the suppression of inflammation by glucocorticoids can improve sarcopenia; glucocorticoids also decrease muscle volume.Skeletal muscle mass is maintained through a dynamic balance between muscle protein synthesis and breakdown.
Glucocorticoids lead to an increase in muscle protein breakdown by activating the ubiquitin-proteasome and lysosomal systems and a decrease in protein synthesis by disrupting growth factor signaling, such as insulin and insulin-like growth factor 1. 25,26 Consequently, patients with RMDs who were hospitalized for high-dose glucocorticoid therapy are at a high risk for sarcopenia progression.Our study demonstrates that only 1-month hospitalized high-dose glucocorticoid therapy decreases muscle volume, which can lead to a predisposition to infection.We need to recognize this risk and try to decrease the glucocorticoid dose and shorten hospitalization as much as possible.
Our data showed that sarcopenia progression within 1 month can be predicted by body weight reduction.In clinical practice, the initial dose of glucocorticoids is determined by considering body weight, whereas the reduction schedule is usually determined as dosebased, such as −10 mg/wk. 27However, the doses in patients who have lost body weight may be higher than the doses based on the actual body weight, which results in greater toxicity, including infection and further muscle volume loss.Our results showed that sarcopenia progression can be predicted by rapid body weight reduction 1 week after glucocorticoid administration, with a cut-off of −1.8 kg/ wk.We should monitor patients' body weights carefully and adjust the glucocorticoid dose accordingly.Although the ratio of sarcopenia was not changed in patients who had precious glucocorticoid treatment after high-dose glucocorticoid therapy, their SMI levels were significantly decreased.This discrepancy means that the ratio of sarcopenia was not changed because the majority of patients already met the criteria for sarcopenia, but SMI levels were decreased further in those patients.
Our study had several limitations.First, this study was conducted retrospectively at a single center with a small sample size and SMI measurement was conducted based on the attending physician's decision, which may have caused a selection bias.However, our study is important in recognizing the sarcopenia risk in patients with RMDs requiring hospitalized high-dose glucocorticoid Second, collected data on SMI and not on grip strength or gait speed.This may lead to an overdiagnosis of sarcopenia.Third, protein intake and physical activity levels were not recorded.Despite these limitations, we believe that our preliminary data are important, and larger studies are needed to confirm our results and establish the optimal management of sarcopenia in such patients.
Our results demonstrated that 1-month hospitalization with high-dose glucocorticoid therapy was associated with sarcopenia in patients with RMDs.Rapid changes in body weight predict sarcopenia progression and should be carefully monitored.

ACK N OWLED G M ENTS
None.

CO N FLI C T O F I NTE R E S T S TATE M E NT
None.

DATA AVA I L A B I L I T Y S TAT E M E N T
The datasets during and/or analyzed during the current study available from the corresponding author on reasonable request.

F I G U R E 1
Association of high-dose GC therapy with SMI and body weight.The incidence of sarcopenia increased in those who were not previously treated with GC (A).The mean change in the SMI from baseline is shown (B).The fat volume did not change, but the muscle volume decreased (C).An early reduction in body weight is observed in patients with sarcopenia progression after high-dose glucocorticoid therapy (D).Red line indicates the average SMI.BW, body weight; GC, glucocorticoid; SMI, skeletal muscle index.
performed the majority of the research and analyzed and interpreted the data.Jun Kikuchi, Kazuoto Hiramoto, Mitsuhiro Akiyama, Shutaro Saito, and Yasushi Kondo collected patient data.Yuko Kaneko designed the research, interpreted the data, and supervised and organized the study; all authors wrote the manuscript.All authors read and approved the final manuscript.
PPROVA L A N D CO N S E NT TO PA RTI CI PATEThis study was approved by the Ethics Committee of the Keio University School of Medicine (approval number: 20130506) and performed in accordance with the principles of the Declaration of Helsinki.The requirement for written informed consent was waived in accordance with Japanese regulations.CO N S E NT FO R PU B LI C ATI O NSince this study was conducted under a retrospective cohort design without any samples taken besides those for clinical use; written informed consent was not acquired, in accordance with the guideline of Ministry of Health, Labor and Welfare of Japan.