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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Objective

Adipose tissue has immunomodulating effects in rheumatoid arthritis (RA), although the exact role is, at present, unclear. The purpose of this study was to determine whether body mass index (BMI) affects response to infliximab in RA patients investigated prospectively.

Methods

In 89 patients with active RA, the BMI was calculated before initiation of infliximab treatment (3 mg/kg intravenously). After 16 weeks of treatment, changes in disease activity were assessed with the Disease Activity Score in 28 joints (DAS28).

Results

The mean ± SD BMI was 26 ± 5 kg/m2 (range 17–42). The BMI correlated positively with the DAS28 at baseline (r = 0.34, P = 0.001). Since selection of study patients according to DAS28 values could influence the clinical response to tumor necrosis factor (TNF) blockade due to regression to the mean because the clinical response is itself based on the change in the DAS28 values, analysis of covariance was used to correct for the baseline DAS28. A highly significant, negative association between the BMI and the absolute decrease in the DAS28 after 16 weeks (P = 0.001) was found also when adjusted for anti–citrullinated protein antibodies.

Conclusion

Although the infliximab dosage is based on body weight, RA patients with a high BMI responded less well to infliximab, a finding that held true when adjusted for the baseline DAS28 or anti–citrullinated protein antibody status. These results support the notion that adipose tissue may be involved in the pathophysiology of RA and could have implications for other immune-mediated inflammatory conditions treated with TNF antagonists.

Adipose tissue is not merely fat resting in the body. Nowadays, it is recognized as an active site that exerts endocrine and immune effects on multiple other organs through the release of adipocytokines (1). These factors include leptin, resistin, adiponectin and visfatin, as well as classic cytokines, such as tumor necrosis factor α (TNFα), interleukin-1 (IL-1), IL-6, and monocyte chemotactic protein 1 (MCP-1), which are possibly expressed by inflammatory cells that infiltrate the fat tissue. Together, these molecules influence immune functions, leading to local and generalized inflammation, which could play a role in the development of several diseases, such as diabetes mellitus, atherosclerosis, rheumatoid arthritis (RA), and osteoarthritis (2–4). Although the actions of various cytokines in RA, a chronic, immune-mediated inflammatory disease mostly affecting the joints, are largely known (5), the role of adipose tissue remains a subject of controversy.

Active disease could lead to weight loss (6) and, consequently, lower body mass index (BMI). Other research has shown, however, that fat mass was independently and positively correlated with C-reactive protein (CRP) levels in female patients with RA (7). Although a positive association between CRP levels and death from cardiovascular causes has been demonstrated (8), death rates in obese RA patients were found to be lower (9). In this latter study, the BMI had a protective effect only when the erythrocyte sedimentation rate was low. Moreover, a higher BMI appears to be associated with less severe radiographic joint damage in RA, even in patients with anti–citrullinated protein antibodies (ACPAs) (10) and/or rheumatoid factor (RF) (11). Although these autoantibodies, especially ACPA, are associated with rapidly progressive, erosive disease (12), this might suggest that adipose tissue is related to milder disease in terms of joint destruction. Thus, the relationship between BMI and signs and symptoms of RA appears to be complex.

A significant proportion of RA patients (∼30%) do not respond well to TNF blockers for reasons that have not yet been fully elucidated (13, 14). We hypothesized that the BMI could affect treatment responses in RA patients. Therefore, we examined the relationship between the BMI at baseline and the primary clinical response to infliximab in a prospective study. Infliximab was chosen because this TNF blocker is dosed per kilogram of body weight.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Disease characteristics and BMI.

