Effects of Tumor Necrosis Factor α Inhibitors Extend Beyond Psoriasis: Insulin Sensitivity in Psoriasis Patients With Type 2 Diabetes Mellitus

Psoriasis has now come to be known as a systemic inflammatory disorder and is associated with increased expression of TNF-α. It predisposes patients to insulin resistance and places them at higher risk for developing DM.^11,12 Systematic reports recommend that there is a link between psoriasis and DM featured by helper T cell (T_H1) cytokines.²⁹ This link can stimulate insulin resistance and metabolic syndrome as well as inflammatory cytokines identified to motivate psoriasis.^29,30 The association between psoriasis and type 2 DM proposes a possible pathophysiologic connection between the 2 diseases. Patients with psoriasis have altered T-cell subtype 1 pathways and dysregulated oxidative and angiogenic mechanisms.^31,32 Many of these immune pathways may similarly predispose psoriasis patients to impaired glucose tolerance and DM. Inflammation may cause insulin resistance and DM through numerous mechanisms. Systemic inflammation linked with psoriasis may lead to high levels of circulating IL-1, IL-6, and TNF-α that predispose patients to impaired glucose tolerance and type 2 DM.³³

Several longitudinal investigations have found that TNF inhibitors improve insulin resistance.^13,14,34-38 Gonzalez-Gay et al¹³ confirmed a rapid beneficial effect of infliximab on insulin resistance and insulin sensitivity in rheumatoid arthritis (RA) patients, which might support the long-term use of drugs that act by blocking TNF-α to diminish the mechanisms implicated in the development of atherosclerosis in patients with RA. Kiortsis et al¹⁴ performed a complete biochemical profile before and after 6 months of treatment with infliximab in 17 patients with ankylosing spondylitis and 28 patients with RA. The researchers found a significant decrease of the HOMA index in the percentile of their patients with the highest insulin resistance (P<.01).¹⁴

Stagakis et al³⁴ found that 12 weeks of treatment with anti-TNF agents may improve insulin resistance in patients with active RA and high insulin resistance. Treatment with anti-TNF agents was shown to restore the phosphorylation status of serine phosphorylation of insulin receptor substrate 1 (Ser312-IRS-1) and AKT (protein kinase B), which are important mediators in the insulin signaling cascade. The investigators concluded that treatment with anti-TNF agents may improve insulin resistance and sensitivity in RA patients with active disease and high insulin resistance.³⁴

Solomon et al³⁵ studied the link between disease-modifying antirheumatic drugs and DM risk in patients with RA and psoriasis. The authors proposed that initiation of treatment with TNF inhibitors in psoriasis patients was associated with a reduced incidence of DM. The results showed a lower risk for developing DM in patients with psoriasis who were treated with a TNF inhibitor compared with numerous other drugs.³⁵

Marra et al³⁶ studied the effects of etanercept on insulin sensitivity in 9 patients with psoriasis. They reported a decrease in insulin resistance evaluated by HOMA after 24 weeks of etanercept treatment.³⁶ Wambier et al³⁷ reported severe hypoglycemia after initiation of anti-TNF therapy with etanercept in a patient with generalized pustular psoriasis and type 2 DM.

Yazdani-Biuki et al³⁸ reported the case of a patient who demonstrated a relapse of type 2 DM after an interruption of prolonged treatment with infliximab, an anti–TNF-α antibody for psoriatic arthritis. The improvement in insulin sensitivity of this patient has been reported along with post hoc evidence that chronic administration of infliximab improves insulin resistance in a small sample of patients with inflammatory joint diseases.¹⁷

Other studies on the effects of TNF inhibitors on insulin resistance and sensitivity have yielded conflicting results. Martínez-Abundis et al³⁹ studied the effects of etanercept on insulin resistance and sensitivity in a randomized trial of psoriatic patients at risk for developing type 2 DM. Results indicated that anti-TNF therapy had no significant influence on insulin sensitivity measured using a hyperinsulinemic clamp during 2 weeks of etanercept treatment in psoriatic patients with risk factors for type 2 DM. The explanation of this discrepancy may be due to the short duration of the study period.

It is still unknown if psoriasis treatment affects a patient’s risk for developing DM. However, Solomon et al³⁵ evaluated the association of incidental DM among patients with prescribed TNF inhibitors or methotrexate and proposed that initiation of treatment with TNF inhibitors was associated with a diminished incidence of DM.

Our study supports and confirms that psoriasis patients treated with TNF-α inhibitors showed improved glycemic indices and insulin resistance compared with control patients treated with other common systemic drugs for psoriasis. We did not take into consideration other conventional risk factors such as hypertension and coronary artery disease. The number of participants included in the current study was not large enough to evaluate each of the anti-TNF agents in a separate group, and participants were not followed up long enough to see the impact of the biochemical changes noted in the results on long-term morbidity or mortality.