Dr. Jacobs has received consultant fees, speaking fees, and/or honoraria (less than $10,000) from Mundipharma.
Special Theme Articles: Obesity and the Rheumatic Diseases
Increase of body mass index in a tight controlled methotrexate-based strategy with prednisone in early rheumatoid arthritis: Side effect of the prednisone or better control of disease activity?†
Article first published online: 27 DEC 2012
Copyright © 2013 by the American College of Rheumatology
Arthritis Care & Research
Volume 65, Issue 1, pages 88–93, January 2013
How to Cite
Jurgens, M. S., Jacobs, J. W. G., Geenen, R., Bossema, E. R., Bakker, M. F., Bijlsma, J. W. J., van Albada-Kuipers, I. A., Ehrlich, J. C., Lafeber, F. P. J. G., Welsing, P. M. J. and on behalf of The Utrecht Arthritis Cohort Study Group (2013), Increase of body mass index in a tight controlled methotrexate-based strategy with prednisone in early rheumatoid arthritis: Side effect of the prednisone or better control of disease activity?. Arthritis Care Res, 65: 88–93. doi: 10.1002/acr.21797
- Issue published online: 27 DEC 2012
- Article first published online: 27 DEC 2012
- Accepted manuscript online: 17 JUL 2012 12:47PM EST
- Manuscript Accepted: 29 JUN 2012
- Manuscript Received: 31 JAN 2012
- Catharijne Stichting
To clarify whether increase of body weight in patients with early rheumatoid arthritis (RA) upon administration of prednisone is a side effect of prednisone or a result of better control of disease activity, we examined the association of prednisone and disease activity with a subsequent change in body mass index (BMI).
In the Computer Assisted Management in Early Rheumatoid Arthritis Trial-II, patients ages ≥18 years with early RA (disease duration <1 year and no prior use of disease-modifying antirheumatic drugs) had been randomized to a methotrexate (MTX)–based tight control strategy with either 10 mg of prednisone (MTX + prednisone) or placebo (MTX + placebo). The MTX + prednisone group had lower disease activity, but gained more weight than the MTX + placebo group (mean ± SD 2.9 ± 4.2 kg versus 1.3 ± 5.3 kg; P = 0.03). Data from patients with monthly measurements of disease activity (Disease Activity Score in 28 joints [DAS28]) and BMI were analyzed with a longitudinal regression (mixed model) analysis with BMI as the dependent variable and treatment strategy and DAS28 as the independent variables, correcting for baseline BMI and possible confounders (sex, age, and rheumatoid factor status).
There was no independent association of glucocorticoid therapy with a change in BMI, but a lower DAS28 was associated with an increased BMI 6 months later. The association of the DAS28 with BMI was most strongly present in postmenopausal women. Clinical cutoff points showed a clear association between DAS28 level and the change in BMI 6 months later.
Weight gain during treatment with prednisone seems attributable to a reduction of disease activity and is probably, at least partly, regained weight.
Rheumatoid arthritis (RA) is characterized by persistent synovitis and systemic inflammation and has a spectrum of extraarticular manifestations, and affects approximately 0.5–1.0% of adults (1). Active RA is associated with altered body composition (2), e.g., cachexia, decreased skeletal muscle mass, and increased body fat. Increased body fat in RA could be especially detrimental, since these patients have an incidence of cardiovascular diseases at least twice as high as the general public (3), with worse outcomes and reduced life expectancy (2, 4–6). This increased incidence is attributed to traditional risk factors for cardiovascular disease, such as obesity, as well as to RA-specific factors, such as inflammation (7).
Both inflammatory and noninflammatory factors may contribute to the altered body composition of RA patients (8, 9), as can pharmacotherapy. For instance, a decrease of body weight is an adverse effect of leflunomide. Patients are especially apprehensive to use glucocorticoids (GCs) based on the fear of side effects, such as increased weight and body fat, although these side effects occur in general mainly when high doses are being administered. Weight gain might also be due to effective treatment of RA, since active RA has been reported to induce weight loss (10), possibly by cytokine effects (11) and loss of appetite.
