To investigate the association between body mass index (BMI) and radiographic joint damage (using the Ratingen Score [RS]) in early rheumatoid arthritis (RA).
To investigate the association between body mass index (BMI) and radiographic joint damage (using the Ratingen Score [RS]) in early rheumatoid arthritis (RA).
The study was carried out in 767 patients with early RA. Standard clinical data, RS, and BMI were evaluated at baseline and after 3 years. Multivariate logistic regression analyses were performed in rheumatoid factor (RF)–positive and RF-negative patients to determine the influence of BMI (<25 versus ≥30 kg/m2) on considerable joint damage (RS ≥7) after 3 years, adjusting for sex, age, disease duration, and disease activity (using the Disease Activity Scale in 28 joints [DAS28]).
Patients of normal weight already had significantly more joint damage at study entry than obese patients (mean RS 4.5 versus 2.4; P = 0.004) and experienced significantly more progression than obese patients (RS 3.4 versus 1.3; P = 0.011). At 3 years, their RS score was twice as high as that of the obese patients (7.5 versus 3.7; P < 0.001). Multivariate regression analyses in both serologic groups revealed significantly higher odds of RS ≥7 in RF-positive patients of normal weight than in RF-positive obese patients (odds ratio [OR] 3.3), but not in RF-negative patients. Male sex (OR 1.6), osteoporosis (OR 2.0), C-reactive protein levels >15 mg/liter versus <5 mg/liter (OR 2.6), and disease activity (DAS28 ≥5.1 versus <3.2; OR 1.9) were independently associated with RS ≥7.
BMI provides a risk estimate of joint damage in RA patients. Further studies are needed to elucidate the association between BMI, RF, and joint damage in RA and the possible role of adipose tissue.
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.
From January 2000 through June 2001, 1,023 patients with recent-onset RA (according to the American College of Rheumatology [formerly, the American Rheumatism Association] revised criteria) (15), who were 18 years of age or older, and whose disease duration was <24 months were consecutively enrolled in a prospective observational study by 16 rheumatologic practices and 38 outpatient clinics in Germany.
Baseline and 3-year followup data included disease activity measures and radiographs of hands, wrists, and forefeet (16). A patient questionnaire covered sociodemographic characteristics, function (measured using the Hannover Functional Questionnaire, with a range of 0–100, where 100 = no limitations) (17), pain, general health, and smoking status. RF was assessed by the types of tests that are common in the cooperative care facilities; the most common test was laser nephelometry, which measured the combined amounts of IgM-, IgA-, and IgG-RF. Results were reported as positive or negative, according to the laboratory's definition.
Radiographic damage was assessed by the Ratingen Score (RS) (16), a modification of the Larsen score. It evaluates 38 joints separately (posteroanterior view; all proximal interphalangeal and metacarpophalangeal joints, 4 sites in the wrists, interphalangeal joints of the great toes, and metatarsophalangeal joints 2–5). The amount of joint surface destruction is graded on a 0–5 scale for each joint, providing a maximum possible score of 190. Each grade represents 20% of the joint surface destruction. All radiographs were scored in sequential order by 1 investigator (RR).
Body length and body weight as well as osteoporosis, symptomatic OA, and finger joint OA were assessed by the physician at study entry and at 3-year followup.
On the basis of the BMI (weight [kg]/height [m2]), patients were classified as normal weight (18.5–24.9 kg/m2), overweight (25–29.9 kg/m2), or obese (≥30 kg/m2). Descriptive statistics were used to show the association between BMI and radiographic joint damage (RS 0–190) at study entry and 3 years later in all patients and in the subgroups of RF-positive and RF-negative patients, as measured at study entry.
Differences between the groups were assessed using the chi-square test for categorical data and analysis of variance for continuous data. Multivariate logistic regression was used to investigate the influence of BMI (<25 and 25–29.9 versus ≥30 kg/m2) on considerable joint damage (RS ≥7). This cutoff extended the minimal detectable change (6.2) in the RS (16) and covered approximately one-third of the patients at the 3-year followup. Age, sex, disease duration (months) at the time the radiographs were obtained, disease activity (measured using the Disease Activity Scale in 28 joints (DAS28; 3.2–5.1 versus >5.1 versus <3.2) (18), CRP (≥15 mg/liter versus 5–15 mg/liter versus CRP <5 mg/liter), osteoporosis (yes versus no), and symptomatic OA of different joints (yes versus no) were taken into account as potential confounders. Obese patients (BMI ≥30 kg/m2) were set as the reference category for calculation of the adjusted odds ratios (ORs). Age and disease duration were used as continuous variables. To investigate the association between BMI and joint damage in RF-positive and RF-negative patients, 2 separate multivariate logistic regression equations were used. P values less than 0.05 were considered significant.
