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Review

Sarcopenia
Anne Tournadre a,c,∗ , Gaelle Vial a,c , Frédéric Capel c , Martin Soubrier a,c , Yves Boirie b,c
a
Service de rhumatologie, CHU Clermont-Ferrand, 58, rue Montalembert, 63003 Clermont-Ferrand, France
b
Service de nutrition clinique, hôpital G.-Montpied, CHU de Clermont-Ferrand, 63003 Clermont-Ferrand, France
c
Unité de Nutrition Humaine, UMR1019 INRA, université Clermont-Auvergne, 63000 Clermont-Ferrand, France

a r t i c l e i n f o a b s t r a c t

Article history: Sarcopenia is defined as a combination of low muscle mass with low muscle function. The term was
Accepted 5 June 2018 first used to designate the loss of muscle mass and performance associated with aging. Now, recognized
Available online xxx causes of sarcopenia also include chronic disease, a physically inactive lifestyle, loss of mobility, and
malnutrition. Sarcopenia should be differentiated from cachexia, which is characterized not only by low
Keywords: muscle mass but also by weight loss and anorexia. Sarcopenia results from complex and interdependent
Sarcopenia pathophysiological mechanisms that include aging, physical inactivity, neuromuscular compromise,
Muscle
resistance to postprandial anabolism, insulin resistance, lipotoxicity, endocrine factors, oxidative stress,
Fat mass
mitochondrial dysfunction, and inflammation. The prevalence of sarcopenia ranges from 3% to 24%
depending on the diagnostic criteria used and increases with age. Among patients with rheumatoid
arthritis 20% to 30% have sarcopenia, which correlates with disease severity. Sarcopenia exacts a
heavy toll of functional impairment, metabolic disorders, morbidity, mortality, and healthcare costs.
Thus, the consequences of sarcopenia include disability, quality of life impairments, falls, osteoporosis,
dyslipidemia, an increased cardiovascular risk, metabolic syndrome, and immunosuppression. The
adverse effects of sarcopenia are particularly great in patients with a high fat mass, a condition
known as sarcopenic obesity. The diagnosis of sarcopenia rests on muscle mass measurements and on
functional tests that evaluate either muscle strength or physical performance (walking, balance). No
specific biomarkers have been identified to date. The management of sarcopenia requires a multimodal
approach combining a sufficient intake of high-quality protein and fatty acids, physical exercise, and
antiinflammatory medications. Selective androgen receptor modulators and anti-myostatin antibodies
are being evaluated as potential stimulators of muscle anabolism.
© 2018 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.

1. Definition strongly associated with morbidity and mortality [2,3]. Sarcopenia

has been recognized as a disease by the World Health Organiza-
The term sarcopenia was initially used to designate age-related tion and included in the International Classification of Diseases (ICD
loss of muscle. However, the definition of sarcopenia now encom- code M62.8) [4].
passes muscle loss related to chronic disease, physical inactivity Cachexia is a complex multifactorial condition characterized by
or impaired mobility, and malnutrition. Although it has been sug- increased catabolic activity during a severe chronic disease associ-
gested that age-related primary sarcopenia could be differentiated ated with high-grade inflammation. The manifestations of cachexia
from secondary sarcopenia due to a chronic disease or loss of mobil- include weight loss with loss of muscle mass and, often, of fat mass;
ity [1], this distinction is difficult to make in everyday practice, metabolic disorders; and anorexia [5]. This definition of cachexia, in
as older patients often have multiple comorbidities. Sarcopenia is which weight loss is the main criterion, is not met in several chronic
defined as loss of muscle mass combined with alterations in phys- diseases such as rheumatoid arthritis (RA), during which the fat
ical function and muscle quality. These last two characteristics are mass remains unchanged or increases, thus potentially explaining
the absence of weight loss despite the loss of muscle mass [6]. This
clinical phenotype known as sarcopenic obesity implies a tight con-
nection between muscle and fat tissue. Sarcopenic obesity plays a
∗ Corresponding author at: Service de rhumatologie, hôpital G.-Montpied, CHU
central role in muscle function and quality impairments and in the
de Clermont-Ferrand, 58, rue Montalembert, 63003 Clermont-Ferrand, France
development of cardiometabolic and bone disorders.
E-mail address: atournadre@chu-clermontferrand.fr (A. Tournadre).

https://doi.org/10.1016/j.jbspin.2018.08.001
1297-319X/© 2018 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.

