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Marked Decrease in Sleepiness in Patients with Sleep Apnea by Etanercept, a Tumor Necrosis Factor- Antagonist

Sleep Research and Treatment Center, Department of Psychiatry (A.N.V., E.O.B., G.T.), and Health Evaluation Sciences (H.-M.L.), Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033; and Pediatric and Reproductive Endocrinology Branch, National Institutes of Health (E.Z., G.P.C.), Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Dr. Alexandros N. Vgontzas, Department of Psychiatry H073, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, Pennsylvania 17033. E-mail: axv3{at}psu.edu.

The proinflammatory cytokines, TNF and IL-6, are elevated in obstructive sleep apnea (OSA) and have been proposed as mediators of excessive daytime sleepiness in humans. We tested the effects of etanercept, a medication that neutralizes TNF and is approved by the FDA for the treatment of rheumatoid arthritis, in eight obese male apneics. These patients participated in a pilot, placebo-controlled, double-blind study during which nighttime polysomnography, multiple sleep latency test, and fasting blood glucose and plasma levels of IL-6, C-reactive protein, insulin, and adiponectin were obtained. There was a significant and marked decrease in sleepiness by etanercept, which increased sleep latency during the multiple sleep latency test by 3.1 ± 1.0 min (P < 0.05) compared with placebo. Also, the number of apneas/hypopneas per hour was reduced significantly by the drug compared with placebo (52.8 ± 9.1 vs. 44.3 ± 10.3; adjusted difference, –8.4 ± 2.3; P < 0.05). Furthermore, IL-6 levels were significantly decreased after etanercept administration compared with placebo (3.8 ± 0.9 vs. 1.9 ± 0.4 pg/ml; adjusted difference, –1.9 ± 0.5; P < 0.01). However, no differences were observed in etanercept vs. placebo in the levels of fasting blood glucose and plasma C-reactive protein, insulin, and adiponectin. We conclude that neutralizing TNF activity is associated with a significant reduction of objective sleepiness in obese patients with OSA. This effect, which is about 3-fold higher than the reported effects of continuous positive airway pressure on objective sleepiness in patients with OSA (0.9 vs. 3.1 min), suggests that proinflammatory cytokines contribute to the pathogenesis of OSA/sleepiness.

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