Eighty-nine patients with active RA, according to the American College of Rheumatology criteria (15), were included in this exploratory study. The baseline demographic and clinical features of the patients of the larger prospective single-center cohort have been described previously (14) and are summarized in Table 1 for those who were included in the present study. Patients were selected for the present analysis based on the availability of BMI data, serum samples obtained at baseline, and standardized followup data on the response to infliximab treatment. All study patients were taking stable dosages of methotrexate (5–30 mg/week), had never taken biologic agents, and had active disease, as defined by a Disease Activity Score in 28 joints (DAS28) ≥3.2. Use of oral corticosteroids (≤10 mg/day) and nonsteroidal antiinflammatory drugs was allowed if the dosage had not been changed within 1 month prior to baseline. Patients who had received an intraarticular injection of steroids within the previous month were excluded.

Table 1. Baseline characteristics of the 89 rheumatoid arthritis patients treated with infliximab, by response group*
 Responders (n = 60)Nonresponders (n = 29)
  • *

    Responders were patients who had a decrease in the Disease Activity Score in 28 joints (DAS28) of ≥1.2 after 16 weeks of treatment. The presence of erosive joint disease was determined radiographically. Serum IgM rheumatoid factor (IgM-RF) titers ≥12.5 units/ml were considered positive. Differences between responders and nonresponders were compared using chi-square test, Student's independent t-test, or Mann-Whitney U test, as appropriate. BMI = body mass index; ACPA = anti–citrullinated protein antibody; ESR = erythrocyte sedimentation rate; IQR = interquartile range; CRP = C-reactive protein; DMARDs = disease-modifying antirheumatic drugs; MTX = methotrexate.

  • P = 0.03.

Age, mean ± SD years52 ± 1455 ± 12
No. (%) female47 (78)19 (66)
BMI, mean ± SD kg/m225.5 ± 4.726.8 ± 4.4
Weight, mean ± SD kg74 ± 1480 ± 14
DAS28, mean ± SD6.1 ± 1.05.5 ± 1.2
No. (%) with erosive disease49 (82)22 (76)
No. (%) with IgM-RF46 (77)20 (69)
No. (%) with ACPA49 (82)21 (72)
ESR, median (IQR) mm/hour35 (23)28 (26)
CRP, median (IQR) mg/liter22 (24)23 (35)
Disease duration, median (IQR) months75 (25–158)94 (45–165)
No. of previous DMARDs, mean ± SD2.1 ± 1.42.2 ± 1.4
MTX dosage, mean ± SD mg/week19.5 ± 8.218.1 ± 8.4
No. (%) taking prednisone40 (67)22 (76)

The presence of IgM-RF and ACPAs, as measured with an anti–cyclic citrullinated peptide 2 enzyme-linked immunosorbent assay (kit RA-96RT, Immunoscan RA Mark 2; Euro-Diagnostica), as well as the presence of erosive joint disease, as determined radiographically, were assessed at baseline. Height and body weight were measured at baseline, and the BMI was calculated as the weight in kilograms divided by the height in meters squared. All patients received infliximab at a dosage of 3 mg/kg administered intravenously at baseline, week 2, week 6, and every 8 weeks thereafter.

Responder status was defined as the difference in the DAS28 (ΔDAS28) after 16 weeks of therapy as compared with baseline. RA patients with ΔDAS28 values ≥1.2 (2 times the measurement error over time), representing a clinically significant improvement, were defined as responders (16). The dichotomy of the ΔDAS28 values <1.2 versus ≥1.2 (on average, comparable with a 20% improvement in the DAS28) was chosen because it is applied in daily clinical practice and is required by insurance companies in The Netherlands for prolongation of reimbursement for TNFα-blocking therapy. Response was also determined according to the European League against Rheumatism (EULAR) response criteria (17), which are divided into 3 categories: good response, moderate response, and no response. Clinical response was evaluated at 16 weeks, since a significant improvement is expected to occur within 3–4 months, after which alternative treatment should be considered (18).

All patients gave written informed consent. The study was approved by the Medical Ethics Committee of the Academic Medical Center, University of Amsterdam.

Statistical analysis.

