Apremilast Use During COVID-19

Apremilast (Otezla; Amgen), a phosphodiesterase-4 (PDE-4) inhibitor, is an oral small molecule inhibitor approved for patients with psoriatic arthritis and/or moderate to severe plaque psoriasis. As physicians continue to assess the safety and efficacy of immunomodulatory medications, they must keep the COVID-19 pandemic in mind. A study aimed to investigate the risk of apremilast treatment with the pandemic in mind.¹

There is emerging evidence that targeted immunosuppression may be helpful in cases of severe COVID-19 infection with cytokine storm, but this effect cannot be generalized to all immunomodulatory medications, according to a study in The Journal of the American Medical Association.² In relation to apremilast, more thorough investigation is needed because it has been shown to inhibit Th1/Th17 immune responses in patients, causing statistically significant decreases in TNF-α, IL-8, IL- 6, and eventually IL-17 after longer periods of treatment (40 weeks).³

“While cytokines are necessary for a competent immune response, severe cases of COVID-19 infection are often characterized by increased levels of proinflammatory cytokines, with serum levels of lL-6 and IL-10 positively correlating with disease severity and organ failure,” the authors wrote.⁴

Researchers did a comparative analysis of the ESTEEM I (NCT01194219) and ESTEEM II (NCT01232283) trials. These 2 placebo-controlled, phase 3 trials included 1,255 adult patients with moderate to severe psoriasis who were randomized in a 2:1 ratio to receive either apremilast 30 mg twice daily (BID) or placebo for 16 weeks.⁵

At week 16, the patients in the placebo arm received apremilast as well and dosing with apremilast was maintained for all patients from week 16 to week 32. Treatment from weeks 32 to 52 was based on the original treatment assignment and the Psoriasis Area and Severity Index (PASI) response at week 32.

At the end of the 16-week placebo-controlled period, the adverse event (AE) of upper respiratory tract infections (URTIs) occurred in 6.5% of placebo-treated patients compared to 8.4% of apremilast-treated patients. Also, nasopharyngitis occurred in 6.9% of placebo-treated patients and 7.3% of apremilast-treated patients. From weeks 16 to 52, rates of URTI and nasopharyngitis increased to 16.9% and 15%, respectively. There was no placebo-control group to include the second and third period of trials for the study analysis.

Based on data from the first 16 weeks of both trials, apremilast has no apparent increased risk of infection compared to placebo, the researchers concluded. This is consistent with a recent case report of a patient with erythrodermic psoriasis who received apremilast during hospitalization for COVID-19 and experienced a mild, uncomplicated infection despite having multiple risk factors for poor outcome (obesity, cancer, and chemotherapy use).⁶

The study was limited due to the absence of a placebo control group in the second and third periods of both trials. Additionally, the trials did not specify whether the URTIs were caused by viral or bacterial pathogens.

“Nonetheless, we believe this study suggests apremilast does not increase the risk of URTI or nasopharyngitis compared to placebo and may be safe to continue during the COVID-19 pandemic, although further research and continued patient observation are recommended,” the authors concluded.

References:

1. Kearns D, Uppal S, Chat V, et al. Assessing the risk of apremilast use for psoriasis during the covid-19 pandemic. JDDonline - Journal of Drugs in Dermatology. Accessed December 14, 2021. https://jddonline.com/articles/assessing-the-risk-of-apremilast-use-for-psoriasis-during-the-covid-19-pandemic-S1545961621P0582X/
2. Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review. JAMA. 2020.
3. Schafer PH, Chen P, Fang L, Wang A, Chopra R. The pharmacodynamic impact of apremilast, an oral phosphodiesterase 4 inhibitor, on circulating levels of inflammatory biomarkers in patients with psoriatic arthritis: substudy results from a phase III, randomized, placebo-controlled trial (PALACE 1). J Immunol Res. 2015;2015:906349.
4. Yang L, Liu S, Liu J, et al. COVID-19: immunopathogenesis and Immunotherapeutics. Signal Transduct Target Ther. 2020;5(1):128.
5. Crowley J, Thaci D, Joly P, et al. Long-term safety and tolerability of apremilast in patients with psoriasis: Pooled safety analysis for >/=156 weeks from 2 phase 3, randomized, controlled trials (ESTEEM 1 and 2). J Am Acad Dermatol. 2017;77(2):310-317 e311.
6. Mugheddu C, Pizzatti L, Sanna S, Atzori L, Rongioletti F. CID-19 pulmonary infection in erythrodermic psoriatic patient with oligodendroglioma: safety and compatibility of apremilast with critical intensive care management. J Eur Acad Dermatol Venereol. 2020.