Rheumatoid arthritis (RA) is a systemic inflammatory disorder that affects 1–2% of adults and frequently leads to progressive joint deformity and disability. This disability is costly, with the direct medical cost of RA disability amounting to between $9,000 and $19,000 per year (1), and the indirect costs, such as loss of work, compounding the expense (2). In addition, greater disability in RA patients portends poorer health outcomes, including higher all-cause and cardiovascular mortality rates (3).
Contributors to disability in RA go beyond articular swelling, tenderness, and deformity. Several of the major extraarticular determinants include mood (4), sleep (5), and the more recently studied body composition. RA patients, on average, have lower body cell mass (6), lower lean mass (7), and higher fat mass (7, 8) as compared to otherwise similar non-RA controls. Lower lean mass and higher fat mass were independently associated with higher levels of disability in RA patients (9). However, distinct from the amount of muscle, the density of muscle may also affect physical functioning. Low muscle density, reflecting reduced muscle contractile units accompanied by fatty replacement (10, 11), was associated with aging, deconditioning, and disuse in the general population (12, 13). As these factors are features of the RA disease state, it is conceivable that low muscle density, in addition to—or even independent of—low muscle mass, may contribute to physical dysfunction in RA patients.
Computed tomography (CT) scanning at the level of the mid-thigh, with quantification of the areas and densities of fat, muscle, and bone, is a validated, reproducible technique for directly assessing whole and regional body composition (14–16). Studies of CT-assessed muscle density in the general population have shown it to be a suitable determinant of muscle quality, in terms of prediction of strength (17, 18), physical performance (18–20), and incidence of mobility limitations (21, 22). However, to date, there have been no studies using CT to assess muscle area or density in the RA population. Most studies have used indirect measures, such as bioelectrical impedance, total body dual x-ray absorptiometry (DXA), or potassium counting.
Therefore, in the present study, we explored the associations of RA disease characteristics with thigh muscle density (TMD), thigh muscle area (TMA), and thigh fat area (TFA), as assessed with quantitative CT. We hypothesized that low thigh muscle density would be associated with disability and low physical performance scores, independently of muscle and fat area.
- Top of page
- PATIENTS AND METHODS.
- AUTHOR CONTRIBUTIONS
In this investigation, which, to our knowledge, is the first to use mid-thigh quantitative CT to measure body composition in RA patients, we observed that the TMD, more so than the TMA and independently of the TFA, was a strong indicator of functional outcomes and physical performance, with each mg/cm3 increase in the TMD being associated with a lower HAQ score, a lower proportion of valued life activities affected, and higher SF-36 physical functioning and SPPB scores. Moreover, in multivariable analyses, RA disease features accounted for approximately one-fourth of the explainable variability in the TMA and TFA and three-fourths of the explainable variability in the TMD.
In recent years, CT-derived muscle density has been established as a marker of muscle quality (11). Density is estimated from CT-derived attenuation coefficients, and low muscle density reflects increased myocellular lipid content and fatty infiltration of the muscle compartment (10). Low muscle density at various sites has been associated with adverse outcomes in several studies of non-RA patients, including frailty (36), reduced physical performance (18–20), increased incidence of mobility limitations (21, 22), increased risk of hip fracture (37), and increased risk of hospitalization (18). However, until now, there have been no studies assessing muscle density in the RA population, let alone associations with functional outcomes. The findings of the present study confirm the importance of this measure in the RA population. Notably, muscle density was a stronger indicator of functional outcomes and physical performance than muscle area, anthropometric parameters, or DXA-derived measures of lean body mass or fat mass, a finding concordant with that of other studies in the general population (18, 37). It is interesting to note that in these studies, in which the enrolled patients were generally older than our cohort by an average of about a decade, the average thigh muscle area and muscle density were similar to those of our RA cohort (21).
Inflammatory cytokines, such as IL-6 and tumor necrosis factor, have been associated with reduced muscle density in non-RA populations (38, 39). Early studies by Roubenoff and colleagues showing reduced body cell mass in RA patients implicated inflammatory cytokines, suggesting a cytokine-driven state of hypermetabolism as the cause (6). Inflammation likely exerts multiple, complex effects on muscle, such as reduced insulin/growth factor sensitivity and accelerated protein degradation. Inflammatory cytokines are clearly associated with muscle wasting in several pathologic states, such as cancer, heart failure, and sepsis (40). Indeed, in our study, the IL-6 level was independently and inversely associated with muscle density and muscle area. In addition, use of HCQ and use of prednisone were also indicators of thigh muscle area and density. While HCQ has not been studied in this context, it is plausible that its effect on muscle density could be mediated by potentiating the activity of lipolytic enzymes by reducing their lysosomal degradation (41, 42), which could, hypothetically, lead to reduced intramyocellular lipid. However, since the association of HCQ with muscle density could be confounded by factors related to the indication for prescribing the drug (i.e., milder disease, etc.), additional study is needed to explore this association.