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Fig. 1. Mechanisms underlying sarcopenia.

Fig. 2. The postprandial anabolic resistance concept: the postprandial anabolic peak
pic is blunted in patients with anabolic resistance, resulting in a negative protein
2. Mechanisms
balance.

The muscle is a biomechanical contractile organ that applies

forces to bone, thereby allowing movement. In addition to this role In the fasting state, the protein balance is negative, since protein
in motricity, however, muscle is essential to metabolic homeosta- synthesis falls below protein catabolism. In contrast, after a meal
sis. Thus, muscle is a key player in glucose uptake, glycogen storage, the protein balance normally becomes positive, as protein synthe-
lipid oxidation, amino acid release, and energy production. Fur- sis increases and proteolysis diminishes, particularly if the meal is
thermore, muscle is indirectly involved in the immune response, high in protein. Aging is associated with impairments in the abil-
as it serves as a reservoir of amino acids that are rapidly avail- ity to synthesize protein in response to various nutritional factors
able to immunocompetent cells. The mechanisms responsible for (dietary protein, amino acids, insulin) [10]. In vitro, stimulation of
sarcopenia are complex and interdependent (Fig. 1). rat muscle protein synthesis to a predefined level requires twice
as much leucine in aged animals than in young animals [11]. The
2.1. Age, physical inactivity, neuromuscular impairments result is a negative protein balance with a steady decline in protein
stores day after day.
Muscle mass declines with increasing age, chiefly at the expense
of fast twitch type II fibers. The median annual decrease in muscle 2.3. Insulin resistance and lipotoxicity, endocrine factors
mass over the lifespan is 0.37% in females and 0.45% in males. Data
on the age at which the decline begins are conflicting. However, Insulin plays a major role in protein metabolism by stimulating
after 70 years of age the annual decrease is 0.70% in females and amino acid transport within tissues, enhancing protein synthesis,
0.90% in males [7]. The age-related loss of muscle mass is due to a and inhibiting proteolysis. However, the effects of insulin on muscle
gradual decline in the synthesis of muscle proteins, including those seem diminished during aging and in obese patients with insulin
present in the contractile apparatus and mitochondria, combined resistance [12,13]. Interestingly, muscle protein renewal correlates
with impaired proteolysis control. The loss of strength (dynapenia) negatively with fat mass [13], suggesting an adverse effect of fat
occurs at a 2- to 5-fold faster rate compared to the loss of muscle mass on muscle protein synthesis. The ectopic accumulation of
mass [7]. This finding suggests that the ability of muscle to generate toxic lipids (ceramides and diglycerides) within skeletal muscle
force (muscle quality) may undergo early alterations due to changes promotes insulin resistance and muscle resistance to anabolism,
in body composition and increases in fat mass [3]. a phenomenon known as muscle lipotoxicity [14]. In aged animals,
Physical inactivity accelerates the loss of muscle mass and adipose tissue expansion and, therefore, fatty acid uptake by adi-
strength. During bed rest, 1 kg of muscle mass is lost after 10 days pose tissue are decreased, resulting in ectopic accumulation of toxic
[8] and 9% of quadriceps strength after only 5 days, even in young lipids within the muscle (myosteatosis) [14].
individuals [9]. Neurological impairments that contribute to the In addition to insulin, other hormones are involved in muscle
loss of muscle include motor cortex atrophy, alterations in neuro- mass loss, notably sex hormones (testosterone, dehydroepiandros-
transmitters, loss of fast twitch fibers leading to a predominance of terone), cortisol, vitamin D, growth hormone (GH), IGF-1, and
slow twitch fibers, and loss of motor neurons responsible for motor myostatin. These hormones act on the activation and proliferation
unit loss and reorganization. of muscle satellite cells, adipogenesis, and proteolysis. However,
the available data are fragmentary and difficult to reconcile given
2.2. Postprandial resistance to anabolism the wide variety of models and targets used in published studies.