Of the 1,023 baseline patients, 916 completed the 3-year study and 767 had available radiographs from the baseline and followup time points. The 767 patients were 22–87 years of age, and disease duration ranged from 2 to 24 months (mean 11 months). Using the BMI, 39.5% were of normal weight (<25 kg/m2), 41.1% were overweight (25–29.9 kg/m2), 15% were obese class I (30–34.9 kg/m2), and 4.4% were obese class II or III (≥35 kg/m2). Six underweight patients (<18.5 kg/m2) were included in the normal weight group. Baseline demographic and clinical characteristics of the patients are summarized in Table 1. Obese patients were significantly older, more frequently women, less frequently current smokers, and had fewer occurrences of osteoporosis than patients with a lower BMI. Mean CRP levels and the proportion of patients taking disease-modifying antirheumatic drugs (DMARDs) were equal in all groups. Obese patients had a significantly higher DAS28 score, worse pain, worse functional capacity, more frequent OA, and a higher number of comorbid conditions than the less heavy patients (Table 1).
|All patients (n = 767)||BMI||P†|
|Normal (<25 kg/m2) (n = 303 [39.5% of total])||Overweight (25–29.9 kg/m2) (n = 315 [41.1% of total])||Obese (≥30 kg/m2) (n = 149 [19.4% of total])|
|Age, mean ± SD||57.2 ± 13||54.9 ± 13||58.8 ± 12||58.7 ± 12||0.000|
|Current smoker, %||21.8||28.0||19.7||13.5||0.008|
|Disease duration, mean ± SD months||11.5 ± 7||12.3 ± 7||11.3 ± 7||11.0 ± 7||0.249|
|RF positive, %||60.9||64.4||60.0||55.7||0.191|
|DAS28, mean ± SD||4.8 ± 1.5||4.6 ± 1.6||4.9 ± 1.4||4.9 ± 1.5||0.048|
|DAS28 >5.1, %||45.8||43.6||45.1||51.7||0.000|
|CRP, mean ± SD mg/liter||21.5 ± 25||20.5 ± 25||22.0 ± 25||22.4 ± 24||0.676|
|General health (NRS 0–10), mean ± SD score||3.2 ± 2.0||3.0 ± 2.0||3.3 ± 1.9||3.7 ± 1.9||0.000|
|Pain (NRS 0–10), mean ± SD score||4.3 ± 2.6||3.9 ± 2.5||4.5 ± 2.6||4.6 ± 2.8||0.010|
|Function (FFbH), mean ± SD score||75 ± 20||79 ± 18||73 ± 20||69 ± 21||0.000|
|Symptomatic OA, %||26.2||18.2||28.6||37.6||0.000|
|Comorbid conditions, mean ± SD number||1.8 ± 1.4||1.3 ± 1.8||2.0 ± 1.9||2.2 ± 1.9||0.000|
|DMARD therapy, %||95.2||93.6||96.7||95.4||0.148|
A higher percentage of patients of normal weight (58%) maintained their initial weight throughout the study period (defined as a change of <2 kg) compared with overweight patients (47%) or obese patients (48%). Substantial weight loss (≥7 kg) was seen in 3% of the patients of normal weight at study entry and 18% of the obese patients, while substantial weight gain (≥7 kg) was equal in all groups (11–12%).
Changes in body weight were independent of baseline DAS28, RF, and modalities of glucocorticoid therapy (never/sometimes/always), but correlated with DAS28 at the end of the study. Patients with high disease activity (3-year followup DAS28 >5.1) (44%) had less frequently maintained their weight than patients with moderate (3.2–5) (52%) or low disease activity (<3.2) (53%), but neither the baseline nor the 3-year DAS28 was associated with total body weight (mean weight 75.0 kg, 74.3 kg, and 75.4 kg among patients with baseline DAS28 <3.2, 3.2–5.1, and >5.1, respectively). Moreover, the 60 patients with substantial weight loss had the same average baseline and 3-year followup DAS28 as the 87 patients with substantial weight gain (baseline and followup DAS28 5.0 and 3.9, respectively, among patients with substantial weight loss and 4.8 and 3.9, respectively, among those with substantial weight gain).
