We evaluated the outcome on insulin resistance and other metabolic parameters among 61 patients with active RA disease, after 12 weeks of treatment with anti-TNF agents. In a subset of patients, we also examined the effect of TNF blockade on the phosphorylation status of IRS-1 and AKT, which are major mediators of insulin signaling. Our findings suggest that treatment with anti-TNF agents may improve insulin resistance and sensitivity in RA patients with active disease and high insulin resistance, and this effect correlates with reduced levels of the insulin-resistant Ser312-phosphorylated form of IRS-1 and increased levels of activated/phosphorylated AKT.
Insulin resistance constitutes a major mechanism in the pathophysiology of metabolic syndrome [38
]. In our cohort of patients with active RA, those with high insulin resistance had significantly higher fasting plasma glucose, serum triglycerides, and systolic blood pressure levels than their counterparts in the low insulin resistance group. Accordingly, patients with metabolic syndrome had an OR of 10.8 for high insulin resistance, independent of the effect of other parameters.
In patients with RA, insulin resistance has been shown to correlate both with anthropometric parameters (abdominal obesity) and high disease activity [13
]. We found that RA patients with high insulin resistance had significantly higher DAS28 values than those with low insulin resistance, and in multivariate analysis, patients in the upper quartile of disease activity (DAS28 > 6.86) had more than six times increased risk (OR 6.4) for high insulin resistance. This is in agreement with our previous result of increased prevalence of metabolic syndrome in RA patients with moderate or high disease activity (OR 9.2 for DAS28 > 3.2) [12
], and corroborates the link between inflammation and insulin resistance in chronic inflammatory disorders.
Previous studies have demonstrated that treatment with TNF antagonists improves insulin sensitivity in RA [18
]. We further corroborate these results by examining the metabolic effects of anti-TNF therapy in a larger cohort of 61 patients with active RA. Among patients with high insulin resistance at baseline, treatment with anti-TNF agents for 12 weeks resulted in significant improvement in insulin sensitivity as evidenced by reduction in the HOMA-IR and increase in the QUICKI indices. Of note, serum triglycerides were reduced by an average 24.5 mg/dl, and HDL-C levels were increased by an average 4.2 mg/dl. Our findings agree with those of Kiortsis, et al
] who reported significant decrease in HOMA-IR and increase in QUICKI among patients with RA and ankylosing spondylitis in the highest tertile of insulin resistance, suggesting that this subset of patients may benefit most from anti-TNF therapy. In accordance with the results of previous studies [18
], we found no correlation between changes in HOMA-IR and fasting insulin levels with improvements in disease activity or CRP level.
We found that treatment with anti-TNF agents resulted in significant reduction in the HOMA-B index of pancreatic beta cell function in RA patients with high baseline insulin resistance. This could be explained by the therapy-driven reduction in the inflammatory burden of the disease and the insulin resistance levels, thus resulting in reduced compensatory beta cell hyperfunction. Whether this effect could lead to preservation of beta cell function in the long term is currently unknown. Intriguingly, a recent epidemiological study found that among patients with RA or psoriasis, the adjusted risk of new-onset DM was lower for individuals on TNF inhibitor (adjusted hazard ratio 0.62) compared with initiation of other non-biologic DMARDs [39
TNF may impair insulin signaling at the level of the IRS proteins, and the Ser307
in humans) residue in IRS-1 has been identified as a site for the inhibitory effects of TNF, with p38 MAPK and inhibitor kB kinase being involved in the phosphorylation of this residue [7
]. TNF mediates insulin resistance by inhibition of AKT activity through a ceramide-activated protein-phosphatase (PP) 2A [35
]. Since anti-TNF therapy significantly reduced HOMA-IR in patients with active RA and high insulin resistance, we examined the extent to which the aforementioned biochemical effects are affected by TNF inhibition. Our western blot assays demonstrated significant reduction in p-Ser312
IRS-1 and increase in p-AKT levels, associated with reduction in HOMA-IR in patients with active RA and high baseline insulin resistance. These alterations were consistent in all but one patient in our study and their magnitude did not correlate with the degree of improvement in disease activity or insulin resistance. To our knowledge, this is the first demonstration that anti-TNF therapy may improve insulin resistance in patients with active RA by reversing defects in the phosphorylation/activation status of the insulin signaling pathway.
To determine whether the observed improvements in insulin resistance and phosphorylation status of IRS-1 and AKT are directly linked to TNF blockade or are secondary to reduction in disease activity and inflammation, we studied seven patients with RA, who received abatacept (CTLA4.Ig) due to high disease activity. Patients treated with abatacept did not demonstrate reduction in HOMA-IR levels over the 12-week study period despite improvement in disease activity, nor did they display any consistent alterations in p-Ser312
IRS-1 and p-AKT levels. It should be noted, however, that these observations are limited to a small number of patients and further documentation in a larger cohort will be required. Moreover, it may be argued that the duration of the study was too short to capture the metabolic effects of abatacept treatment, or that we did not evaluate changes in other molecules implicated in insulin resistance such as expression of the protein-tyrosine phosphatase (PTP)-1B or the glucose transporter (GLUT)-4 [32
Although our results suggest a beneficial effect of anti-TNF treatment on insulin signaling in RA patients with high insulin resistance, the clinical importance of such treatment in reducing risk of cardiovascular disease in the long term remains to be determined. In the interim, clinical decisions for initiation of anti-TNF or other biologic agents in RA should be based on disease activity and severity indices [40
]. To this end, according to the existing EULAR recommendations, 'adequate control of disease activity is necessary to lower the cardiovascular disease risk' in RA patients [41
]. Consequently, anti-TNF agents may be preferred as first-line biologic treatment in patients with active RA and high inflammatory burden, and metabolic abnormalities or insulin resistance.