The decrease in the mass of muscle protein is the net result of 3. Oxidative stress and mitochondrial dysfunction
an imbalance between protein synthesis (anabolism) and proteol-
ysis (catabolism). Protein synthesis requires an adequate supply of Sarcopenia is associated with loss of muscle mitochondria and
amino acids from the diet or from proteolytic processes. Anabolism mitochondrial enzymes, mitochondrial DNA mutations and, even-
is triggered chiefly by the intracellular insulin signaling pathway tually, alterations in fatty acid beta-oxidation and in the function
and insulin-like growth factor-1 (IGF-1) receptor pathway (IGF- of the mitochondrial respiratory chain that produces energy in the
1/AKT/mTOR), which also inhibit proteolysis. Catabolism involves form of ATP. Together with impairments in cellular antioxidant
many specific proteolytic pathways, including the ATP-dependent properties, this age-related mitochondrial dysfunction contributes
ubiquitin-proteasome complex, which is influenced by multiple to the accumulation of reactive oxygen species (ROS), which alter
factors (inadequate nutrient intake, physical inactivity, hormone the function of myofibrils, motor neurons, and the sarcoplas-
deficiencies, and proinflammatory cytokines). The main finding mic reticulum and impair muscle regeneration [7]. Increased ROS
from studies on this topic is that aging is related, not to a basal dis- levels indicating exacerbated oxidative stress correlate with loss
order in protein renewal, but to a blunting of the anabolic response of handgrip strength in older women [7]. The decline in mito-
to food intake known as postprandial anabolic resistance (Fig. 2). chondrial oxidative capacity can also promote lipid accumulation

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Table 1
Criteria and cutoffs used to diagnose sarcopenia.

EWGSOP ESPEN SIG IWGS Sarcopenia with FNIH

limited mobility

Muscle mass
DXA SMI kg/m2 ≤ 7.26 (M) LM total kg SMI kg/m2 ≤ 7.23 (M) SMI kg/m2 ≤ 6.81 (M) LMApp kg < 19.75 (M)
≤ 5.54 (F) ≤ 5.67 (F) ≤ 5.18 (F) < 15.02 (F) LMApp /BMI
< 0.789 (M) < 0.512 (F)
Muscular function
Handgrip kg BMI – – – < 26 kg (M) < 16 kg (F)
kg/BMI < 1 (M) < 0.56 (F)
Walking speed < 0.8 m/s < 0.8 m/s < 1 m/s < 1 m/s 6MWT< 400 m –
Timed get-up-and-go test > 10 s – – – –

EWGSOP: European Working Group on Sarcopenia in Older People (Cruz-Jentoft et al., 2010); ESPEN SIG: Special Interest Group “cachexia-anorexia in chronic wasting
diseases” (Muscaritoli et al., 2010); IWGS: International Working Group on Sarcopenia (Fielding et al., 2011); Sarcopenia with limited mobility: Society for Sarcopenia
Cachexia and Wasting Disorders (Morley et al., 2011); FNIH Sarcopenia project (Studenski et al., 2014); LM: lean mass; App: appendicular; SMI: skeletal muscle mass index;
BMI: body mass index; 6MWT: 6-minute walking test; M: male; F: female.

