Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by inflammation of the synovial tissue, which causes damage to articular cartilage and subchondral bone (1, 2). The progression of joint damage differs significantly between patients. Poor prognostic factors include persistent synovitis, early erosive disease, extraarticular findings, rheumatoid factor (RF) and anti–cyclic citrullinated peptide autoantibodies, HLA–DR4 shared epitope alleles, family history of RA, poor functional status, and elevated acute-phase responses (erythrocyte sedimentation rate and/or C-reactive protein [CRP]) (3).
While these and many more potential risk factors were evaluated repeatedly in previous decades, one other factor has not been sufficiently evaluated: the anthropomorphic stature of the RA patient, usually measured as body mass index (BMI). It expresses nutritional status, and may be complicated by metabolic abnormalities and general organ dysfunction, including type 2 diabetes mellitus, cardiovascular disease, and stroke. Many studies have shown increased morbidity and mortality in patients with a high BMI (4–7).
Internists are aware of the risks regarding increased body mass and endocrinologic diseases and, similarly, orthopedists find abundant affirmations of the risk of too much body mass, especially in patients with osteoarthritis (OA) of the knee (8, 9). On the other hand, it is well documented in the literature that the prevalence of osteoporosis is significantly higher among women and men with a low BMI than among overweight people (10–12). Research has proven BMI to be the most statistically significant risk factor for a decrease in bone mineral density (BMD) and low trauma fractures (13).
In rheumatology, data from Kaufmann et al (14) showed that increased radiographic joint damage is significantly correlated with lower BMI. They found the concentration of serum biomarkers of cartilage collagen breakdown and proteoglycan turnover to be correlated with joint destruction in RA, and hence considered BMI to be a sensitive and inflammation-independent predictor of radiographic outcome of RA. The present study was undertaken to determine whether BMI is associated with radiographic damage in patients with RA and whether this association differs in RF-positive and RF-negative patients.
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- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
BMI, a simple anthropometric measure that provides a marker of nutritional status, was shown to interact with radiographic joint damage in a large cohort of patients with early RA. The association already existed at baseline (mean disease duration 11 months) and progressed in the following years. Probably the most striking finding was that normal weight, unquestionably beneficial to health in the general population, turned out to be a risk in patients with RA.
A similar association was repeatedly found with BMD. High body weight and BMI are associated with lower osteoporosis risk (19, 20). Evidence from the National Osteoporosis Risk Assessment study showed decreased odds of osteoporosis and lower bone loss with increasing BMI (21). In the Early Postmenopausal Intervention Cohort study, early postmenopausal women in the lowest BMI tertile were shown to have baseline BMD measurements that were nearly 12% lower and experienced a >2-fold increase in bone loss when compared with women in the highest BMI tertile (20).
The exact physiologic mechanisms underlying the beneficial effects of high body mass or body fat are still widely unknown. Mechanical loading on weight-bearing bones and estrogen synthesis in adipose tissue have been suggested as possible mechanisms (22). Nevertheless, although a recent study showed significant positive correlations between estrogen levels and BMI in postmenopausal women, a correlation between estrogen levels and bone marker levels has not been demonstrated (23).
In recent years, adipocytokines have also been thought to play a role in the mechanisms controlling the association of body constitution with bone mass. However, contradictory results have been reported for the association between adipocytokines and bone metabolism (24).
Scariano et al (25) investigated the role of leptin, a polypeptide hormone that is secreted by adipose cells and influences bone formation. They found the circulating level of leptin to be directly correlated with BMI and positively associated with activity of alkaline phosphatase, a bone-specific marker of osteoblast activity. Therefore, they suggested that leptin levels influence osteoblast activity.
Gunaydin et al (26), who evaluated serum leptin levels and their association with disease activity markers in RA patients, also found the leptin levels to be positively correlated with BMI, but they found no correlations with tumor necrosis factor α levels and clinical or laboratory parameters of disease activity. They concluded that circulating leptin levels do not seem to reflect disease activity. Similar results and conclusions were found in a Japanese study (27). Unfortunately, neither study investigated whether there is an association between leptin level and joint damage, irrespective of disease activity.
In contrast to osteoporosis, where the association between anthropometric characteristics, adipocytokines, and bone formation has been of interest for years, similar investigations on bone destruction in RA are only in their beginning stages. Except for Kaufmann et al (28), who investigated the influence of BMI on radiographic progression in RA patients, BMI is, at best, considered a confounder that should be adjusted for in the equations.
Our data support Kaufmann's results on the association between BMI and joint damage and add the observation that there might be different mechanisms in RF-positive and RF-negative patients. Further studies, especially in a larger number of RF-negative patients, are needed to confirm our results and to explain the underlying mechanisms. It is possible that, due to the overall lower joint destruction in RF-negative patients, a potential association between BMI and joint destruction has not yet been seen. Yet, it is also possible that different autoimmune conditions are associated with different biochemical processes in the arthritic joint.
We also confirmed Kaufmann's assumption of BMI as an inflammation-independent predictor of joint damage in RA patients. Moreover, we did not find an association between weight loss or gain and disease activity or joint damage. Weight loss was not associated with higher disease activity or more joint damage. Therefore, it seems unlikely that the association between low BMI and higher joint damage reflects cachexia associated with severe systemic disease. Weight loss was more frequent in patients who were obese. It seems obvious that in the case of obese patients, more weight can be lost without falling below the initial BMI class.
Since scientific evidence is lacking, there is reason to question the “established” risk factors in RA. The associations between signs and symptoms of the disease and outcome are not straightforward. Escalante and colleagues (29), who found a “paradoxical effect of BMI on survival in rheumatoid arthritis,” concluded that “the role of adiposity in RA may be more important than previously thought,” and Dayer et al (30), who investigated the potentially antiinflammatory properties of adipose tissue, suggested that, in addition to other functions, adipose tissue may give rise to a host-defense mechanism against local inflammation by inducing antiinflammatory interleukin-1 receptor antagonist (IL-1Ra) in adipocytes by producing interferon-β. So the beneficial influence of high body mass may be explained by the up-regulation of IL-1Ra in white adipose tissue (31). Otero et al (32), who also recently showed that the adipose tissue secretes a large variety of highly active proteins, including cytokines, chemokines, and hormone-like factors, suggested that adipose tissue is an active player and not simply a bystander in the modulation of inflammatory immune response.
Further studies are needed to elucidate the underlying mechanisms of the association between BMI and joint damage in RA. These studies should also focus on possible variations of adipocytokines in RF-positive and RF-negative patients. Despite our findings of a possible protective effect of obesity on radiographic joint damage, obesity still is, as seen in this study, an important source of increased pain, increased functional disability, impaired health, and impaired quality of life in patients with RA (33).
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- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
The authors wish to thank those rheumatologists who enrolled at least 15 patients each: S. Wassenberg, Ratingen; M. Hammer, Sendenhorst; W. Demary and U. von Hinüber, Hildesheim; F. Hamann and A. Teich, Leipzig; K. L. Schmidt, Bad Nauheim; E. Gromnica-Ihle, Berlin; G. Hein, Jena; R. Haux, Berlin; R. Dreher, Bad Kreuznach; D. Pick, Grafschaft-Holzweiler; M. Stoyanova-Scholz, Duisburg; H. Menninger, Bad Abbach; H. Zeidler, Hannover; H. E. Schröder, Dresden; M. Braun, Cuxhaven; J. Braun, Herne; J. Lautenschläger, Bad Pyrmont; B. Lang, Baden-Baden; A. Thiele, Wuppertal; and L. Gross, Bad Bramstedt.