Introduction

Fibromyalgia syndrome (FMS) is one of the most common musculoskeletal disorders, with prevalence rates of 3–6% across different countries in the world [1]. Although there is a wide range of symptoms, the main somatic symptoms are chronic musculoskeletal pain, stiffness, and fatigue, all of which are related to the muscle system and its functioning [2]. The compound effect of FMS symptoms often has a significant impact on the physical performance and functional ability in patients with FMS [3, 4], and it was shown that patients with FMS had a considerable reduction in functional performance and muscle strength as compared with healthy individuals [5, 6].

Although there have been significant new findings in the understanding of the pathogenesis of FMS, the exact mechanisms have yet to be identified. In the etiology of this syndrome, a crucial role is played by complex interactions among peripheral (e.g., neuromuscular) and central (central and autonomic nervous systems, hormonal and psychological) mechanisms [7].

Although there have been many studies investigating the impact of FMS on muscle fibers, no definitive results have been obtained. Some of these studies have shown specific alterations in muscle fibers caused by local hypoxia due to vasomotor dysregulation, chronic inflammation, and oxidative damage using microscopy, histochemistry, electron microscopy, magnetic resonance imaging (MRI), electrophysiologic tests, and ultrastructural techniques, and others showed no difference between patients and controls [8,9,10,11,12,13,14,15,16,17].

In some studies, it has been reported that the muscle symptoms are due to the inactivity caused by the combination of pain and decreased physical capacity, which may lead to a progressive deconditioning by creating a vicious cycle. As a sign of deconditioning, a decrease in muscle strength was reported in patients with FMS compared with healthy controls [18], but the relationship between a decrease in muscle strength and inactivity in FMS could not be clearly demonstrated, which may be due to different components such as emotional status and motivation [19].

The studies reported above were not standardized; for example, the trapezius muscle as an affected muscle was assessed, but muscles such as triceps, biceps, and gastrocnemius were rarely evaluated in these studies [9, 17]. In addition, patients with at least 2 years of diagnosis were included and patients with newly diagnosed FMS were not studied as a rule. Furthermore, the study groups consisted of a limited number of patients because the methods involved were invasive and expensive. In spite of all these unknowns, exercise programs are recommended in almost all FMS guidelines; they improve muscle strength and the quality of life of the patient.

In light of this information, the following questions need to be answered: Are there any other extremity muscles involved except symptomatic muscles in FMS? If asymptomatic muscles are involved in FMS, is there any difference between patients with newly diagnosed and established FMS in asymptomatic muscle involvement? Is there any relationship between the involved muscles and quality of life parameters such as pain, fatigue, severity of illness, physical mobility, and emotional status?

In order to find the answers to these questions in a large-scale study, musculoskeletal ultrasound (US), which is an easy, inexpensive, and non-invasive method that can directly display muscle mass instead of invasive and expensive methods such as biopsy and MRI was selected.

The aim of this study was to evaluate whether the asymptomatic upper and lower extremity muscles evaluated using US were different from healthy controls in both newly diagnosed and established FMS and to assess whether muscle measurements were related to fatigue and disease severity, as well as quality of life.

Material and methods

Study setting

This study was conducted on 152 subjects (102 patients and 50 healthy controls) from January 2015 to January 2019. The study included patients with FMS aged between 18 and 65 years who had been admitted to the outpatient clinic and had been diagnosed according to the American College of Rheumatology (ACR) 2013 classification criteria for at least 12 months (n = 52) and/or newly diagnosed (0–3 months) (n = 50). Sex, age, and body mass index (BMI) and occupation-matched healthy volunteers (n = 50) with no FMS criteria from among the relatives of patients were included as the control group.

The exclusion criteria for all subjects were any surgery, fracture and/or trauma, inflammatory, metabolic or endocrine diseases, severe osteoarthritis, alcohol/drug abuse or dependence, vitamin D and B12 deficiency, progressive central and peripheral nervous system disorders, known cancer, and cardiac, respiratory, and psychiatric diseases, as well as any motor and mental disabilities. Also, pregnancy, lactation, and participation in a rehabilitation program within the last 6 months were excluded.

