In the present study, we found that, after controlling for confounders, RA increases the risk of having a low skeletal muscle mass in women almost 3-fold compared with that in female controls of similar age. After adjusting for age, smoking, disease duration, corticosteroid dosage, disease activity, HAQ-DI score, BMI and comorbidities, we also found that a failure to combined treatment with csDMARDs was associated with a 2.4-fold risk of low skeletal muscle mass.
Torii et al. (12) described a higher prevalence of low muscle mass in RA patients (49%) in Japan, and similar findings were also found by two independent studies performed in RA patients from Morocco and Turkey (39.8% and 43.3%, respectively) (13, 8). However, the rate of low skeletal muscle mass observed in our patients with RA was lower (27.8%), closer to that found in studies performed in Europe and in the United States, in which the reported rates of low muscle mass vary from 20% to 28.6% (7, 10). An even lower prevalence of low muscle mass in RA has been reported in two additional studies, one of which was performed in Spain and the second of which was reported in the United States (13% and 11%, respectively) (9, 11). Such variations can be attributable to differences in the population of RA patients being included, such as differences in race and genetic predisposition, different RA duration at the time of the study, more severe disease at the time of the inclusion, contribution of comorbid diseases and non-similarity of the therapeutic strategies. Also, these studies have a high heterogeneity in their inclusion criteria (6, 9, 13, 12).
This issue is important because there are several variables that can influence the presence of myopenia, including sex, age, severity of the disease and comorbidities, which should be considered in comparing the results across the different studies.
Our findings of a higher prevalence of low muscle mass in women with RA compared with controls are consistent with the data reported by other case-control studies. A similar result was identified by Alkan et al. in Turkey with a rate of low muscle mass of 20% in their patients with RA versus 7% in their controls (7).
Several studies have also compared the frequency of low skeletal muscle mass in RA patients with controls (6, 8–10). Delgado-Frias et al. in Spain described a frequency of low muscle mass of 13% in RA patients compared to 6% in controls (9), whereas Tournadre et al. in France identified a frequency of low muscle mass of 28.6% in RA patients but only in 4.8% in their controls (10). These studies support our findings that the presence of RA increases the risk of low muscle mass in comparison with the population included as a control.
Nevertheless, relatively few studies have identified the risk of low muscle mass in RA adjusting by confounders (6, 9, 10, 12, 13). After controlling the multivariate logistic regression analysis for other potential risk factors, we identified that the risk of low skeletal muscle mass is increased in RA patients, independently of the other traditional factors associated with sarcopenia. This fact should alert physicians to detect this feature earlier in RA patients and establish adequate strategies for avoiding complications.
In relation to the main aim of our study, we demonstrated a significant association between the failure to combined therapy with csDMARDs and low muscle skeletal mass in RA. To our best knowledge, this finding has not been reported previously. Other works have tested the link between treatment with glucocorticoids and myopenia, an association that was not observed in our study, probably because our patients used lower corticosteroid doses. Ngeleu et al., for example, reported in their RA patients a higher dose of glucocorticoids compared with our study (mean 11 mg/day vs. 4.9 mg/day, respectively), with corticosteroids being a drug that in high doses contributes to the decrease in skeletal muscle mass.
Dao et al. explored the association between low muscle mass and the lack of treatment with DMARDs, identifying a higher frequency of low muscle mass and obesity (sarcopenic obesity) in patients with RA not being treated with synthetic disease modifying anti-rheumatic drugs (DMARDs) (16).
The results of this work support our hypothesisthat in RA patients, the failure to achieve adequate control of the disease is a risk factor for impaired muscle mass. This is consistent with the knowledge that persistent inflammatory disease activity, a decrease in physical performance, and the overexpression of pro-inflammatory cytokines, adipokines and other molecules increase muscle degradation, leading to the development of low muscle mass in these patients (5, 14).Inflammation has been shown to reduce muscle mass in both cachexia and sarcopenia. We consider our findings that a failure to combined treatment with csDMARDs is associated with a greater risk of low skeletal muscle mass in RA women to be relevant for clinical care in RA patients. Therefore, other therapeutic strategies might need to be considered earlier in non-responders to combined therapy with csDMARDS. Some studies have identified that biological agents such as etanercept or tocilizumab could have a protective effect on the maintenance of adequate lean mass (10, 15, 36). Due to their potent effects in suppressing inflammation by inhibiting cytokines such as TNF-a and IL–6, biologic agents might reduce the catabolic effects of these and other molecules, thus collaborating with the positive effects on muscle associated with a control of the disease activity (10, 37).
An evident limitation of our study is the late start of biological therapies, which are usually not considered until two or three different combinations of csDMARDs fail, so we did not have a group with early biological treatment for comparison. However, we used a therapeutic protocol that is common in countries with financial restrictions on the use of expensive drugs, and thus our findings may be useful for many clinical settings. A future cohort comparing RA patients treated early with biologics versus treated with combined therapy with csDMARDs at a similar point of disease duration is required.
Other limitations of our study should be noted. We did not measure nutritional status, and malnutrition is a precipitant factor for muscle deterioration. Future studies should include the analysis of nutritional status as a relevant factor in these patients with RA. Also, this study focused in the measurement of muscle mass, but a complete assessment of muscle function, muscular strength, and assessment of nutrition in conjunction with muscle mass is relevant for a more complete assessment of sarcopenia (5, 3). Rheumatoid cachexia instead is a syndrome characterized by a loss of cell mass and body mass not only involving skeletal muscle but also usually involving a decrease in fat mass (4, 5). A complete assessment of sarcopenia, rheumatoid cachexia, and malnutrition evaluation of these three features should be considered in future studies.