Impact of body weight on the achievement of minimal disease activity in patients with rheumatic diseases: a systematic review and meta-analysis

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by inflammation of the synovial tissue that leads to bone erosion and progressive disability. Its prevalence of 0.5–1% in the general population makes it the most common chronic inflammatory condition [1]. Psoriatic arthritis (PsA) is a chronic inflammatory joint disease affecting up to 40% of patient with psoriasis, with a prevalence of 0.3–1% in the general population and leading to severe physical limitations and disabilities [2].

Besides articular manifestations, PsA and RA are characterized by an increased cardiovascular (CV) risk [3, 4], as represented by a higher prevalence of metabolic syndrome and of some of its major features (obesity, hypertension, hypercholesterolemia, hypertriglyceridemia, impaired fasting glucose) [5], increased platelet reactivity [6–8], higher degree of subclinical atherosclerosis [4, 9], impairment of endothelial function, and arterial stiffness [10–12]. In particular, several studies have shown a higher prevalence of obesity in patient with PsA and patients with RA than in the general population. Obesity causes an abnormal expression of adipokines (e.g., tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6], adiponectin, leptin), which leads to a proinflammatory status. Thus, obesity can be considered a low-grade, chronic systemic inflammatory disease [13, 14]. Moreover, immune-mediated inflammation may act synergistically with obesity-mediated inflammatory status and may influence disease activity in rheumatic diseases [13, 15, 16]. Some studies [17] suggested that obese patients with rheumatic diseases exhibit a lower rate of low disease activity achievement during treatment with antirheumatic drugs. However, these results were challenged and not confirmed by other studies [18, 19]. In the present meta-analysis, we evaluated whether obesity and overweight impact the clinical response in patients with PsA and patients with RA receiving treatment with traditional disease-modifying antirheumatic drugs (DMARDs) or biologic DMARDs.

A protocol for this review was prospectively developed, detailing the specific objectives, the criteria for study selection, the approach to assessment of study quality, the outcomes, and the statistical methods.

As reported in Additional file 1: Figure S1, of the 603 retrieved studies, 583 were excluded because they were reviews or case reports or were judged to be off the topic after scanning the title and/or the abstract. Another three studies were excluded after full-length paper evaluation because they reported only data about radiographic joint damage progression. Thus, 17 studies [7, 15–19, 24–34] (10 on RA and 7 on PsA) comprising a total of 6693 patients (1562 with PsA and 5131 with RA) were included in the analysis. All the included studies stratified the study population according to the presence of obesity. In addition, eight studies [17–19, 29–33] also reported data on overweight patients.

MDA and body weight

All the 17 studies [7, 15–19, 24–34] provided data about achievement of MDA in 1765 obese patients with PsA or RA receiving a treatment with traditional or biologic DMARDs. As showed in Fig. 1, the remission rate was significantly lower in the 1765 obese patients than in the 3349 normal-weight subjects (30.9%, [95% CI 21.1–42.8%] vs. 50.0% [95% CI 38.8–61.1%]) with a corresponding OR of 0.447 (95% CI 0.346–0.577, p < 0.001, I ² = 62.6%, p < 0.001). The heterogeneity was not reduced by the exclusion of one study at a time. Overall, the risk of not achieving MDA attributable to the presence of obesity was 38.2%.

Interestingly, a significant difference was also found in eight studies [17–19, 29–33] in which researchers reported data on overweight patients and showed a significantly lower prevalence of MDA achievement in the 1579 overweight patients (297 with PsA and 1282 with RA) than in the 1794 normal-weight subjects (OR 0.867, 95% CI 0.757–0.994, p = 0.041, I ² = 64%, p = 0.007) (Fig. 2). The heterogeneity was not reduced by the exclusion of one study at a time.