Subjects were informed about the study, and their written consent was obtained at the beginning of the study. The approval of the ethics board of the local ethics committee was obtained, and the study was conducted in accordance with the principles of the Helsinki Declaration.

Demographic characteristics

Demographic and disease characteristics including age, sex, BMI, occupation, and disease duration (months) were recorded.

Outcome measurements

Fatigue Severity Scale

The Fatigue Severity Scale (FSS) is a questionnaire with 9 items related to how fatigue interferes with physical activities and rates its severity according to a self-report scale. The item scores range from 1 (strongly disagree) to 7 (strongly agree). The total score is between 9 and 63.

Fibromyalgia Impact Questionnaire

The Fibromyalgia Impact Questionnaire (FIQ) was used to assess the severity of the disease, functional disability, and specific quality of life. The total score was evaluated between 0 and 100 with higher scores indicating a greater impact of the FMS on the patient. An FIQ total score from 0 to 38 indicates a mild effect, 39 to 58 indicates a moderate effect, and 59 to 100 indicates a severe effect.

Nottingham Health Profile

The Nottingham Health Profile (NHP) contains 38 items divided into six domains (energy, pain, emotional reactions, sleep, social isolation, physical mobility). The overall NHP score was obtained by averaging the domain scores. The NHP total and domain scores range from 0 (no perceived distress) to 100 (maximum perceived distress).

Musculoskeletal US

All measurements were performed with the patient in the supine position with the head in a neutral position without a pillow. Real-time imaging of cross-sectional thickness (CST) [for deltoid, biceps brachii (BB), triceps brachii, forearm flexor, tibialis anterior, and gastrocnemius medialis] and cross-sectional areas (CSAs) [quadriceps femoris (QF)] was performed using a US device (GE Logiq P5; General Electric, Korea) and a 7–12-MHz linear array transducer, by an experienced specialist. The transducer was placed on the line, and special care was taken to avoid applying excessive pressure. This scanning was repeated 3 times to reduce the measurement errors, and the mean of 3 measurements was taken.

Study protocol

All US evaluations were performed by a blinded specialist. Also, assessments with the FSS, FIQ, and NHP were performed by another blinded specialist.

Comparisons

Patients groups and healthy volunteers were compared in terms of the US and outcome measurements. Also, comparisons of the patient groups’ US measurements and evaluation parameters were made by a blinded specialist.

Statistical analysis

The Statistical Package for the Social Sciences (SPSS 22.0 for Windows) software package was used in the analysis of the data. In descriptive statistics, the data were expressed as mean ± standard deviation (SD) and mean (SD) for continuous variables and as percentages (%) for nominal variables. Normality of distribution was evaluated using the Kolmogorov-Smirnov test. Differences among the groups were evaluated by the Kruskal-Wallis test with post hoc testing using the Mann-Whitney U test. Spearman’s correlation coefficients were calculated to assess the univariate relationship between the US results and outcomes in patients with FMS. For significant correlations, logistic regression analysis was performed. p values of < 0.05 were considered statistically significant.

The sample size and power calculations were based on detecting differences of 10% in CSA or thickness ratio between the groups, assuming a standard deviation of 10%, an ɑ level of 0.05, and a desired power of 80%. These assumptions generated a sample size of 31 subjects per group.

Results

The mean age of the patients was 42.18 (7.52) years, and all were women (100%). The mean duration of disease was 19.67 (20.31) months. The mean disease duration was 48.24 (11.75) months and 1.67 (0.50) months in the established FMS group (n = 52, group 1) and in the newly diagnosed group (n = 50, group 2), respectively. The distribution and comparison of demographic characteristics of the patient and control groups are presented in Table 1.