within skeletal muscle even when the dietary fat intake remains of dependency [28]. Sarcopenia is associated with a 50% increase
unchanged. in the risk of admission, a 20-day increase in hospital stay length,
and a 34% to 58% increase in hospital care costs [29,30].
3.1. Inflammation About 20% to 30% of patients with RA have a decrease in muscle
mass [18,31]. Loss of muscle mass correlates with disease severity,
Elevated levels of C-reactive protein, IL-6, and TNF␣ may pro- disease activity, and quality of life [32–34]. Although loss of mobil-
mote muscle loss and are associated in older individuals with ity is usually ascribed to the joint involvement, it explains only 20%
declines in muscle mass and muscle strength [15]. IL-6 overex- of the decrease in walking speed. Body composition is the other
pression in transgenic mice induces muscle wasting, which can be major determinant [35]. The alterations in walking ability, quality
reversed by administering an IL-6 receptor antagonist [16]. TNF␣ of life, and self-sufficiency are even more marked in patients with
injection in mice activates the proteolytic pathways, notably those sarcopenic obesity [28,34,35]. Changes in the ratio of lean mass
involving the proteasome, and impairs muscle function [17]. In over fat mass are probably also involved in the development of the
patients with RA, IL-6 inhibition by tocilizumab is associated with cardiometabolic comorbidities seen in RA. Thus, a low body mass
lean mass gains, whereas fat mass does not increase [18]. The data index (BMI) is associated with increases in the risks of cardiovas-
on TNF␣ antagonists are less consistent [18]. cular disease [36] and metabolic syndrome, whereas the opposite
A single study assessed the anabolic muscle response after meals is true in the general population [37]. That muscle, fat, and bone
and after exercise [19]. The patients had RA without sarcopenia. No tissues are closely linked has been suggested for several years but
differences were found with matched controls [19]. Insulin resis- remains controversial. In a prospective 3-year cohort study of 65-
tance is also associated with RA. Both proinflammatory cytokines year-old retirees in Switzerland, sarcopenia was associated with a
(IL-6, TNF␣) and glucocorticoids promote insulin resistance in RA 2.3-fold increase in the risk of osteoporotic fracture after adjust-
[20]. Oxidative stress contributes to skeletal muscle dysfunction ment on age, gender, and the FRAX score [38]. Nevertheless, in a
in animal models of collagen-induced arthritis [21]. Rats with cohort of women in the US, bone mineral density (BMD) was the
collagen-induced arthritis exhibit protein metabolism alterations, main determinant of the fracture risk, which was not increased by
fatty acid accumulation, and mitochondrial dysfunction, as well as the presence of sarcopenia [39]. Muscle mass loss in patients with
muscle wasting, supporting the hypothesis that joint inflammation RA is associated with a BMD decrease at the hip but not with the
is associated with muscle lipotoxicity [22]. Among hormonal fac- fracture risk [40].
tors, myostatin is regulated during chronic inflammation and may
therefore be involved in inflammatory sarcopenia via its catabolic 5. Diagnosis
effects [23].
The EWGSOP diagnostic criteria perform best in predicting the
4. Epidemiology and impact of sarcopenia on health fall risk. Both muscle mass and muscle strength or physical perfor-
mance must be measured [1,24,25] (Box 1).
The prevalence of sarcopenia varies across populations and
according to the definitions and cutoffs used. Prevalences of 3% to
24% have thus been reported in individuals older than 65 years [24] Box 1
Criteria for the diagnosis of sarcopenia (EWGSOP)a
(Table 1). Using the criteria and cutoffs defined by the European
Working Group on Sarcopenia in Older People (EWGSOP) [25], the Low muscle mass Anthropometry Arm muscle area ≤ 21.4 cm2 in males,
prevalence is 7.1% when both loss of muscle mass and loss of mus- ≤ 21.6 cm2 in females Bioimpedance analysis SMI < 8.87 kg/m2 in
males, < 6.42 kg/m2 in females FFMI ≤ 17 kg/m2 in males, ≤ 15 kg/m2 in
cle function are required and 11% when only the muscle mass loss
females Computed tomography at L3 Lumbar SMI < 55 cm2 /m2 in
criterion is required [24]. males, < 39 cm2 /m2 in females Dual-energy X-ray absorptiometry (DXA)
Sarcopenia has major adverse effects on function, metabolism, Appendicular SMI < 7.26 kg/m2 in males, < 5.45 kg/m2 in females
morbidity, and mortality. Thus, sarcopenia is associated with func- Low muscle strength Handgrip strength: varies with BMI and gender
tional disabilities, quality of life impairments, falls, osteoporosis, Males: BMI ≤ 24, 29 kg; 24 < BMI ≤ 28, 30 kg; BMI ≥ 29, 32 kg Females:
BMI ≤ 23, 17 kg; 23 < BMI ≤ 26, 17.3 kg; 26 < BMI ≤ 29, 18 kg; BMI > 29,
dyslipidemia, an increased cardiovascular risk, metabolic syn- 21 kg
drome, and immunosuppression. Both muscle mass and muscle Low physical performance usual gait speed (< 0.8 m/s) timed get-up-and-go
function (strength, walking speed) are independently associated test > 10 s Short Physical Performance Battery (SPPB)
with mortality [2,26,27]. Decreases in both muscle mass and mus- a
EWGSOP defines sarcopenia as at least one muscle mass criterion plus at least
cle function are associated with a 3.7-fold increase in mortality [26] one muscle strength or physical performance criterion. SMI: skeletal muscle mass
and a 2-fold increase in the fall risk [24], as well as with a greater risk index; FFMI: fat-free mass index.

