The Potential Effect of TNF-α Antagonist Therapy in Rheumatoid Arthritis may Depend on the Degree and Severity of Insulin Resistance Before the Onset of this Therapy

We have read with great interest the elegant study performed by Ferraz-Amaro et al. on the potential effect of TNF-α blockade in patients with rheumatoid arthritis (RA) [1].

With respect to this, we have prospectively followed a cohort of nondiabetic patients who had RA refractory to conventional DMARDs, including methotrexate, and who, due to disease severity, underwent anti-TNF-α-infliximab therapy. Among them, a subgroup of 33 consecutive RA patients who were on periodical treatment with infliximab and who agreed to participate in the study were assessed to determine the short-term effect of this drug on insulin resistance, biomarkers of endothelial dysfunction, ghrelin, and adipokine profile.

In keeping with the data from Ferraz-Amaro et al. [1], in our series, we observed a significant increase of body mass index (BMI) when values obtained before the onset of infliximab therapy were compared with those observed after 2 years of infliximab therapy [2]. Since we also observed a rapid increase of ghrelin levels, a hormone that is implicated in RA-associated cachexia, following infliximab infusion, we hypothesized that TNF-α antagonist therapy might play a role in the increase of BMI observed in RA patients by an increase in ghrelin levels. However, the study by Ferraz-Amaro et al. does not support our hypothesis [1].

Ferraz-Amaro et al. did not observe a significant effect of the TNF-α blockade on insulin resistance in RA after 1 year of treatment [1]. This is in contrast with most studies that showed improvement of insulin resistance following TNF-α antagonist therapy. In this regard, Kiortsis et al. performed a complete biochemical profile before and after 6 months of treatment with infliximab in 17 patients with ankylosing spondylitis and in 28 patients with RA [3]. They used the HOMA index to measure insulin resistance and the QUICKI to measure insulin sensitivity. In the whole study group, no significant changes of the HOMA index or QUICKI were seen. However, the authors demonstrated that those patients with ankylosing spondylitis and RA that initially were in the tertile of patients with the highest insulin resistance experienced the greatest reduction in HOMA and the greatest increase of the QUICKI [3]. These results suggested that the TNF-α blockade may have positive effects on insulin sensitivity in the most insulin resistant patients with chronic inflammatory rheumatic diseases. In accordance with Kiortosis et al., we found a dramatic decrease of insulin resistance and an improvement of insulin sensitivity following an infusion of infliximab in our series of RA patients with severe disease [4]. In our study HOMA decreased in most patients. In addition, the decrease in HOMA values was more important in those RA patients with the higher values of HOMA before infliximab infusion [4].

Therefore, we feel that the most important finding that may help to explain the differences between most studies and this one reported by Ferraz-Amaro et al. may be the basal values of HOMA-IR at the onset of the study. In this regard, the mean±standard deviation (SD) HOMA-IR found in the series by Ferraz-Amaro et al. was only 1.6±0.8. This result means that most patients did not fulfill definitions for insulin resistance as it is generally considered to be present if HOMA-IR index is higher than 2.29. With respect to this, in our series of nondiabetic RA patients undergoing TNF-α antagonist therapy the mean±SD basal HOMA-IR index before infliximab infusion was 3.4±2.3 that showed a dramatic reduction (2.7±2.2) immediately after infliximab infusion [4].

Taken together, we feel that we cannot exclude a positive beneficial metabolic effect of TNF-α antagonist therapy on insulin metabolism. However, it is possible that the beneficial metabolic effects mediated by TNF-α antagonist therapy may be mainly observed in individuals presenting insulin résistance and metabolic syndrome at the onset of this biologic therapy.

• References

• 1 Ferraz-Amaro I, Arce-Franco M, Muñiz J, López-Fernández J, Hernández-Hernández V, Franco A, Quevedo J, Martínez-Martín J, Díaz-González F. Systemic Blockade of TNF-α does not Improve Insulin Resistance in Humans. Horm Metab Res 2011; 43: 801-808
• 2 Gonzalez-Gay MA, Gonzalez-Juanatey C, Miranda-Filloy JA, Martin J, Garcia-Unzueta MT, Llorca J. Response to ‘Infliximab therapy increases body fat mass in early rheumatoid arthritis independently of changes in disease activity and levels of leptin and adiponectin: a randomized study over 21 months’. Arthritis Res Ther 2011; 27; 13: 404
• 3 Kiortsis DN, Mavridis AK, Vasakos S, Nikas SN, Drosos AA. Effects of infliximab treatment on insulin resistance in patients with rheumatoid arthritis and ankylosing spondylitis. Ann Rheum Dis 2005; 64: 765-766
• 4 Gonzalez-Gay MA, De Matias JM, Gonzalez-Juanatey C, Garcia-Porrua C, Sanchez-Andrade A, Martin J, Llorca J. Anti-tumor necrosis factor-alpha blockade improves insulin resistance in patients with rheumatoid arthritis. Clin Exp Rheumatol 2006; 24: 83-86