Open Access

Use of methotrexate therapy is not associated with decreased prevalence of metabolic syndrome

  • Hennie G Raterman1,
  • Alexandre E Voskuyl1,
  • Ben AC Dijkmans1, 2 and
  • Michael T Nurmohamed3Email author
Arthritis Research & Therapy200911:413

DOI: 10.1186/ar2805

Published: 21 September 2009

With great interest, we read the article by Toms and colleagues [1] in the previous issue of Arthritis Research & Therapy, in which they assessed prevalences of metabolic syndrome (MetS) in rheumatoid arthritis (RA) patients. Moreover, they identified demographic and clinical factors that may be associated with MetS. Toms and colleagues found prevalences of up to 45% of MetS and demonstrated older age and health status (health assessment questionnaire) to be associated with MetS irrespectively of the definition used. Of most interest, an association between methotrexate (MTX) use and decreased presence of MetS was observed in patients more than 60 years of age. The investigators hypothesized that this may be attributed to a drug-specific effect (and not to an anti-inflammatory effect) either by changing levels of adenosine, which is known to interact with glucose and lipid metabolism, or by an indirect effect mediated through concomitant folic acid administration, thereby decreasing homocysteine levels.

Recently, we also examined the prevalence of MetS in (a subgroup of) RA patients in the CARRÉ investigation, a prospective cohort study on prevalent and incident cardiovascular disease and its underlying cardiovascular risk factors [2]. The findings of Toms and colleagues stimulated us to perform additional analyses in our total study population (n = 353).

The prevalences of MetS were 35% and 25% (Table 1) according to criteria of National Cholesterol Education Program (NCEP) 2004 and NCEP 2001, respectively. In multivariate backward regression analyses, we found significant associations between body mass index, pulse rate, creatinine levels, hypothyroidism and diabetes mellitus and the presence of MetS independently of the criteria used (Table 2). However, an independent association between single use of MTX or use of MTX in combination with other disease-modifying antirheumatic drugs, on the one hand, and a decreased prevalence of MetS, on the other hand, could not be demonstrated (even in the subgroup of patients over the age of 60).
Table 1

Characteristics of the study population

 

MetS presenta

MetS absenta

MetS presentb

MetS absentb

  
 

n = 84

n = 265

n = 121

n = 228

Pvaluea

Pvalueb

Demographics

      

   Age, years

63.8 (± 8)

63.1 (± 7)

64.3 (± 8)

62.7 (± 7)

0.46

0.045

   Female, percentage

76

63

74

62

0.022

0.028

RA-related characteristics

      

   DAS28

4.2 (± 1.3)

3.9 (± 1.4)

4.1 (± 1.3)

3.8 (± 1.4)

0.21

0.062

   ESR, mm/hour

22 (10-35)

16 (9-30)

20 (10-34)

17 (9-31)

0.059

0.33

   CRP, mg/L

11 (4-21)

6 (3-16)

8 (3-18)

6 (3-19)

0.021

0.46

   RA duration, years

7 (4-10)

7 (4-10)

7 (4-10)

7 (5-10)

0.83

0.19

   Erosion, percentage

77

83

79

83

0.20

0.36

   Number of DMARDs

1 (1-2)

1 (1-1)

1 (1-2)

1 (1-1)

0.26

0.43

   MTX current, percentage

62

60

63

59

0.71

0.46

   MTX only, percentage

39

39

41

38

0.95

0.67

   SSZ only, percentage

8

13

9

14

0.23

0.22

   HCQ only, percentage

1

4

3

4

0.31

0.55

   Combination of DMARDs, percentage

31

25

29

25

0.24

0.38

   TNF-blocking agent, percentage

11

9

11

9

0.73

0.65

   Prednisolone only, percentage

1

2

3

1

1.00

0.42

Cardiovascular risk factors

      

   Current smoker, percentage

26

31

25

32

0.42

0.15

   Pack-years, years

17 (0-34)

19 (2-38)

19 (0-35)

18 (2-38)

0.23

0.75

   BMI, kg/m2

30 (± 4)

26 (± 5)

29 (± 4)

25 (± 5)

