To the Editor:

We read with great interest the article by Klaasen et al (1), who reported that rheumatoid arthritis (RA) patients who have a high body mass index (BMI) exhibited a diminished clinical response to infliximab treatment, and that adipose tissue could play a role in the pathophysiology of RA. However, they did not suggest possible mechanisms.

We speculate that soluble interleukin-2 receptor (sIL-2R), a marker of T lymphocyte activation, might influence the clinical response to infliximab in RA patients. Although it has not yet been extensively studied, Kuuliala et al recently demonstrated that low baseline sIL-2R levels may be predictive of a rapid clinical response in patients with conventional treatment–refractory RA being treated with infliximab (2). Also, it has been reported that human leptin enhanced the proliferation and activation of circulating T lymphocytes in a dose-dependent manner, by stimulating the synthesis of IL-2 (3). Because leptin concentrations are positively correlated with the BMI (4), it is possible that obese RA patients have increased leptin levels, which could activate circulating T lymphocytes (increased IL-2 and sIL-2R), thus resulting in a diminished clinical response to infliximab.

Furthermore, we wonder about the percentage of smokers in each BMI group in the study by Klaasen et al (1), because smoking can increase sIL-2R levels (5), which might affect the clinical response to infliximab (6) and act as a confounding factor. Recently, Abhishek et al demonstrated that anti–tumor necrosis factor α (anti-TNFα) agents were less effective in the treatment of RA in current smokers (6), and we speculate that this might also be due to levels of sIL-2R that were increased because of smoking (5).

It has been shown that anti-TNFα therapy does not modulate leptin in patients with severe RA (7). We thus speculate that the IL-2–sIL-2R system might not be influenced by infliximab itself, but instead by serum leptin levels associated with BMI.

Therefore, it would be of interest to measure serum leptin and sIL-2R levels and ascertain smoking status in addition to BMI when evaluating the clinical response to infliximab. Further studies are needed to investigate our speculations on the possible role of leptin as well as the potential effect of racial differences, as white patients have previously been shown to have significantly higher sIL-2R levels than black patients (mean 455 units/ml versus 365 units/ml; P < 0.001) (5).

  • 1
    Klaasen R, Wijbrandts CA, Gerlag DM, Tak PP. Body mass index and clinical response to infliximab in rheumatoid arthritis. Arthritis Rheum 2011; 63: 35964.
  • 2
    Kuuliala A, Nissinen R, Kautiainen H, Repo H, Leirisalo-Repo M. Low circulating soluble interleukin 2 receptor level predicts rapid response in patients with refractory rheumatoid arthritis treated with infliximab. Ann Rheum Dis 2006; 65: 269.
  • 3
    Martin-Romero C, Santos-Alvarez J, Goberna R, Sanchez- Margalet V. Human leptin enhances activation and proliferation of human circulating T lymphocytes. Cell Immunol 2000; 199: 1524.
  • 4
    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.
  • 5
    Tollerud DJ, Kurman CC, Nelson DL, Brown LM, Maloney EM, Blattner WA. Racial variation in serum-soluble interleukin-2 receptor levels: a population-based study of healthy smokers and nonsmokers. Clin Immunol Immunopathol 1994; 70: 2749.
  • 6
    Abhishek A, Butt S, Gadsby K, Zhang W, Deighton CM. Anti-TNF-α agents are less effective for the treatment of rheumatoid arthritis in current smokers. J Clin Rheumatol 2010; 16: 158.
  • 7
    Gonzalez-Gay MA, Garcia-Unzueta MT, Berja A, Gonzalez-Juanatey C, Miranda-Filloy JA, Vazquez-Rodriguez TR, et al. Anti-TNF-α therapy does not modulate leptin in patients with severe rheumatoid arthritis. Clin Exp Rheumatol 2009; 27: 2228.

Jae Il Shin MD*, Se Jin Park MD†, Ji Hong Kim MD‡, * Yonsei University College of Medicine, Severance Children's Hospital, Seoul, South Korea, † Ajou University School of Medicine Ajou University Hospital Suwon, South Korea, ‡ Yonsei University College of Medicine Severance Children's Hospital Seoul, South Korea.