GCs are not only used in RA for their symptomatic effect, but also have been proven to have joint-sparing properties in early RA; therefore, they can be considered disease-modifying antirheumatic drugs (DMARDs) (12). Next to being clinically effective, GCs are cost effective and readily available worldwide (13).
In the recent Computer Assisted Management in Early Rheumatoid Arthritis Trial-II (CAMERA-II), patients received intensive once-monthly monitored care with a step-up strategy with methotrexate (MTX) using a tight control and treat-to-target (remission) approach and were randomized to additional therapy with either 10 mg of prednisone (MTX + prednisone group) or placebo (MTX + placebo group) (14). The MTX + prednisone group had significantly less disease activity and erosive joint damage compared to the MTX + placebo group. Patients gained weight in both groups, but significantly more in the MTX + prednisone group, with a mean ± SD weight gain of 2.9 ± 4.2 kg versus 1.3 ± 5.3 kg in the MTX + placebo group (P = 0.03).
Prednisone might have caused this additional weight gain and therefore a gain in body mass index (BMI) via metabolic effects or by an increase of appetite, but also by better suppression of disease activity. To unravel the effects of prednisone and reduced disease activity, the aim of this study was to examine to what extent prednisone and disease activity were related to changes in BMI over time in the CAMERA-II study.
Significance & Innovations
Body weight gain following treatment with (low to moderate dose) prednisone of patients with early, active rheumatoid arthritis seems attributable to a reduction of disease activity.
Patients' and doctors' apprehension to use low-dose prednisone in early rheumatoid arthritis because of its alleged weight-increasing effect is largely unfounded, but could impede the start of this symptom-controlling and joint-sparing disease-modifying antirheumatic drug.
PATIENTS AND METHODS
We reported the design, intervention, and main analyses of the CAMERA-II trial in detail elsewhere (14). To summarize, we recruited 236 participants ages ≥18 years with early RA (disease duration <1 year and no prior use of DMARDs). Patients were randomized into an MTX-based tight control strategy with either 10 mg of prednisone (MTX + prednisone) or placebo (MTX + placebo) added over 2 years. MTX treatment was tailored to the individual patient's disease activity at monthly visits, based on predefined response criteria aiming for remission. At each visit, if the response criteria were not met, the dosage of MTX was increased by 5 mg/week until remission or until the maximum dosage of 30 mg/week (or maximum tolerable dose) was reached. If patients did not meet the predefined goal of remission 4 weeks after reaching the maximum (tolerable) dose, MTX was administered subcutaneously. If this did not result in remission, the next treatment strategy was administering another DMARD. At the start of the study, the next DMARD strategy step was the addition of cyclosporine, but shortly after starting the trial, an amendment of the study protocol was made replacing the cyclosporine step by the addition of adalimumab. The study had been approved by the medical research ethics committees of all participating centers and informed consent was obtained from all of the patients.
BMI and disease activity measurements.
BMI was used as a variable for body mass, assuming height was constant over time; weight was measured and documented at each visit. In 12 cases, height was not recorded or could not be retrieved, leaving 224 of the 236 patients in the CAMERA-II trial for the present evaluation. In total, in 67% of all visits by the 224 patients, BMI could be calculated. Table 1 shows the demographic and baseline data; these did not significantly differ from the original study population. Disease activity was measured using the Disease Activity Score assessing 28 joints for swelling and tenderness (DAS28) (15).
|MTX + prednisone (n = 109)||MTX + placebo (n = 115)||P†|
|Female sex, no. (%)||65 (60)||71 (62)||0.75|
|Age, mean ± SD years||54.4 ± 13.2||52.8 ± 12.9||0.36|
|RF-positive status, no. (%)||60 (55)||70 (61)||0.26|
|DAS28, mean ± SD‡||5.8 ± 1.3||5.6 ± 1.1||0.16|
|BMI, mean ± SD kg/m2||25.7 ± 4.1||26.0 ± 4.0||0.60|
|Height, mean ± SD cm||173 ± 10||172 ± 10||0.31|
Group differences in means for continuous data were tested for significance using independent-samples t-tests. For differences in categorical data, chi-square tests were performed.