Since changes in body weight were independent of disease activity, antirheumatic treatment was independent of body weight or BMI. Among the BMI groups, there was no difference in the proportion treated with DMARDs during the study (data not shown) or after 3 years (87.4% of patients of normal weight, 83.2% of patients who were overweight, and 83.8% of patients who were obese), or with a DMARD combination (23.5%, 18.7%, and 27.7%, respectively), biologic agent (6.0%, 8.6%, and 6.8%, respectively), or glucocorticoids (57.1%, 51.0%, and 54.7%, respectively) after 3 years.
At study entry as well as at study end, patients of normal weight had as many swollen joints (28-joint swollen joint count) and had erosive RA as frequently as overweight or obese patients, but they had significantly more eroded joints (RS 0–38), higher radiographic joint damage and higher RS (RS 0–190), and more frequently had considerable erosions (RS ≥7) than patients with higher BMI scores. Even though all patients were treated similarly and disease activity remained significantly lower in patients of normal weight (DAS28 at 3-year followup 3.50, 3.55, and 3.94 among those with BMI <25 kg/m2, 25–29.9 kg/m2, and ≥30 kg/m2, respectively) (P = 0.006), they experienced significantly more radiographic progression over 3 years than obese patients (Table 2).
|All patients (n = 767)||BMI||P†|
|Normal (<25 kg/m2) (n = 303)||Overweight (25–29.9 kg/m2) (n = 315)||Obese (≥30 kg/m2) (n = 149)|
|SJC (0–28), mean ± SD||6.9 ± 6.1||6.68 ± 6.0||7.03 ± 6.1||7.07 ± 6.1||0.727|
|Erosive RA, %||64.3||68.3||61.6||61.7||0.168|
|Total eroded joints (0–38), mean ± SD||2.8 ± 3.9||3.3 ± 4.6||2.5 ± 3.4||2.2 ± 3.0||0.006|
|RS (0–190), mean ± SD||3.5 ± 6.9||4.5 ± 9.6||3.1 ± 4.6||2.4 ± 3.5||0.004|
|RS ≥7, %||16.0||20.5||14.6||10.1||0.012|
|SJC (0–28), mean ± SD||2.8 ± 4.2||3.0 ± 4.2||2.6 ± 3.9||3.03 ± 4.92||0.331|
|Erosive RA, %||79.8||80.2||80.6||77.2||0.670|
|Total eroded joints (0–28), mean ± SD||4.5 ± 5.4||5.3 ± 6.3||4.4 ± 4.9||3.2 ± 3.6||0.000|
|RS (0–190), mean ± SD||6.1 ± 3.5||7.5 ± 11.2||6.0 ± 8.6||3.7 ± 4.8||0.000|
|RS ≥7, %||28.6||32.0||30.5||17.4||0.003|
|Radiographic progression years 1–4 (RS 0–190), mean ± SD||2.8 ± 6.9||3.4 ± 8.4||2.9 ± 6.5||1.3 ± 3.7||0.011|
|Rate of progression/month from baseline, mean ± SD||0.078 ± 0.19||0.092 ± 0.22||0.084 ± 0.18||0.039 ± 0.09||0.011|
BMI-related differences in radiographic joint damage were independent of sex and were evident in younger and older women, and were possibly independent of age in men; the latter, however, could not be confirmed due to the small number of obese men (8 obese men <55 years, 18 obese men ≥55 years) (Figures 1 and 2).
The overall higher RS in older women was partly driven by osteoporosis, which was significantly more frequent in women ≥55 years (21%) than in those <55 years of age (5%). While osteoporosis correlated significantly with the RS (mean RS 8.01 in patients with osteoporosis and 5.32 in those without osteoporosis; P = 0.010), OA of the knee, hip, shoulder, or fingers did not contribute to the RS, whereas the few patients with OA of the wrist (n = 33) had a significantly higher RS than patients without wrist OA (9.57 and 5.44, respectively, in those with and those without wrist OA; P = 0.006).
Patients of normal weight differed significantly in joint damage (RS) by RF serology (mean RS 9.7 and 4.6 in RF-positive and RF-negative patients, respectively), while this difference did not exist in obese patients (RF-positive 4.1 versus RF-negative 3.4). The mean total RS in the RF-positive obese patients therefore was lower than that of the RF-negative patients of normal weight.