Continuous data are reported as the mean ± SD if normally distributed and as the median and interquartile range (IQR) if not normally distributed. The 1-sample Kolmogorov-Smirnov test was used to test for normal distribution. Student's unpaired t-test or, where appropriate, Mann-Whitney U test was used to compare responders and nonresponders. Pearson's correlation coefficient was used to investigate the relationship between BMI and disease activity. Categorical data are shown as percentages, and differences were analyzed by chi-square or Fisher's exact test or were analyzed linearly by linear association. BMI was divided into 3 categories (<20 kg/m2, 20–30 kg/m2, and >30 kg/m2), and one-way analysis of variance (ANOVA) with Bonferroni post hoc test was used to compare patient characteristics in these 3 groups, as well as to compare the 3 categories of clinical response according to the EULAR criteria. The association between the ΔDAS28 and the BMI at baseline was adjusted for the DAS28 values at baseline with the use of an analysis of covariance (ANCOVA). To adjust for the DAS28 at baseline, logistic regression was used to test whether the BMI and the DAS28 at baseline predicted treatment response. Logistic regression was also used to test the influence of the BMI, the DAS28, and the presence of ACPAs at baseline on the presence of erosions at baseline. Standard statistical software (SPSS version 16.0.2) was used for all statistical analyses. P values less than or equal to 0.05 were considered significant.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Baseline patient characteristics.

Eighty-nine RA patients were evaluated. Demographic and clinical features are shown in Table 1. Sixteen weeks after initiation of treatment, the mean ± SD DAS28 decreased from 5.9 ± 1.1 to 4.1 ± 1.4 (P < 0.001). Sixty of the 89 patients (67%) experienced a decrease in the DAS28 (ΔDAS28) of ≥1.2 and are referred to as responders. According to the EULAR response criteria, 27%, 53%, and 20% of patients achieved a good response, a moderate response, and no response, respectively. All baseline characteristics of the study patients were tested for differences between responders (ΔDAS28 ≥1.2) and nonresponders (ΔDAS28 <1.2), but only the baseline DAS28 was significantly higher in the responder group than in the nonresponder group (6.1 ± 1.0 versus 5.5 ± 1.2; P = 0.03) (Table 1).

BMI and clinical characteristics at baseline.

The mean ± SD BMI was 26 ± 5 kg/m2 (range 17–42) at baseline, and it was not significantly different between responders and nonresponders when response was defined as a decrease in the DAS28 of ≥1.2 after 16 weeks of infliximab treatment (P = 0.20) (Table 1). Next, we divided the BMI into 3 categories and tested all baseline characteristics of the study patients (Table 2). Of the 89 RA patients, 8 (9%) had a BMI of <20 kg/m2, 66 (74%) had a baseline BMI of 20–30 kg/m2, and 15 (17%) had a BMI of >30 kg/m2. The presence of erosive disease (P = 0.02), ACPA positivity (P = 0.03), and the DAS28 value (P = 0.02) at baseline were significantly different between the 3 BMI groups. Other characteristics showed no significant differences between the 3 BMI categories. Interestingly, when the baseline BMI, presence of ACPAs, and the disease duration were entered into a logistic regression model to predict erosive disease, all 3 parameters were independently related to its presence (P = 0.053, P = 0.003, P = 0.006, respectively) (data not shown).

Table 2. Baseline characteristics of the 89 rheumatoid arthritis patients treated with infliximab, by BMI group*
 BMI group
<20 kg/m2 (n = 8)20–30 kg/m2 (n = 66)>30 kg/m2 (n = 15)
  • *

    The presence of erosive joint disease was determined radiographically. Serum IgM rheumatoid factor (IgM-RF) titers ≥12.5 units/ml were considered positive. Differences between body mass index (BMI) groups were compared using chi-square test or one-way analysis of variance with Bonferroni post hoc test, as appropriate. DAS28 = Disease Activity Score in 28 joints; ACPA = anti–citrullinated protein antibody; ESR = erythrocyte sedimentation rate; IQR = interquartile range; CRP = C-reactive protein; DMARDs = disease-modifying antirheumatic drugs; MTX = methotrexate.