< 0.001

< 0.001

   Creatinine, μmol/L

89 (± 21)

89 (± 16)

91 (± 22)

87 (± 14)

0.99

0.070

   Renal clearance, mL/minute

81 (± 24)

72 (± 19)

77 (± 23)

73 (± 19)

0.003

0.062

   Pulse, beats per minute

76 (± 11)

73 (± 9)

75 (± 11)

73 (± 9)

0.005

0.015

   Diabetes mellitus, percentage

14

3

12

3

< 0.001

0.001

   Hypothyroidism, percentage

12

2

9

2

0.001

0.003

aMetabolic syndrome (MetS) according to National Cholesterol Education Program (NCEP) 2001; bMetS according to NCEP 2004. Continuous variables are presented as means (± standard deviations) in cases of normal distribution or as medians (interquartile ranges) in cases of non-normal distribution. BMI, body mass index; CRP, C-reactive protein; DAS28, disease activity score using 28 joint counts; DMARD, disease-modifying antirheumatic drug; ESR, erythrocyte sedimentation rate; HCQ, hydroxychloroquine; MTX, methotrexate; RA, rheumatoid arthritis; SSZ, sulfasalazine; TNF, tumour necrosis factor.

Table 2

Variables associated with metabolic syndrome

 

Univariate

Multivariatea

 

OR

95% CI

Pvalue

OR

95% CI

Pvalue

Body mass index

1.2

1.1-1.3

< 0.001

1.2

1.1-1.3

< 0.001

Pulse

1.03

1.01-1.06

0.011

1.03

1.00-1.06

0.020

Creatinine

1.01

1.00-1.02

0.080

1.02

1.00-1.03

0.017

Hypothyroidism

4.5

1.5-13.2

0.007

4.7

1.5-15.0

0.009

Diabetes mellitus

4.8

1.8-12.9

0.002

4.5

1.4-15.2

0.014

aIn multivariate analyses, the following variables were used: gender, age, prednisolone only, methotrexate only, sulfasalazine only, hydroxychloroquine only, tumour necrosis factor-blocking agents, combination of disease-modifying antirheumatic drugs, pack-years, smoking, erosions, DAS28 (disease activity score using 28 joint counts), body mass index, pulse rate, creatinine levels, renal clearance, hypothyroidism and diabetes mellitus. CI, confidence interval; OR, odds ratio.

Therefore, to get more support for a drug-specific effect, it is of interest to know whether or not in the study of Toms and colleagues the MTX effect was present only in the group of RA patients with single use of MTX or in the group of MTX-treated patients with other antirheumatic drugs. As patients with MetS were significantly older, it would give further information whether age was an independent risk factor for MetS in regression analyses. Moreover, as readers, we are not informed about comorbidities like diabetes and clinical hypothyroidism, which are notorious cardiometabolic risk factors. On the whole, we could not confirm a plausible protective role for the use of MTX and presence of MetS, and hence further investigation is required to explain the discrepancy between our findings and those of Toms and colleagues.

Abbreviations

MetS: 

metabolic syndrome

MTX: 

methotrexate

NCEP: 

National Cholesterol Education Program

RA: 

rheumatoid arthritis.

Declarations

Authors’ Affiliations

(1)
Department of Rheumatology, VU University Medical Center
(2)
Department of Rheumatology, Jan van Breemen Institue
(3)
Department of Internal Medicine, VU University Medical Center

References

  1. Toms TE, Panoulas VF, Douglas KMJ, Kitas GD: Methotrexate therapy associates with a reduced prevalence of the metabolic syndrome in rheumatoid arthritis patients over the age of 60: more than just an anti-inflammatory effect? A cross-sectional study. Arthritis Res Ther. 2009, 11: R110-10.1186/ar2765.PubMed CentralView ArticlePubMed
  2. Raterman HG, van Eijk IC, Voskuyl AE, Peters MJ, Dijkmans BA, van Halm VP, Simsek S, Lems WF, Nurmohamed MT: The metabolic syndrome is amplified in hypothyroid rheumatoid arthritis patients: a cross-sectional study. Ann Rheum Dis. 2008

Copyright

© BioMed Central Ltd 2009

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