It was also notable that both fat and muscle areas were lower in prednisone users in our study. There may be several mechanisms underlying this finding. For one, prednisone-treated patients undergo an apparent redistribution of fat from the periphery to the trunk (43), and for another, glucocorticoid therapy may induce muscle wasting and has been associated with low muscle area (44). These indicators are potential targets for intervention that may improve muscle quality and functional outcomes.
The strong, independent association of lower muscle density and higher fat area with limitation in physical performance and disability suggest that these outcomes might be improved by interventions designed to increase muscle density and/or decrease fat. For example, it has been shown that in a study of non-RA patients, muscle area was the same or greater in obese individuals compared to non-obese controls, but muscle density was lower (45). When obese individuals participated in a 16-week weight loss program, there was an increase in muscle density (46), and other studies have shown that changes in muscle density parallel changes in strength during resistance detraining and retraining (13). From a functional standpoint, resistance exercises have already been shown to be effective in reducing pain and fatigue scores, as well as increasing strength and certain measures of physical performance in the RA population (47–50). However, as no studies in RA patients have used CT to determine body composition, the effects of exercise on muscle density in RA are still unknown. Although the duration of intentional exercise and sedentary activities was associated with some thigh composition measures in univariate analyses, we did not observe strong independent associations in multivariable models. This could indicate a true lack of association, or it may be a reflection of the imprecision of self-reported physical activity among RA patients. A clinical trial using a physical activity intervention would be preferred in order to clarify the role of physical activity in altering body composition in RA patients as a means of improving function.
In addition to CT, we also investigated two other methods of determining body composition: DXA and anthropometry. In general, the anthropometry results were poorly correlated with the functional outcome measures and essentially did not add to the information obtained via CT. Some DXA-derived measures of body composition, however, showed associations with functional outcomes similar to those of the CT-derived measures, and it would appear that appendicular lean mass and appendicular fat mass are potentially reasonable surrogates (9). In clinical practice, neither CT nor DXA is yet practical for use in measuring body composition. It is possible that other anthropometric parameters, such as thigh circumference or caliper skinfold assessment of thigh fat, could be a feasible surrogate for clinical practice; however, these were not evaluated in our study.
In our study, both a lower TMD and a higher TFA were significantly associated with a risk of affected obligatory VLAs, but the TMD was not associated with committed or discretionary VLAs. Obligatory VLAs are those considered necessary for survival and self-sufficiency, including walking to get around, getting around one's community by car or public transportation, and taking care of one's basic needs, such as bathing, washing, getting dressed, or taking care of personal hygiene (51). That these types of activities appear to be more strongly influenced by thigh composition than either committed or discretionary VLAs is intriguing. Since our study population was older and generally had more longstanding RA, it is plausible that our subjects have learned ways to participate in these activities despite their physical performance limitations, or they have already adapted and eliminated these from consideration as being important life activities.
The data from our study are cross-sectional, making these findings hypothesis-generating. Both a longitudinal, prospective cohort study of body composition and, eventually, a randomized controlled trial for interventions would be needed to confirm these postulations. Aside from the cross-sectional nature of our investigation, there are additional limitations. First, our study population was older, with relatively longstanding RA, and while a broad distribution of RA characteristics was represented, most had low-to-moderate disease activity with only mild-to-moderate disability. Second, our CT scans were regional, at only the mid thigh, which may provide a more limited estimate of whole body composition. Analysis of cross-sections from multiple body regions would be a useful future study. Third, we did not include measures of muscle strength, which would have permitted a more complete assessment of muscle quality.
In summary, 3 main conclusions can be drawn from this investigation. First, CT of the mid-thigh is a promising technique for directly assessing regional body composition in RA patients, allowing the determination of muscle area, fat area, and muscle density. Second, RA disease features play an important role in thigh composition, accounting for a large proportion of the explainable variability. Third and perhaps most important, muscle density appears to be a stronger indicator of physical functioning than muscle area in RA patients, with associations that are independent of fat mass. Further studies are needed to determine whether interventions aimed at increasing muscle density will improve the disability and poor physical performance that are so characteristic of this population.
- Top of page
- PATIENTS AND METHODS.
- AUTHOR CONTRIBUTIONS
We would like to thank the staff of the Johns Hopkins Bayview Medical Center General Clinical Research Center, the field center of the Baltimore Multi-Ethnic Study of Atherosclerosis (MESA) cohort, and the MESA Coordinating Center at the University of Washington, Seattle. We are indebted to the dedication and hard work of ESCAPE RA staff members Marilyn Towns, Michelle Jones, Patricia Jones, Marissa Hildebrandt, Shawn Franckowiak, and Brandy Miles, as well as to the participants in the ESCAPE RA study who graciously agreed to take part in this research. Drs. Uzma Haque, Clifton Bingham III, Carol Ziminski, Jill Ratain, Ira Fine, Joyce Kopicky-Burd, David McGinnis, Andrea Marx, Howard Hauptman, Achini Perera, Peter Holt, Alan Matsumoto, Megan Clowse, Gordon Lam, and others generously recommended their patients for this study. We would especially like to thank Dr. Luigi Ferrucci for providing the equipment and expertise required to analyze the thigh CT scans in the study.