  • P = 0.02.

  • P = 0.03.

Age, mean ± SD years50 ± 1557 ± 1153 ± 15
No. (%) female6 (75)47 (71)13 (87)
DAS28, mean ± SD5.6 ± 1.25.9 ± 1.06.5 ± 1.0
No. (%) with erosive disease7 (88)56 (85)8 (53)
No. (%) with IgM-RF7 (88)50 (76)9 (60)
No. (%) with ACPA7 (88)55 (83)8 (53)
ESR, median (IQR) mm/hour31 (21)36 (27)31 (24)
CRP, median (IQR) mg/liter23 (27)24 (33)17 (15)
Disease duration, median (IQR) months75 (21–169)112 (49–164)54 (31–129)
No. of previous DMARDs, mean ± SD2.0 ± 1.42.5 ± 1.61.7 ± 1.1
MTX dosage, mean ± SD mg/week19 ± 8.119 ± 8.418.8 ± 8.7
No. (%) taking prednisone2 (25)22 (33)3 (20)

Relationship between the BMI and the clinical response to infliximab in RA.

We found a positive correlation between the BMI and the DAS28 values at baseline (r = 0.34, P = 0.001). Both variables were normally distributed according to the Kolmogorov-Smirnov test (P = 0.36 for the BMI and P = 0.57 for the DAS28). Since selection of study patients according to DAS28 values can influence the clinical response to tumor necrosis factor (TNF) blockade due to regression to the mean because the clinical response is itself based on the change in the DAS28 values (19), ANCOVA was applied to correct for the baseline DAS28. This analysis showed that the BMI significantly influenced the ΔDAS28 after 16 weeks (P = 0.001, B = −0.094 [95% confidence interval (95% CI) −0.149, −0.038]).

This effect was driven by a change in the tender joint count, swollen joint count, and visual analog scale (VAS) domains of the DAS28. In the same way as described above, to adjust for these 3 domains at baseline, ANCOVA was used to test the relationship between the BMI and the decrease in the tender joint count, swollen joint count, and VAS, with the following results: for the tender joint count, P = 0.001, B = −0.482 (95% CI −0.745, −0.218); for the swollen joint count, P = 0.06, B = −0.196 (95% CI −0.401, 0.009); and for the VAS, P = 0.04, B = −1.080 (95% CI −2.107, −0.052). There was no statistically significant relationship between the BMI at baseline and a decrease in the CRP levels at 16 weeks.

The BMI and the DAS28 significantly predicted responders (ΔDAS28 ≥1.2) to infliximab treatment, as demonstrated in a logistic regression model (P = 0.03 and P = 0.01, respectively; Nagelkerke's R2 = 0.14). When the BMI was divided into 3 categories, the percentage of responders (ΔDAS28 ≥1.2) significantly decreased in the groups with a higher BMI (84%, 75%, and 50% for BMI groups <20 kg/m2, 20–30 kg/m2, and >30 kg/m2, respectively; P = 0.04) (Figure 1A). Similar statistically significant results were obtained when the BMI at baseline was categorized according to the guidelines of the World Health Organization (underweight ≤18.4 kg/m2, normal 18.5–24.9 kg/m2, overweight 25.0–29.9 kg/m2, and obese ≥30 kg/m2) (data not shown).

thumbnail image

Figure 1. Clinical response and body mass index (BMI) in rheumatoid arthritis (RA) patients after 16 weeks of treatment with infliximab. Infliximab was administered to 89 RA patients at a dosage of 3 mg/kg of body weight, given intravenously, at baseline, week 2, week 6, and week 14. A, Percentages of patients defined as responders according to the Disease Activity Score in 28 joints (DAS28), by BMI group at baseline. Responders (n = 60) were those who experienced a decrease of ≥1.2 in the DAS28. B, BMI values at baseline according to the European League Against Rheumatism (EULAR) response group at 16 weeks. All 89 patients were classified into 1 of the 3 EULAR response categories: no response, moderate response, or good response. Values are the mean ± SD. = P ≤ 0.05.