In RF-positive patients, the BMI was negatively correlated with radiographic joint damage (ρ = −0.160, P < 0.001). This association was independent of whether baseline or 3-year measurements of BMI or RF were used for the correlation. Again, a similar correlation did not exist in RF-negative patients (ρ = 0.001, P = 0.991).
The same could be demonstrated for presence of considerable joint damage (RS ≥7), which affected 34% of the RF-positive and 20% of the RF-negative patients. Among the RF-positive patients, twice as many of those who were of normal weight as those who were obese had an RS ≥7 (40%, 35%, and 19% of those with BMI <25 kg/m2, those with BMI 25–29.9 kg/m2, and those with BMI ≥30 kg/m2, respectively; P = 0.005), while there was no such association in RF-negative patients (19%, 24%, and 17%, respectively; P = 0.389). Figure 3 shows the mean and 95% confidence interval (95% CI) RS in RF-positive and RF-negative patients in the 3 BMI groups.
Multivariate logistic regression analyses in all patients revealed significantly higher probabilities of considerable joint damage (RS ≥7) in patients of normal weight compared with overweight or obese patients, even though the ORs were controlled for age, disease duration at the time the radiographs were obtained, sex, current smoking status (yes versus no) or pack-years smoked (linear or stratified; 0, 1–10, 11–20, or ≥21 pack-years), RF (positive versus negative), osteoporosis (yes versus no), and disease activity (DAS28 and CRP). Symptomatic OA, irrespective of location, did not increase the risk for having an RS ≥7. Even the inclusion of the baseline RS as the strongest predictor of further joint damage did not significantly alter the result. Although each 1-unit increase in the baseline RS significantly increased the risk for considerable damage at 3 years (OR 1.49, 95% CI 1.4–1.6, P < 0.001), the influence of BMI on radiographic outcome remained an independent risk factor.
Corresponding equations in the 2 subgroups of RF-positive and RF-negative patients showed that the association between BMI and radiographic joint damage was restricted to RF-positive patients. While in the subgroup of RF-positive patients all covariate risks for considerable joint damage remained the same as in the sample of all patients (data not shown), the adjusted OR for considerable joint damage in patients of normal weight compared with obese patients increased to 3.34 and thus was the highest OR for any of the investigated risk parameters (Table 3). In the subgroup of RF-negative patients, however, considerable joint damage was associated solely with elevated CRP titers (CRP ≥15 mg/liter versus <5 mg/liter OR 2.56, 95% CI 1.17–3.69), and not with BMI (Table 3).
|Sample (n)||Referent (n)||Adjusted OR||95% CI||P|
|Men (216)||Women (548)||1.57||1.10–2.27||0.018|
|RF-positive (465)||RF-negative (299)||1.63||1.14–2.35||0.008|
|CRP 5–15 mg/liter (258)||CRP <5 mg/liter (399)||2.11||1.44–3.11||0.000|
|CRP ≥15 mg/liter (107)||CRP <5 mg/liter (399)||2.57||1.15–4.35||0.006|
|DAS28 3.2–5.0 (312)||DAS28 <3.2 (314)||1.44||0.98–2.13||0.063|
|DAS28 ≥5.1 (138)||DAS28 <3.2 (314)||1.86||1.12–3.07||0.016|
|Osteoporosis (87)||No osteoporosis (677)||2.02||1.22–3.34||0.006|
|Disease duration (months)||1.03||1.01–1.05||0.001|
|BMI <25 (302)||BMI ≥30 (149)||2.60||1.54–4.37||0.000|
|BMI 25–29.9 (313)||BMI ≥30 (149)||2.24||1.34–3.76||0.002|
|BMI <25 (195)||BMI ≥30 (83)||3.34||1.78–6.61||0.000|
|BMI 25–29.9 (187)||BMI ≥30 (83)||2.64||1.37–5.06||0.004|
|BMI <25 (107)||BMI ≥30 (66)||1.86||0.77–4.49||0.163|
|BMI 25–29.9 (126)||BMI ≥30 (66)||1.98||0.86–4.55||0.106|
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).
Dr. Westhoff had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study design.Westhoff, Rau, Zink.
Acquisition of data. Westhoff, Rau.
Analysis and interpretation of data. Westhoff, Zink.
Manuscript preparation. Westhoff, Zink.
Statistical analysis. Westhoff.
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.