Sensitivity analyses

To minimize the impact of several confounding factors on the difference in MDA achievement between obese or overweight patients and normal-weight control subjects, we pooled data from the five studies [18, 19, 25, 27, 34] in which researchers reported adjusted risk estimates. This sensitivity analysis consistently confirmed the lower MDA achievement, both in obese (OR 0.481, 95% CI 0.385–0.602) and in overweight patients (OR 0.657, 95% CI 0.521–0.829), than in normal-weight control subjects. In addition, these results were confirmed after we excluded studies [18, 27, 28] defining obesity as BMI >25 kg/m² and the study [32] defining MDA as an on-treatment DAS28 < 5.1 (Additional file 1: Figure S2).

Publication bias

Funnel plots of effect size versus standard error for studies evaluating the association of BMI with MDA rate were quite symmetrical, suggesting absence of publication bias and of small-study effect (Additional file 1: Figure S3). Egger’s test confirmed the absence of publication bias both for studies on obesity (p =0.285) and for studies on overweight (p = 0.314).

Meta-regression analysis

To further assess the impact of BMI on decreasing chances of remission, some meta-regression analyses were performed. While follow-up, age, male sex, and treatment duration affected the difference in MDA achievement between obese or overweight patients and normal-weight subjects (Z-value 2.66, p = 0.008; Z-value 3.19, p = 0.001; Z-value −2.29, p = 0.022; Z-values 3.0, p = 0.003, respectively) (Fig. 3), baseline DAS28, disease duration, CRP, and ESR at baseline did not (Z-value −0.22, p = 0.827; Z-value −1.08, p = 0.277, Z-value −1.60, p = 0.108; and Z-value 1.62, p = 0.104, respectively) (Additional file 1: Figure S4).

In the present meta-analysis, we evaluated the impact of obesity or overweight on the achievement of MDA in patients with PsA and patients with RA receiving treatment with traditional or biologic DMARDs. We found a significantly lower MDA achievement in obese patients (BMI >30 kg/m²) than in those with a normal weight (BMI <25 kg/m²). Interestingly, a significant difference has been also documented in overweight patients (BMI from 25 to 30 kg/m²) compared with those with a normal weight (BMI <25 kg/m²). Moreover, all results were confirmed when we separately analyzed patients with RA and patients with PsA.

Meta-regression analyses refined and extended our findings. Interestingly, we found that follow-up, treatment duration, age, and male sex affected the difference in MDA achievement between obese patients and normal-weight subjects. In detail, we found that a progressive increase in treatment duration leads to a lower difference in the rate of MDA achievement between obese patients and those with a normal weight. This result might suggest that obese patients may need a longer-lasting antirheumatic treatment to achieve MDA. However, data about the time needed to achieve MDA are not available; thus, further studies with ad hoc designs are needed to verify this hypothesis.

With regard to age and sex, we found that the reduction in MDA achievement due to obesity is more significant in males and in younger subjects. This finding is of particular interest, considering that some previous data suggested that a young age and male sex are able to identify patients most likely to achieve MDA during treatment with antirheumatic drugs [30, 35]. Thus, according to our results, obesity could hamper the effect of these predictors of MDA achievement. However, these results could be due to chance, and further studies evaluating potential underlying mechanisms are needed to address this issue.

Several different mechanisms may be involved in the explanation of the impact of obesity on MDA achievement. It is known that adipose tissue has an endocrine function because it secretes many molecules (adipokines) involved in the inflammatory network. These mediators include mainly adiponectin, leptin, plasminogen activator inhibitor-1 (PAI-1), IL-6, and TNF-α. Adiponectin is an anti-inflammatory cytokine. A low concentration of adiponectin is associated with insulin resistance and impaired endothelium-dependent vasodilation. Low serum levels of adiponectin have been reported in several chronic diseases such as obesity and psoriasis. Both leptin and PAI-1 induce endothelial dysfunction. In addition, IL-6 and TNF-α promote insulin resistance in skeletal muscle and liver as well as proinflammatory activity in synovial tissue. Moreover, TNF-α induces endothelial dysfunction and liver synthesis of clotting factors, thus predisposing individuals to atherosclerosis and atherothrombosis [36]. High levels of TNF-α and IL-6 eventually reduce adiponectin production by adipose tissue, determining a self-maintained system.