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Finally, patients were analyzed according to the EULAR response criteria. BMI values were significantly higher in the nonresponder group as compared with the good responder group (P = 0.03 [95% CI 0.39, 7.23] by one-way ANOVA with Bonferroni post hoc test) (Figure 1B).

Most RA patients in our study had ACPAs in their serum. These antibodies are associated with a more aggressive disease course, and it was suggested recently that ACPA-positive patients represent a specific RA disease subset (20). The BMI at baseline was also negatively correlated with the ΔDAS28 after 16 weeks in the ACPA-positive subgroup (data not shown).

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Adipose tissue may have immunomodulating effects in RA, although its exact role is presently unclear. Hence, we investigated prospectively whether the BMI is associated with response to infliximab in RA patients. The baseline BMI showed a positive correlation with the baseline DAS28, indicating a more-active disease in our heavier patients. Of importance, a higher BMI resulted in a decreased clinical response to infliximab (as determined by both the DAS28 and the EULAR criteria) after 16 weeks of treatment, even after adjustment for baseline DAS28 or ACPA status, in spite of the fact that this drug is dosed per kilogram of body weight. To the best of our knowledge, this is the first published study to evaluate the effect of BMI on the response to TNF blockade in any immune-mediated inflammatory disease, of which RA is a prototype.

These findings do not seem to be the result of pharmacologic factors. It is known that the response to infliximab is related to serum concentrations of the drug (21) and that the volume of distribution of infliximab corresponds to the intravascular space (22). Since the infliximab dose is adjusted for body weight and since the intravascular space is relatively small in the more obese, one might expect serum infliximab concentrations to be higher in the more obese patients, although published data are presently lacking. However, our study clearly indicated that despite the higher infliximab doses used in patients with increased BMI, the clinical response was diminished. Furthermore, it is conceivable that high levels of disease activity, which are associated with a better response to TNF blockade (14), could lead to rheumatoid cachexia and a reduced BMI (6), but we observed the opposite in this cohort of patients. Therefore, the adipose tissue itself might play a role in creating a more therapy-resistant state.

Adipose tissue is a source not only of proinflammatory cytokines, such TNF and IL-6, but also of specific adipocytokines (1). Serum levels of, for example, leptin, resistin, adiponectin, and visfatin are all increased in RA patients as compared with healthy controls (23). Several of these mediators may be associated with clinical signs and symptoms of RA (23–26) and the induction of resistance to TNF blockade, but their role in the process of joint destruction may be more complex. Our results showed that a high BMI was associated with fewer erosions at baseline, and as earlier studies have shown, obesity might have a protective effect on radiologic joint damage over time (10, 11). More specifically, adiponectin (26) and leptin (23) concentrations have been found to be negatively correlated with joint damage in RA patients. Thus, adipose tissue–derived mediators may be one of the long sought after missing links in the uncoupled occurrence of synovial inflammation and joint destruction that may be observed in chronic arthritis (27). It should be noted, however, that the effect of BMI on the ΔDAS28 after 16 weeks was driven by a change in the tender joint count, swollen joint count, and VAS domains of the DAS28, rather than the CRP levels, which could represent evidence against a mechanism involving adipose tissue–derived mediators of inflammation.

