JCM | Free Full-Text | Waist Circumference and Body Mass Index as Predictors of Disability Progression in Multiple Sclerosis: A Systematic Review and Meta-Analysis
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1. Introduction
Multiple sclerosis (MS) is the most common immune-mediated, inflammatory demyelinating condition of the central nervous system (CNS), characterized by progressive neurodegeneration, gliosis, and neuroinflammation [1]. Common symptomatology ranges from muscle weakness, hypertonia, sensory deficits, cognitive decline, and bladder and bowel problems to sexual dysfunction [1]. In the last decade, there has been an increased research interest in the role of comorbid cardiovascular conditions in the progression of disability in people with MS (PwMS). More specifically, common cardiovascular comorbidities, including hypertension, type 2 diabetes mellitus (T2DM), dyslipidemia, and obesity, have been shown to increase cumulative disability and disability progression [2,3,4]. In addition, obesity and a high body mass index (BMI) have been associated with increased odds for myocardial infraction, acute ischemic stroke, metabolic syndrome, and T2DM [5].
Furthermore, obesity has been shown to increase the incidence of MS in teenagers and young adults. In a recent study, the risk for developing MS in subjects whose BMI exceeded 27 kg/m2 at the age of 20 was two-fold higher than that in normal-weighted subjects of the same age [6]. Moreover, several mendelian randomization studies support the hypothesis that increased BMI and obesity influence a subject’s susceptibility to MS with the odds ranging from 1.21 to 1.4 [7,8,9]. Potential biological mechanisms still remain unknown, but two major hypotheses have been put forth: (a) chronic-low grade inflammatory response due to obesity; and (b) lower circulating levels of vitamin D in adults and children with high BMI [10,11]. Beyond the risk for developing MS, obesity has been shown to have a detrimental impact on MS progression. In PwMS with a comorbid obesity, decreased physical activity has been linked to the worsening of neuro-inflammation and cognitive decline and an increased risk of disability accrual [3,12,13].
To this day, there is a strong belief that PwMS have an increased risk of being overweight and/or obese, with preventive strategies being heralded as integral for the clinical management of MS. With respect to implemented anthropometric measures of obesity, cardiovascular research suggests that waist circumference (WC), compared to BMI, has a stronger association with metabolic risk in clinical practice [14]. Nevertheless, there is a dearth of evidence regarding the comparative efficacy of WC and BMI for the assessment of obesity and related disability in MS. Based on the previous considerations and given the clinical implication of comorbid obesity in PwMS, the aim of this systematic review and meta-analysis was two-fold. First, we sought to provide comparative estimates of the WC and BMI in PwMS, and second, we aimed to investigate potential associations between WC and BMI, including demographic and specific MS characteristics, including the Expanded Disability Status Scale (EDSS) and disease duration.
4. Discussion
In the present systematic review and meta-analysis, the pooled mean WC among PwMS was estimated at 87.27 cm (95%CI [84.07; 90.47]), with the corresponding pooled mean BMI being 25.73 (95%CI [25.15; 26.31]). When stratifying by gender, female PwMS had a mean WC of 87.83 cm (95% CI [83.93, 91.73]), while male PwMS had a statistically significantly higher mean WC by 6.81 cm (corresponding to 94.67 cm (95% CI [92.56, 96.78]). Based on the ranges of the WC and BMI in the normal population [39,40,41], our findings indicate that PwMS fall within the normal range when evaluated based on the WC but in the overweight range when evaluated based on the BMI. This discrepancy may be due the fact that BMI is a function of weight and height, whereas WC does not account for body stature and may thus be complementary to BMI for obesity assessments in clinical practice. To overcome the inherent limitations of both BMI and WC, the waist-to-height ratio has been recently introduced as an index for central adiposity with improved performance in predicting cardiometabolic risk. Nevertheless, waist-to-height data in the PwMS population were not available for meta-analysis.