A further relevant information that could be derived from our study is the prevalence of obesity in patients with rheumatic disease. Interestingly, patients were consecutively enrolled in the included studies, and among 6693 patients (1562 with PsA and 5131 with RA), the prevalence of obesity or overweight was about 50%. This finding further strengthens the hypothesis of the high prevalence of cardiometabolic risk factors in patients with rheumatic diseases [4, 37]. Much data in the literature supports this possibility [38–40], and the finding that the vascular morbidity/mortality of patients with rheumatic diseases resembles that of patients with type 2 diabetes mellitus further helps define the severity of the CV risk in this clinical setting [41]. In fact, obesity is associated with a hyperexpression of TNF-α and other adipokines (e.g., IL-6, leptin, adiponectin) and transforming growth factor-β, which leads to a chronic proinflammatory state. Moreover, subjects with rheumatic diseases exhibit an enhanced prevalence of the metabolic syndrome and of some of its major features (obesity, hypertension, hypercholesterolemia, hypertriglyceridemia, and impaired fasting glucose). However, such an association does not entirely explain the extent of premature atherosclerosis in subjects with rheumatic diseases, and inflammation appears to act synergistically with traditional vascular risk factors (VRFs). In fact, several studies demonstrated that patients with rheumatic diseases had increased platelet reactivity [6–8], a higher grade of subclinical atherosclerosis [4, 9], impairment of endothelial function, and arterial stiffness [10–12], as compared with control subjects matched for CV risk factors. In this setting, antirheumatic treatment was demonstrated to have beneficial effects on lowering the CV risk in these patients by controlling systemic inflammation, with maximum effect in those who achieved MDA [8].

Our study has some potential limitations. First, the studies included in our meta-analysis had different inclusion and exclusion criteria, and there was significant heterogeneity among the studies. Interestingly, all studies used standardized BMI cutoffs to define the presence/absence of obesity/overweight. However, three studies that defined obesity as a BMI >25 kg/m² [18, 27, 28] did not provide separate data for overweight and obesity. Interestingly, when we repeated the analyses after excluding these three studies, all results were entirely confirmed. A further potential source of bias is the lack of data about changes in BMI during the study period. Some evidence in the literature suggested that treatment with antirheumatic drugs is able to modify BMI [3, 42] and that weight loss is able to increase the MDA achievement rate [5]. This should be taken into account when interpreting results of the present meta-analysis.

The definition of MDA was highly variable among studies. The cutoff to define MDA achievement was based on an on-treatment DAS28 score <2.6 in seven studies [17, 18, 25, 28, 29, 33, 34], <5.1 in one study [32], and according to the Coates criteria in six studies on PsA [7, 15, 16, 19, 24, 30]. In addition, both DAS28 and Coates criteria also include ESR and CRP values for the assessment of disease activity. Because obesity is associated with low-grade inflammation [13], ESR and CRP levels can result in elevated independently of disease activity. This may lead to a misclassification of MDA achievement. To overcome this problem, newer criteria for MDA definition, specific for obese patients and independent of ESR and CRP, should be used in future studies. Furthermore, there are some major differences in the prevalence of clinical and demographic data of enrolled patients, and, with the meta-regression approach, we were able to adjust results for some but not all potential confounders. Thus, extreme caution is necessary in interpretation of the overall results.

Although it was not possible to conclusively ascertain sources of heterogeneity, all results were confirmed in all subgroups and sensitivity analyses, and no publication bias was found in our analyses. Moreover, to take into account the effect of confounding factors on the difference in the MDA achievement between obese or overweight patients and normal-weight control subjects, we repeated the analysis by pooling only data adjusted for potential confounders, and all results were confirmed. Differences in the types of rheumatic disease studied might represent a potential source of bias. In particular, 10 of the 17 studies included in our meta-analysis were performed with patients with RA, whereas the remaining 7 studies were of patients with PsA. Interestingly, the results obtained in the primary analysis were entirely confirmed when we separately analyzed data on PsA and RA.

Despite some limitations, the results of our study suggest that obesity and overweight reduce the chances to achieve MDA in patients with rheumatic diseases starting treatment with antirheumatic drugs.