This study has some limitations. First, the number of patients studied is relatively small. Second, we did not have access to an independent cohort in which to confirm our findings. However, the Gruppo Italiano di Studio sulla Early Arthritis (GISEA) Registry study, which collected data from all RA and spondylarthropathy patients treated with biologic agents in 14 centers in Italy, also recently found that obesity is associated with a lower response to various biologic agents (28), thus confirming our findings. The validity of our findings is also supported by the observation that when BMI was divided into 3 categories, the percentages of responders significantly decreased in the groups with higher BMI (84%, 75%, and 50% in those with a BMI of <20 kg/m2, 20–30 kg/m2, and >30 kg/m2, respectively). Third, data on total fat mass as compared with regional fat mass, as well as levels of various adipocytokines, were not available, but the current study does provide a rationale for more detailed studies on the role of adipose tissue in conditions such as RA, psoriasis, and Crohn's disease in relation to the response to anti-TNF therapy. Fourth, response was measured after 16 weeks of treatment, and we therefore cannot exclude the possibility that RA patients with a higher BMI could respond later as compared to RA patients who are leaner. We chose a fixed end point of 16 weeks to assess the primary response to infliximab treatment, since the secondary response defined at later time points may be influenced by entirely unrelated mechanisms, including the development of human antichimeric antibodies against infliximab (29).

In conclusion, RA patients with a high BMI exhibited a diminished clinical response to infliximab treatment, despite drug dosing based on body weight. This finding suggests that adipose tissue could play a role in the pathophysiology of RA.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Tak 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 conception and design. Klaasen, Wijbrandts, Gerlag, Tak.

Acquisition of data. Klaasen, Wijbrandts, Gerlag, Tak.

Analysis and interpretation of data. Klaasen, Wijbrandts, Gerlag, Tak.