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Muscle mass can be estimated using a simple anthropomet- inflammation and nutritional status (hemoglobin, albumin, CRP,
ric method that consists in computing the corrected arm muscle IL-6, TNF␣), oxidative stress (protein carbonylation, oxidized LDL),
area after measuring the triceps skinfold thickness [41]. Although and hormonal status (testosterone, IGF-1, DHEA, vitamin D). None
few studies have assessed the performance and reproducibility of these markers is specific of sarcopenia. The serum creatinine
of anthropometric methods, the corrected arm muscle area per- level reflects the muscle mass in individuals whose renal func-
formed better than BMI in predicting mortality [41]. Bioimpedance tion is normal. A low serum creatinine level is associated with an
analysis (BIA) is an inexpensive alternative to dual-energy X-ray increase in mortality [44]. Serum creatinine could be used in com-
absorptiometry (DXA) for obtaining an immediate measurement bination with another renal function marker, cystatin, to define a
of lean mass but does not directly evaluate the muscle and bone sarcopenia index [44]. Circulating free nucleic acids, procollagens,
compartments. BIA values vary with the degree of hydration of agrin, myokines, and proteomic parameters are being evaluated as
the individual, have not been validated in patients with chronic biomarkers for sarcopenia.
diseases, and underestimate lean mass. DXA is currently the inves-
tigation of reference for evaluating total body composition. DXA
provides measurements of muscle mass, fat mass, and bone mass. 6. Management of sarcopenia
DXA results can be used to compute the skeletal muscle mass
index (SMI) by normalizing the lean mass of the four limbs to A healthy diet and sufficient physical activity are the main deter-
either height (in Europe) [1,25] or BMI (in the US) [42]. SMI cutoffs minants of energy homeostasis and body composition changes.
relative to a standard population have been determined for sar- Inflammation, insulin resistance, and physical inactivity promote
copenia. Although DXA is the method of reference for accurately fat deposition, anabolic resistance, and lipotoxicity within the
measuring body compartments and determining whether fat tis- sarcopenic muscle. Sarcopenia therefore requires a multimodal
sue is located in the subcutaneous or visceral compartment, it is management approach combining a nutritional strategy targeting
a global, projected, two-dimensional technique that does not take nutrient quality and intake, exercise, and antiinflammatory and
into account any possible interactions among tissue types. Com- anabolic medications.
puted tomography (CT) of the lumbar spine with slices at the level
of L3 followed by image analysis using dedicated software pro- 6.1. Nutrition
vides an estimate of lumbar skeletal muscle mass (psoas, rectus
abdominis, external oblique, and paraspinal muscles). Peripheral In patients with age-related sarcopenia who are older than
quantitative CT (pQCT) is a more recently developed tool that 65 years, the daily recommended protein intake is 1 to 1.2 g/kg/day
is used in clinical research. With pQCT, three-dimensional trans- instead of 0.8 g/kg/day [45]. Protein supplements, notably essen-
verse slices can be obtained at all four limbs and used to assess tial amino acid supplements including leucine may benefit muscle
bone mass, muscle mass, and muscle density in the same vol- mass and function, although the benefits are inconsistent [46]. The
ume. rates of digestion and absorption, the modalities of protein intake
Handgrip strength is used as a measure of muscle strength. throughout the day, and the synergistic effects of protein with
Available tools for assessing physical performance include walking physical exercise or other nutrients are key determinants of the
speed measurement, the step-on-stool test, or the Short Physi- effectiveness of the protein intake [47].
cal Performance Battery (SPPB) combining a measure of balance, Vitamin D diminished lipotoxicity and exerted anabolic effects
walking speed, and the get-up-and-go test [25]. A sarcopenia on muscle in animal studies [48]. In males older than 65 years,
screening questionnaire (SARC-F) can be helpful in patients older when used in combination with leucine-enriched whey protein for
than 65 years [1]. 6 weeks, vitamin D supplementation increased both postprandial
A broad spectrum of phenotypes is associated with sarcopenia, protein synthesis and muscle mass [49]. Supplemental n-3 polyun-
ranging from loss of both muscle mass and fat mass (cachexia and saturated fatty acids (omega-3) or monounsaturated fatty acids
pre-cachexia) to absence of weight loss or even weight gain (sar- contributed to decrease insulin resistance and lipotoxicity [50];
copenic obesity). Criteria for evaluating the severity of sarcopenia prevented fat mass increases; and improved protein anabolism,
have been developed [25]. Presarcopenia is characterized by low muscle mass, and muscle function [51].
muscle mass that has no impact on muscle strength or physical Appetite stimulants have been tested more specifically in
performance. Sarcopenia is defined as low muscle mass combined patients with cachexia. Examples include megestrol acetate, a pro-
with loss of muscle strength or physical performance. Severe sar- gestin medication, which can be given alone or with L-carnitine;
copenia is low muscle mass with both low muscle strength and low thalidomide, and ghrelin.
physical performance. Obesity or sarcopenic obesity can be defined
as low muscle mass as assessed using DXA (SMI) combined with a
fat mass greater than 28% in males and 40% in females. Sarcopenic 6.2. Physical activity
obesity precedes and predicts loss of self-sufficiency, whereas nei-
ther obesity alone nor sarcopenia alone is independently associated Even low-level physical activity induces decreases in the car-
with loss of self-sufficiency [28]. Nevertheless, these methods are diovascular risk, insulin resistance, and mortality [52,53]. Physical
neither readily available in everyday practice nor reimbursed by the activity diminishes lipotoxicity by increasing mitochondrial fatty-
French statutory health system. Furthermore, they do not allow a acid beta-oxidation by muscle cells and increases the synthesis
noninvasive or minimally invasive assessment of fatty infiltrates of muscle protein. Exercise benefits muscle strength and physi-
within muscle tissue [1,25]. This is regrettable, as muscle quality, cal performance but does not consistently increase muscle mass
which results from body composition, muscle function, and muscle [46]. The optimal exercise modalities and the patient subgroups
fat content is a far better marker of both loss of mobility and mor- most likely to benefit remain to be determined. Ideally, a physi-
tality [3]. In oncology, muscle quality is recognized as a predictor cal training program should combine aerobic exercise to improve
of survival [43]. cardiovascular function and endurance and to decrease fat mass
The complex and multifactorial pathophysiology of sarcopenia with strength exercises to increase muscle mass [54]. In RA, phys-
is a major obstacle to identifying a specific biomarker that would ical exercise programs should be individually tailored to disease
be easily available and would reflect both muscle mass and mus- stage, disease activity, and general health status. Intensive exercise
cle function. The most widely cited markers reflect the level of programs designed to increase muscle mass and muscle strength

