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

Psoriasis is a chronic inflammatory disorder associated with increased expression of proinflammatory mediators such as tumor necrosis factor (TNF) α.¹ Anti-TNF drugs (eg, etanercept, adalimumab, infliximab) were proven to be highly effective for the treatment of psoriasis over the last 2 decades.² Interestingly, TNF inhibitors have been thought to be effective in improving insulin resistance in patients with type 2 diabetes mellitus (DM) by blocking TNF, which is involved in the inflammatory condition in DM.

Type 2 DM is a common chronic condition characterized by hyperglycemia resulting from a combination of peripheral and hepatic insulin resistance and impaired insulin secretion.³ It is characterized by defects in both insulin secretion and insulin sensitivity.^4,5 Type 2 DM has been linked with a marked increase in cardiovascular disease, morbidity, and mortality.⁶ Evidence-based literature regarding the role of chronic inflammation as an important pathogenetic factor in type 2 DM has been growing.^7-9 It also has been suggested that pharmacological strategies to reduce this underlying associated silent inflammation are useful in treating DM, which also is true for other conditions such as obesity, metabolic syndrome, and cardiovascular diseases.¹⁰

Psoriasis predisposes patients to insulin resistance and may put them at risk for developing DM.^11,12 The association between psoriasis and DM suggests that systemic immunosuppression also may diminish the risk for developing DM. Several longitudinal studies have found that TNF inhibitors improve insulin resistance.^13,14 Dandona et al¹⁵ reported a considerable decrease of TNF-α levels with the concurrent restoration of insulin sensitivity during weight loss.

Pereira et al¹⁶ found a notable connection between psoriasis, DM, and insulin resistance with an odds ratio of 2.63 of abnormal glucose homeostasis in patients with psoriasis compared to controls. Yazdani-Biuki et al¹⁷ proved that extended administration of anti–TNF-α antibody was able to improve insulin sensitivity in insulin-resistant patients. The same finding was established by Kiortsis et al.¹⁴

In this prospective controlled study, we evaluated the effects of anti-TNF agents on insulin resistance and sensitivity in psoriasis patients with type 2 DM treated with anti-TNF agents.

Methods

A total of 70 patients attending the dermatological outpatient clinics at Farwaniya Hospital (Kuwait City, Kuwait) between January 2012 and September 2014 were enrolled in the study and were randomly distributed into 2 equal groups (n=35 each). The study was approved by the hospital ethics committee. Patients were included in the study if they had moderate to severe psoriasis (ie, psoriasis area severity index score ≥10) with documented type 2 DM and high fasting plasma glucose (FPG) levels (ie, >10 mmol/L). Patients who were currently being treated with oral hypoglycemic agents but not insulin therapy were included in the study. Patients were excluded if they had phototherapy within the last 4 weeks, prior biologic therapy, current and prior insulin therapy, a change in oral hypoglycemic drug dosage in the last 2 months, other serious systemic illness (eg, malignancy, hepatitis B or C virus, metabolic or endocrine disease), and/or abnormal laboratory investigations (eg, liver/kidney profile, chest radiograph abnormality, positive Mantoux test). All of the patients enrolled in the study provided informed consent and underwent routine baseline investigations including complete blood cell counts, general health profile, chest radiograph, antinuclear antibody test, Mantoux test, FPG and insulin levels, glycated hemoglobin (HbA_1C), homeostasis model assessment (HOMA), routine urine examination, and enzyme-linked immunosorbent assay for tuberculosis. The study group was treated with anti-TNF agents, and the control group received conventional antipsoriatic medications.

All the patients included in the study had high FPG levels (ie, >10 mmol/L) at the time of enrollment and were currently being treated with oral hypoglycemic agents. The dose of oral hypoglycemic agents was unchanged for at least 2 months before entry into the run-in period and throughout the 24-week study period. Demographic details including sex, age, medical history (eg, type of psoriasis, prior and concomitant treatments) were collected from the participants’ clinical histories. Participants from both groups were appropriately matched in terms of age, sex, body weight, body mass index, and duration of type 2 DM (Table 1). The primary end point of the study was to analyze and compare clinical and serum data collected at baseline and after 24 weeks of therapy.

A complete biochemical profile was repeated in both groups after 24 weeks of treatment. Each participant underwent a baseline short insulin sensitivity test immediately before treatment and at 4 and 24 weeks of treatment. We assessed insulin resistance via HOMA, calculated as follows: FPG [mmol/L] × fasting serum insulin [pmol/L] / 22.5.¹⁸ Oral glucose tolerance tests were performed to calculate the HOMA of insulin resistance. Serum insulin concentration was determined via enzyme-linked immunosorbent assay.