The clinical implications of WC and BMI assessments were further explored, analyzing the association between disability and the two different anthropometric evaluation tools. EDSS, as the main clinical disability index for PwMS, was found to have a weak positive correlation with WC. Additionally, our results indicated a bidirectional relationship between EDSS and WC. More specifically, a 1-point increase in the EDSS score was shown to result in a 4 cm increase. Accordingly, a 1 cm increase in the WC resulted in a 0.15-point increase in the EDSS. In our view, lower physical activity and increased levels of disability in PwMS, which are directly associated with an increase in visceral fat deposits, explain, in part, the bidirectional relationship between the EDSS and WC. Lastly, although there was a significant association between the level of disability (EDSS score) and WC, no association was found between BMI and disability progression in PwMS.
The positive bi-directional association between WC and disability progression in PwMS could be attributed to physical deconditioning resulting from reduced mobility, fatigue, and physical inactivity. More specifically, when compared to healthy individuals, the wide majority of PwMS have been shown to have reduced aerobic capacity [42], normal-to-low maximal exercise capacity [43], and significantly decreased walking endurance. Additional studies highlight that a lack of physical exercise combined with physical deconditioning acts as a contributing factor to the reduced walking capacity observed in PwMS. On this note, the role of chronic fatigue should not be overlooked, as it is an equally important contributing factor related to the physical inactivity and reduced mobility seen in these patients [44]. More specifically, chronic fatigue, which is a frequently occurring phenomenon in PwMS with mild disability, has been linked to physical deconditioning, which, in turn, has been shown to be associated with increased neuromuscular fatigability, and, in turn, reduced walking capacity [45]. Accordingly, active participation in physical exercise activities in PwMS has been shown to have a gradual or non-linear heart rate response that is analogous to that in healthy individuals, suggesting that physiological deconditioning is linked to MS-related autonomic dysfunction [43].
Several considerations should be taken into account when interpreting the previous findings. To begin, research has shown that the influence of genetic and environmental factors associated with a high BMI contribute to MS development [6,7]. More specifically, a BMI > 27 kg/m2 during puberty and early adolescence is associated with a significantly increased risk of MS development [6,7]. Moreover, research has proposed the existence of a possible underlying mechanism between obesity and an increased risk of developing MS, mediated by the actions of the immune system and hormonal factors. More specifically, studies propose that obesity, as expressed by an increased BMI, directly influences the immune system via the actions of specific hormones, including adiponectin and leptin, thereby fostering a pro-inflammatory environment [6,7]. Despite the association between a higher BMI and increased susceptibility to MS development, however, there are conflicting data in the literature concerning the correlation between BMI and disease progression and disability in PwMS.
Furthermore, when compared to BMI, WC has a distinctive advantage as a prognostic index, due to its sensitivity in detecting abdominal obesity, which has been shown to be predictive of cardiovascular pathology risk and type 2 Diabetes Mellitus (T2DM) even in individuals with a normal BMI [45]. Notably, research indicates that WC more accurately predicts cardiovascular risk and T2DM in PwMS compared to the BMI, which underestimates adiposity in these patients [46,47]. Moreover, multiple studies have demonstrated a significant association between an increased WC and elevated risks of cerebral small vessel disease, T2DM, and neurological disability [48,49]. Consequently, WC emerges as a more accurate prognostic indicator of the cardiovascular burden in PwMS, which has been linked to an elevated risk of cerebral small vessel disease and neurological disability.
Given the increased risk of cardiovascular comorbidities in PwMS and their detrimental impact on the overall disease severity and disability progression, WC and BMI in the upper normal ranges can still have a negative effect on disease progression and the overall quality of life of PwMS and are correlated with the patient’s disability levels [27,28,32,36]. Concerning the potential underlying pathophysiological mechanisms, several pathways appear to be linking obesity and neuroinflammation.