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often raise difficulties with implementation and patient adher- require investigations into the mechanisms underlying sarcopenia
ence. in patients with inflammatory conditions and reduced mobility. In
addition, readily available and noninvasive biomarkers are needed
6.3. Biotherapies to ensure the early identification of patients at high risk for sar-
copenia. Treatment targets will need to be validated. Preventive
The metabolic effects of cytokine antagonists, notably on mus- and curative strategies combining nutrition optimization, physical
cle anabolism, remain controversial and require further study. activity, and long-term targeted medications will have to be devel-
In several studies, TNF␣ antagonist or IL-6 antagonist therapy oped. The recommendations and diagnostic tools discussed in this
was associated with weight gain in patients with RA or spondy- article apply to age-related sarcopenia. These data must now be val-
loarthritis (SpA). Although body composition changes have been idated in patients with chronic inflammatory joint disease in order
documented in treated patients, few data are available on muscle to establish decision algorithms and clinical practice guidelines for
strength and function, changes in energy expenditure and physical identifying, preventing, or delaying the onset of sarcopenia.
activity, and dietary intakes. The data should therefore be inter-
preted with caution. Body composition does not seem to change in
the short term in patients with RA treated with TNF␣ antagonists, Disclosure of interest
although an increase in fat mass has been reported after 2 years of
treatment [55–57]. IL-6 antagonist therapy may hold promise for The authors declare that they have no competing interest.
the treatment of cachexia in patients with cancer [58]. After 1 year
of RA treatment with the IL-6 antagonist tocilizumab, patients had
gained weight due to an increase in lean mass with no increase References
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Please cite this article in press as: Tournadre A, et al. Sarcopenia. Joint Bone Spine (2018), https://doi.org/10.1016/j.jbspin.2018.08.001