Table 1 Demographic characteristics of the participants
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There was no difference in demographic characteristics between the groups. The disease durations of groups 1 and 2 were significantly different (p = 0.001).

The distribution and comparison of the outcome measurements according to the groups are presented in Table 2. There was no significant difference between the patient groups (p > 0.05), and there were statistically significant differences between the patient groups and healthy controls in terms of all measurements (p = 0.001).

Table 2 Distribution and comparison of the outcome scales
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The deltoid muscle thickness was similar in the 3 groups (2 patient groups and control group). All other muscle measurements were lower in the established FMS group than in the control group (p < 0.05). All muscle measurements except the forearm flexor muscle in the newly diagnosed patient group were lower than in the control group (Table 3).

Table 3 Distribution and comparison of the musculoskeletal US
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BB and QF muscle measurements were found to be negatively correlated with the FSS in the established FMS group. The QF muscle CSA was also negatively correlated with NHP energy, social isolation subscales, and total scores (p < 0.05) (Table 4). In the newly diagnosed group, QF muscle CSAs were negatively correlated with fatigue severity, quality of life, energy subscales, and total scores (p < 0.05) (Table 4).

Table 4 Correlation results between musculoskeletal US and outcome measurements
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In the regression analysis for significant correlations in the established FMS group, BB and QF muscle measurements were significantly correlated with fatigue severity, and QF was also significantly correlated with quality of life overall score, energy, and social isolation levels (Table 5). In the newly diagnosed group, QF muscle measurements were significantly correlated with fatigue severity, quality of life overall score, and energy levels (Table 6).

Table 5 Regression analysis results in the established group (group 1)
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Table 6 Regression analysis results in the newly diagnosed group (group 2)
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Discussion

This study has shown that, whether FMS was newly diagnosed or established, muscle measurement values and quality of life parameters were found to be significantly decreased in all patients compared with healthy controls.

In patients with both established and newly diagnosed FMS, decreased QF muscle CSA is significantly correlated with increased fatigue severity and decreased overall quality of life and energy levels. Moreover, in patients with established FMS, there was a significant correlation between the decrease in QF muscle CSA and increased social isolation and between the decrease in BB muscle CST and increased fatigue severity.

Fibromyalgia is a syndrome in which a wide range of symptoms leads to a generalized pain that negatively affects the patient’s quality of life [20]. The pathophysiology of FMS is still unclear and research is ongoing. As the most important findings of FMS are chronic muscular pain, muscle stiffness, and muscle fatigue, muscles have been one of the most interesting targets to reveal the pathophysiology.

In the studies conducted so far, muscles were evaluated either through direct methods such as biopsy, electrophysiology, and MRI or indirect methods such as functional evaluation of muscles and muscle strength measurements. Studies using histochemistry, electrophysiology, and ultrastructural techniques have assessed deltoid, trapezius, brachioradialis, BB, tibialis anterior, and quadriceps muscles. Minor mitochondrial anomalies, capillary deficiency, impaired capillary microcirculation, and specific and non-specific muscle fiber changes in quadriceps and trapezius muscles were reported in some of these pathophysiology studies [8,9,10,11,12,13,14,15,16], and there was no difference between healthy sedentary controls in others [21,22,23,24]. Some studies noticed that muscles with tender points were affected [25], but asymptomatic muscles were not affected in other studies [26, 27].

Despite these contradictory results in direct evaluations of muscles, it was generally accepted until recently that patients with FMS had decreased muscle strength compared with healthy controls [28, 29]. However, some authors studied the knee extensor and elbow flexor muscles and reported muscle strength loss [30,31,32], whereas others found no differences [33, 34]. They reported that the decrease in muscle strength could be explained by a decrease in physical activity and progressive fitness loss. Another study has also been shown that the emotional state, pain, sleep disorder, and lack of motivation might also affect muscle strength measurements [19].