To study the independent influence of the prednisone treatment strategy and disease activity on BMI over time, a longitudinal regression (mixed model) analysis with random intercept was performed, with BMI over time as the outcome variable and time, time squared, treatment strategy (MTX + prednisone versus MTX + placebo), and the DAS28 (concurrent and previous) as independent variables. DAS28 values with time lags of 0 (concurrent), 1, 3, and 6 months between the (change in) DAS28 and BMI were tested in the model to select the most appropriate (prospective) association, since the effect of disease activity on BMI was assumed not to be instantaneously present. Also, time squared as a variable and a categorical disease activity variable (i.e., remission = DAS28 <2.6, low disease activity = DAS28 2.6 to <3.2, moderate disease activity = DAS28 3.2 to ≤5.1, and high disease activity = DAS28 >5.1) were included in the model to test for nonlinear associations between the DAS28 and BMI over time.
Rheumatoid factor status (positive/negative), sex, and age were also included in the model as possible confounders. Sex and age (cutoff of 55 years) were combined into 4 categories to account for the influence of postmenopause status in women. Modification of the effect of disease activity on BMI over time by treatment strategy or sex/age was investigated through interaction terms. In addition, the interaction between treatment strategy and time was tested, since the influence of treatment might not be constant over time. Finally, BMI obtained 6 months prior to the outcome was added as an autoregressor to the model to examine the longitudinal association of a change in the independent variables with a change in BMI.
To arrive at a final regression model, a backward selection strategy was used, omitting variables that were not statistically related to the outcome variable unless they were confounders (i.e., inducing a change in the regression coefficients of >10% of the treatment strategy or DAS28 upon removal). Treatment strategy and the DAS28 as the main variables of interest to our aim were always retained in the model. All variables and interaction terms used to analyze the research question of the study are shown in Table 2.
|Positive RF status|
|DAS28 at baseline|
|Previous 6-month DAS28#|
|Previous 3-month DAS28#|
|Previous 1-month DAS28#|
|DAS28 × treatment strategy|
|DAS28 × sex/age|
|Treatment strategy × time|
|Previous 6-month BMI|
The statistical program SPSS, version 15.0, was used for all statistical analyses and P values less than 0.05 were considered statistically significant.
The final model (Table 3) shows that BMI increased over time (P = 0.006), and that this increase diminished over time (time squared variable in model: b = −0.00007, P = 0.017). There was no independent association of treatment strategy (i.e., prednisone therapy) with a change in BMI (b = 0.31, P = 0.593) (Table 3). When tested, the interaction between treatment strategy and time showed no impact on the difference in effect between the 2 treatment groups on BMI over time and was therefore not included in the final model.
|Intercept||23.63||21.87, 25.39||< 0.001|
|Time squared||−0.00||−0.00, −0.00||0.017|
|MTX + prednisone||0.31||−0.84, 1.46||0.593|
|MTX + placebo†||0||–||–|
|Previous DAS28‡||−0.10||−0.17, −0.04||0.002|
|Previous DAS28 × men ages <55 years||0.09||0.00, 0.17||0.046|
|Previous DAS28 × men ages ≥55 years||0.13||0.06, 0.21||0.001|
|Previous DAS28 × women ages <55 years||0.10||0.02, 0.17||0.010|
|Previous DAS28 × women ages ≥55 years†||0||–||–|
|Men ages <55 years||−1.54||−3.54, 0.47||0.131|
|Men ages ≥55 years||−0.87||−2.57, 0.82||0.310|
|Women ages <55 years||−1.29||−2.86, 0.28||0.106|
|Women ages ≥55 years†||0||–||–|
|Previous BMI§||0.13||0.09, 0.17||< 0.001|
Disease activity obtained 6 months earlier (previous DAS28) was associated with a decrease in BMI (b = −0.10, P = 0.002) (Table 3). The DAS28 obtained at other time points was associated less with a change in BMI. The overall interaction between this previous DAS28 and the sex/age variable was also significant (P = 0.009). As shown by the positive regression coefficient in 3 of the 4 categories of the sex/age interaction term, the association between a higher previous DAS28 and a decrease in weight was mainly present in women ages ≥55 years (postmenopausal women) (Table 3 and Figure 1).