On the one hand, fat tissue has been found to be associated with the overproduction of pro-inflammatory adipokines and, on the other hand, with the attenuation of anti-inflammatory adipokines [50]. Adipokines, which are soluble factors secreted by adipose tissue, play diverse roles in biological processes and are implicated in the chronic inflammatory state associated with obesity [50]. A recent study by Breden and colleagues suggests a clear gender dichotomy, with obese female individuals having higher circulating levels of total and high-molecular-weight adiponectin and leptin serum concentrations [51]. They impact immune function, metabolism, and the nutritional status. The lean adipose tissue stroma is comprised of regulatory T cells (Treg cells), invariant natural killer cells (iNKT cells), M2 macrophages, natural killer cells (NK cells), innate lymphoid cells type 2 (ILC2), and eosinophils, collectively fostering an anti-inflammatory milieu [50]. Obesity alters the balance of the anti-inflammatory environment, promoting the creation of a pro-inflammatory state characterized by a substantial increase in M1 macrophages and neutrophils, CD8+ T cells, and T helper 1 cells [50]. Simultaneously, there is a decrease in Treg cells, ILC2 cells, iNKT cells, and Th2 immunosuppressive mediators (such as IL-4, IL-10, and TGF-β), combined with the decreased activation of peroxisome proliferator-activated gamma (PPAR-γ), crucial for sustaining the homeostasis of the adipose tissue [50]. Collectively, these factors result in a chronic low-grade inflammatory state, disrupting both local and systemic immune system regulation, increasing the susceptibility to and progression of autoimmune disorders, such as MS, while exhibiting fluctuations depending on patient age, age at MS onset, and early vs. late stages of MS [50].
4.1. Issues to Be Addressed
Following the discussion above, several factors have been identified to be addressed in future research. First, there is a need for a more consistent measurement of WC and height. Over the course of MS, especially in patients with higher disability levels, there is an increased chance of musculoskeletal disorders that may affect height measurements and/or protrusion (in PwMS that use a wheelchair), which may result in measurement discrepancies.
Second, while BMI remains a primary measure of obesity in clinical settings, emerging evidence underscores its inadequacy as a reliable estimator of obesity. Findings from studies involving patients with spinal cord injuries support our hypothesis that BMI has a reduced efficacy in explaining the variance in measured percent fat mass compared to individuals without such injuries [52,53]. These limitations can be attributed to potential measurement error and BMI’s inherent inability to differentiate between fat and fat-free mass, as well as its inability to accurately assess body fat distribution. In our opinion, a combination of anthropometric measurements, including height, weight, waist circumference, the waist-to-height ratio, and bioelectrical impedance analysis should be recorded for each patient with MS.
Taking into consideration the information discussed above and the recent finding of Lutfullin and colleagues that suggest that the presence of obesity at MS onset is correlated with higher disease severity and poorer outcomes [54], we suggest that WC should be used as a complementary assessment measure in clinical settings for various reasons. First, WC is a measure of abdominal and visceral obesity, thereby accurately differentiating between the fat distribution patterns seen in PwMS, as opposed to BMI, which measures the overall body fat solely based on an individual’s weight and height. Second, since visceral fat deposition is closely related to cardiovascular factors, which may worsen MS symptom severity and disease progression, using WC in clinical practice could be a more representative, and possibly reliable, measure of visceral fat changes in these patients. Third, bearing in mind the potential of WC for detecting fat distribution alterations, which result from decreased kinesis and changes in patients’ metabolism, it may be a more representative monitoring tool of body fat distribution in the long-term. Lastly, this study established a positive relationship between WC and EDSS, thereby further emphasizing its potential use as an additional monitoring tool for disease severity.
4.2. Limitations
To our knowledge this is the first study that attempts to estimate the mean WC of PwMS. Nonetheless, our study is not without limitations. First, there is a high degree of heterogeneity among included studies in terms of methodology, population characteristics, and reported outcomes. Second, the analyzed sample is small and relatively young with a low degree of disability (in studies reporting EDSS). Third, concomitant disease-modifying therapies, comorbidities, and further confounders could not be included in the meta-regression (as only aggregate data were reported in the included studies). Fourth, as subgroup analyses based on the MS type could not be performed due to data unavailability, our results warrant replication for different MS patient populations in future studies.
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