As a first in the literature, in the present study, instead of evaluating the most involved and frequently studied muscles such as the trapezius, we assessed multiple upper and lower extremity muscles in which contradictory results have been reported using musculoskeletal US, which is a non-invasive, safe, and inexpensive method of direct imaging of the muscle. Musculoskeletal US is a valid and reliable method for the direct evaluation of muscle mass. There is an increasing trend and increasing evidence of validity in medicine for the use of US for the direct imaging of musculoskeletal pathology [35]. Unlike studies that focused on muscle strength, there was no correlation between muscle size, pain, and emotional state in the present study, which may suggest a more objective evaluation of muscles through the use of US.

As a result of our study, all muscle sizes except the deltoid muscle were found to be decreased compared with healthy controls. We think that this result cannot be explained only by inactivity because patients with newly diagnosed and established FMS were evaluated in 2 different groups, unlike the studies reported above, where only patients with established FMS were included. As a first study in the literature, it was found that the muscles were affected from the onset of the disease.

It has been reported that the presence of long-term physical inactivity and immobilization might trigger mitochondrial changes and related muscle atrophies as in previous FMS studies [36]. In addition, the distribution of muscle fiber type, energy needs, and the involvement of antigravity muscles may change muscle atrophy development rates and some muscle may develop rapid atrophy [36, 37].

One of the major results of this study was the presence of muscle involvement even in newly diagnosed disease, in other words, inactivity-related muscle weakness, fatigue, and related inactivity when the vicious cycle is not yet fully developed, suggesting that inactivity cannot explain the intramuscular changes in muscle weakness in FMS alone as reported previously. Therefore, contrary to studies proposing inactivity-related peripheral muscle effects and atrophy in the muscles, we believe that the condition is much more related with the disease itself, maybe creating a vicious cycle of disease progression, and inactivity-related muscle changes become prominent. Also, there was no correlation between physical mobility and muscle measurements, which supports our view.

In a recent study, it was reported that there were similarities between sarcopenia and FMS in terms of muscle mass and function, as well as factors such as insulin-like growth factor 1 and proinflammatory cytokines [38]. In patients with sarcopenia, as in our patients with FMS, the decrease in muscle mass in the lower extremities was more significant and earlier than in the upper extremity. Although primary sarcopenia is seen in old age, a secondary form can be related with immobility, malnutrition, and cachexia [39]. With a very indirect opinion, it could be interpreted that FMS may be an early aging disease.

As another result of our study, the correlation of QF muscle CSA with parameters such as fatigue and energy loss in patients with newly diagnosed FMS and the addition of the BB muscle to this picture in patients with established FMS may indicate a central regulation disorder. It was noted in studies evaluating pathophysiology of fatigue that autonomic nervous system dysfunction may cause an insufficient physiologic response to stressors and an increase in oxidative stress due to a peripheral microcirculation disorder in the whole body as well as energy depletion and fatigue [7, 40]. Although the oxidative stress increase in muscle and related mitochondrial damage has been shown to decrease energy production, the same phenomenon is seen in the entire body as a result of autonomic nervous system dysfunction. In other words, the whole body is affected by the altered central regulation, suggesting the direct effect of this regulation disorder on muscle fibers and triggering inactivity by increasing the general symptom such as fatigue. However, it seems more plausible to claim that a generalized effect of central regulation and sympathetic system dysfunction might initiate the vicious cycle.

Limitations

The most important limitation of our study is that we cannot support our work with histopathologic evaluations and biopsies. In addition, although this is the first study to include an evaluation of large muscle groups in the upper and lower extremities using US, it is important to analyze comparative studies with healthy people so that the results will be better understood.

As a conclusion, both upper and lower extremity muscles were found to be affected in patients with FMS compared with healthy controls, even at the time of a new diagnosis. Furthermore, even in patients with newly diagnosed FMS, the decrease in muscle size, especially in the lower extremity, was associated with an increase in fatigue severity and a decrease in energy level and overall quality of life. We think that this situation should be taken into consideration in the treatment and follow-up of the disease.