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Longterm Anti-Tumor Necrosis Factor-α Treatment in Patients with Refractory Rheumatoid Arthritis: Relationship Between Insulin Resistance and Disease Activity

To the Editor:

Patients with rheumatoid arthritis (RA) experience increased mortality rates, with cardiovascular disease as the most important cause of death compared to the general population¹. Traditional and nontraditional risk factors including systemic inflammation, effects of several antirheumatic treatments, and increased insulin resistance contribute to the atherogenesis in RA². Insulin resistance plays an important role in the development and progression of atherosclerotic lesions in patients with autoimmune rheumatic diseases, including RA³. Obesity and increased RA disease activity have been found to be associated with increased insulin resistance, whereas suppression of disease activity results in a marked reduction of this last condition⁴. Studies have found that suppression of RA disease activity with conventional disease modifying agents resulted in improvement in insulin sensitivity (and its associated cardiovascular risk factors)⁵.

Tumor necrosis factor-a (TNF-a) is a well defined proinflammatory cytokine with a wide range of activities including initiation and amplification of the inflammatory cascade both in RA and in atherogenesis. Studies found that anti-TNF-a treatment reduces RA disease activity and also improves insulin sensitivity, although the latter effect remains controversial^6,7. Two independent groups have also recently reported an independent association of insulin resistance with atherosclerosis in RA^8,9. We assessed whether longterm treatment with etanercept or infliximab may result in reduction of insulin resistance in patients with refractory RA and whether there are relationships between insulin resistance and disease activity.

In a prospective study 38 consecutive female patients with RA fulfilling the American College of Rheumatology 1987 criteria were analyzed (Table 1). All patients showed active disease as defined by the Disease Activity Index (DAS), using a 28-joint score (DAS28 > 3.2) at baseline; they were nonresponders or did not tolerate at least 2 previous disease modifying antirheumatic drugs. Patients received TNF-a blockers (etanercept, n = 20, 25 mg twice weekly; infliximab, n = 18, 3 mg/kg at 0, 2, 6 weeks, and every 8 weeks thereafter), stable doses of nonsteroidal antiinflammatory drugs, prednisolone (< 7.5 mg/day), and methotrexate (MTX; 10 mg/week) during the study. Patients were excluded from the study if they had a history of blood hypertension, diabetes mellitus, or endocrine or metabolic disorders, as well as current treatment with drugs that might influence glucose metabolism or lipid-lowering agents. A control group included 20 women with RA with stable therapy (prednisone < 7.5 mg/day and MTX 10 mg/week). Concentrations of plasma glucose and serum insulin (Abbott, Chicago, IL, USA) were evaluated using a microparticle enzyme immunoassay on the Axsym system (for insulin). Insulin resistance was estimated by the homeostasis model assessment for insulin resistance (HOMA) using the following formula: fasting serum insulin (µU/ml) ´ fasting plasma glucose (mmol/l)/22.5; and the Quantitative Insulin Sensitivity Check Index (QUICKI) using the formula: 1/log insulin (µU/ml) + log glucose (mg/dl)^10,11. Measurements were made on blood samples collected before the administration of the TNF-a blockers and after 12 and 24 weeks from the starting dosage. Body weight and body mass index (BMI) were assessed at each visit, when blood samples were collected. The changes observed before and after etanercept or infliximab were assessed by paired t-test for normally distributed data and Wilcoxon's signed-rank test for non-normally distributed data.

Table 1. Baseline characteristics of patients with active RA.

The study showed that BMI remained unchanged throughout the study period, whereas DAS28 score decreased significantly from baseline to Week 12 (4.8 ± 0.9 vs 3.5 ± 0.6) and then to Week 24 (2.1 ± 0.5) (p < 0.01 for both), in patients with anti-TNF-a treatment, and not significantly in nontreated RA patients (controls) from baseline to Week 12 (4.4 ± 0.8 vs 3.3 ± 0.4) and to Week 24 (2.8 ± 0.6; p < 0.01). At baseline and after 12 weeks no significant differences for the HOMA index or for the QUICKI were observed between the groups with or without anti-TNF-a treatment.

However, after 24 weeks from baseline, a significant decrease of the HOMA index (1.445 vs 1.733; p < 0.01) and a significant increase of the QUICKI (0.361 vs 0.378; p < 0.01) were found in RA patients who had anti-TNF-a treatment. Interestingly, no differences were found between RA patients treated with either infliximab or etanercept, and no significant changes were observed in the RA control group. The changes in HOMA index and QUICKI from 0 to 12 weeks showed no significant correlations with DAS28. By contrast, changes in DAS28 from 0 to 24 weeks were significantly associated with the HOMA index (p < 0.02) and the QUICKI (p < 0.01; Figure 1), and the changes in DAS28 were not significantly associated with insulin resistance in patients not treated with anti-TNF-a. In this study, changes in insulin resistance were significantly associated with changes in disease activity in treated patients, as shown by Dessein, et al^4,8. A recent study by Gonzalez-Gay, et al showed a percentage reduction in the HOMA index immediately after infliximab infusion¹². Our longterm study confirmed that the reduction of the HOMA index (20% at Week 24) was progressive in all RA patients treated with anti-TNF-a therapy, with no difference for the 2 different TNF blockers (etanercept and infliximab). These changes were associated with a decrease in disease activity. Our findings are consistent with observations by Dessein, et al that high C-reactive protein concentrations were associated with insulin resistance and that the QUICKI was not different in RA patients compared with healthy controls^4,8. Thus, our results seem to show that different longterm anti-TNF-a treatments improve both disease activity and insulin resistance.

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Figure 1. Correlations between changes in DAS28 and HOMA index (A, B) and the QUICKI (C, D) after 12 weeks (A, C) and 24 weeks (B, D) of therapy with anti-TNF-a blockers.

These results suggest that longterm use of TNF-a blockers might also interfere with some of the mechanisms implicated in development of atherosclerosis and might reduce the cardiovascular risk profile in patients with RA.

BRUNO SERIOLO, MD; CARMELA FERRONE, MD; MAURIZIO CUTOLO, MD, Research Laboratory and Academic Unit of Clinical Rheumatology, Department of Internal Medicine and Medical Specialities, University of Genova, Genova, Italy. Address reprint requests to Prof. B. Seriolo, Research Laboratory and Academic Unit of Clinical Rheumatology, Department of Internal Medicine and Medical Specialities, University of Genova, Viale Benedetto XV, no. 6, 16132 Genova, Italy. E-mail: seriolob@unige.it

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