Inclusion of the previous DAS28 as a categorical variable with clinically relevant cutoff points (i.e., remission, low disease activity, moderate disease activity, and high disease activity) instead of as a continuous variable in the model showed that higher DAS28 categories were related to a higher decrease in BMI, confirming that the previous DAS28 could be evaluated as a continuous variable (Figure 2).
We found that the effect of time on the change in BMI decreased over time and that the change in BMI was explained by disease activity. Therefore, to confirm that the effect of disease activity on BMI reduces over time, we did an additional analysis adding the interaction term previous DAS28 and time to the model. This analysis confirmed that the effect of the previous DAS28 on BMI decreased over time (b = 0.003, P < 0.001).
We did not find an independent effect of 10 mg of prednisone added to an MTX-based tight control strategy on BMI, but a lower DAS28 was associated with a higher BMI. This suggests that effective treatment lowering disease activity of RA results in weight gain, possibly irrespective of the type of DMARD used. In the CAMERA-II trial, weight gain was significantly higher, but disease control was also significantly better in the MTX + prednisone arm than in the MTX + placebo arm. In another study investigating anti–tumor necrosis factor treatment (10), a mean weight gain of 1.8 kg over 2 years was observed, which is in between the weight gain of 1.3 kg for the MTX + placebo group and 2.9 kg for the MTX + prednisone group in the CAMERA-II trial.
An association between high disease activity and weight loss is to be expected, since patients with active RA can be in a catabolic state, with symptoms such as weight loss, loss of appetite, and fatigue (16) that improve once the active disease is controlled (10). On the other hand, high disease activity might also induce passive physical behavior, which could be another reason to gain weight. In our study, previously higher disease activity was predictive of less subsequent weight gain, mainly earlier in the disease course and in older women.
A strength of our study is the availability of longitudinal data from a randomized double-blind study evaluating identical treatment strategies, with the exception of the additional prednisone or placebo, and appropriate analysis accounting for the within-subject and between-subject variance (mixed-model analysis). This provided an opportunity to optimally study and untangle the longitudinal associations of prednisone and disease activity with BMI.
There are a few limitations to our study. A main limitation is that we cannot discern whether the increase in BMI is caused by fat or lean body mass, the former being a negative effect and the latter being a positive effect. In addition, we do not have information on the distribution of types of fat. Another limitation is that the overall interrelationships of prednisone and disease activity on BMI are net effects. We cannot distinguish between individual hypothetical effects explaining weight gain, such as GC-induced increase of appetite or metabolic effects, via the genomic mechanism of transactivation (17, 18), and diminished cytokine-induced weight loss. On the other hand, decreasing disease activity might result in increased physical mobility, which could reduce body weight through fat loss. An alternative explanation could be the higher frequency found in CAMERA-II of nausea associated with the higher mean dose of MTX in the MTX + placebo group. The difference between the 2 treatment arms was analyzed as a prednisone effect, not taking into account further strategy steps. Furthermore, we did not record the menopause status of women, but used an age cutoff of 55 years instead. The found effect was most pronounced in postmenopausal women, but we do not have an explanation for that; more research is needed. The menopause state of women with RA and the (hormonal) influence of this on weight gain and the influences of disease activity and GCs herein should be addressed further. Also, there is a need to identify which body mass (fat mass and/or lean muscle mass) is responsible for the overall weight change seen in active RA and cardiovascular outcomes. Therefore, the distribution and type of fat mass should be addressed and studied further as well.
Our results suggest that the apprehension of patients to receive GCs because of an alleged weight-increasing effect needs refining: body weight gain, which is at least partly regaining (healthy) weight, following treatment with (low to moderate dose) prednisone of patients with early, active RA seems attributable to a reduction of disease activity.
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. Ms Jurgens 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. Jurgens, Jacobs, Geenen, Bossema, Bakker, Bijlsma, van Albada-Kuipers, Lafeber, Welsing.
Acquisition of data. Jurgens, Jacobs, Bakker, Bijlsma, van Albada-Kuipers, Ehrlich.
Analysis and interpretation of data. Jurgens, Jacobs, Geenen, Bossema, van Albada-Kuipers, Lafeber, Welsing.
- 12Effects of glucocorticoids on radiological progression in rheumatoid arthritis. Cochrane Database Syst Rev 2007; 1: CD006356., , , .