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

  • Hennie G Raterman1,

    Affiliated with

    • Alexandre E Voskuyl1,

      Affiliated with

      • Ben AC Dijkmans1, 2 and

        Affiliated with

        • Michael T Nurmohamed3Email author

          Affiliated with

          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 present a n = 84

          MetS absent a n = 265

          MetS present b n = 121

          MetS absent b n = 228

          P value a

          P value b

          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

          P value

          OR

          95% CI

          P value

          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.View 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, in press.

          Copyright

          © BioMed Central Ltd 2009

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