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

The authors would like to thank Dr. Beatrijs M. Lodde (Academic Medical Center, University of Amsterdam) for expert editorial assistance.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES
  • 1
    Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 2006; 6: 77283.
  • 2
    Guzik TJ, Mangalat D, Korbut R. Adipocytokines—novel link between inflammation and vascular function? J Physiol Pharmacol 2006; 57: 50528.
  • 3
    Lajeunesse D, Pelletier JP, Martel-Pelletier J. Osteoarthritis: a metabolic disease induced by local abnormal leptin activity? Curr Rheumatol Rep 2005; 7: 7981.
  • 4
    Muller-Ladner U, Neumann E. Rheumatoid arthritis: the multifaceted role of adiponectin in inflammatory joint disease. Nat Rev Rheumatol 2009; 5: 65960.
  • 5
    McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol 2007; 7: 42942.
  • 6
    Roubenoff R, Roubenoff RA, Ward LM, Holland SM, Hellmann DB. Rheumatoid cachexia: depletion of lean body mass in rheumatoid arthritis. Possible association with tumor necrosis factor. J Rheumatol 1992; 19: 150510.
  • 7
    Giles JT, Bartlett SJ, Andersen R, Thompson R, Fontaine KR, Bathon JM. Association of body fat with C-reactive protein in rheumatoid arthritis. Arthritis Rheum 2008; 58: 263241.
  • 8
    Verma S, Szmitko PE, Ridker PM. C-reactive protein comes of age. Nat Clin Pract Cardiovasc Med 2005; 2: 2936.
  • 9
    Escalante A, Haas RW, del Rincon I. Paradoxical effect of body mass index on survival in rheumatoid arthritis: role of comorbidity and systemic inflammation. Arch Intern Med 2005; 165: 162429.
  • 10
    Van der Helm-van Mil AH, van der Kooij SM, Allaart CF, Toes RE, Huizinga TW. A high body mass index has a protective effect on the amount of joint destruction in small joints in early rheumatoid arthritis. Ann Rheum Dis 2008; 67: 76974.
  • 11
    Westhoff G, Rau R, Zink A. Radiographic joint damage in early rheumatoid arthritis is highly dependent on body mass index. Arthritis Rheum 2007; 56: 357582.
  • 12
    Meyer O, Labarre C, Dougados M, Goupille P, Cantagrel A, Dubois A, et al. Anticitrullinated protein/peptide antibody assays in early rheumatoid arthritis for predicting five year radiographic damage. Ann Rheum Dis 2003; 62: 1206.
  • 13
    Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther 2008; 117: 24479.
  • 14
    Wijbrandts CA, Dijkgraaf MG, Kraan MC, Vinkenoog M, Smeets TJ, Dinant H, et al. The clinical response to infliximab in rheumatoid arthritis is in part dependent on pretreatment tumour necrosis factor α expression in the synovium. Ann Rheum Dis 2008; 67: 113944.
  • 15
    Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31: 31524.
  • 16
    Van Gestel AM, Haagsma CJ, van Riel PL. Validation of rheumatoid arthritis improvement criteria that include simplified joint counts. Arthritis Rheum 1998; 41: 184550.
  • 17
    Van Gestel AM, Prevoo ML, van 't Hof MA, van Rijswijk MH, van De Putte LB, van Riel PL. Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis: comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism Criteria. Arthritis Rheum 1996; 39: 3440.
  • 18
    Furst DE, Keystone EC, Fleischmann R, Mease P, Breedveld FC, Smolen JS, et al. Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2009. Ann Rheum Dis 2010; 69 Suppl I: i229.
  • 19
    Greenwood MC, Rathi J, Hakim AJ, Scott DL, Doyle DV. Regression to the mean using the disease activity score in eligibility and response criteria for prescribing TNF-α inhibitors in adults with rheumatoid arthritis. Rheumatology (Oxford) 2007; 46: 11657.
  • 20
    Klareskog L, Catrina AI, Paget S. Rheumatoid arthritis. Lancet 2009; 373: 65972.
  • 21
    Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfarlane JD, et al. Therapeutic efficacy of multiple intravenous infusions of anti–tumor necrosis factor α monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998; 41: 155263.
  • 22
    Klotz U, Teml A, Schwab M. Clinical pharmacokinetics and use of infliximab. Clin Pharmacokinet 2007; 46: 64560.
  • 23
    Rho YH, Solus J, Sokka T, Oeser A, Chung CP, Gebretsadik T, et al. Adipocytokines are associated with radiographic joint damage in rheumatoid arthritis. Arthritis Rheum 2009; 60: 190614.
  • 24
    Choi HM, Lee YA, Lee SH, Hong SJ, Hahm DH, Choi SY, et al. Adiponectin may contribute to synovitis and joint destruction in rheumatoid arthritis by stimulating vascular endothelial growth factor, matrix metalloproteinase-1, and matrix metalloproteinase-13 expression in fibroblast-like synoviocytes more than proinflammatory mediators. Arthritis Res Ther 2009; 11: R161.
  • 25
    Ebina K, Fukuhara A, Ando W, Hirao M, Koga T, Oshima K, et al. Serum adiponectin concentrations correlate with severity of rheumatoid arthritis evaluated by extent of joint destruction. Clin Rheumatol 2009; 28: 44551.
  • 26
    Giles JT, Allison M, Bingham CO III, Scott WM Jr, Bathon JM. Adiponectin is a mediator of the inverse association of adiposity with radiographic damage in rheumatoid arthritis. Arthritis Rheum 2009; 61: 124856.
  • 27
    Van den Berg WB. Joint inflammation and cartilage destruction may occur uncoupled. Springer Semin Immunopathol 1998; 20: 14964.
  • 28
    Ferraccioli G, Trotta F, Punzi L, Ferri C, Sarzi Puttini CP, Bambara LM, et al. Body weight and response to biologics in RA and spondyloarthritides: obesity reduces the rate of remission-response: the GISEA Registry [abstract]. Ann Rheum Dis 2010; 69 Suppl 3: 675.
  • 29
    Wolbink GJ, Vis M, Lems W, Voskuyl AE, de Groot E, Nurmohamed MT, et al. Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis. Arthritis Rheum 2006; 54: 7115.