An Oral Phosphodiesterase Inhibitor (Apremilast) for Inflammatory Rosacea in Adults: A Pilot Study

Rosacea is a chronic skin disorder characterized by facial flushing, persistent erythema, telangiectasias, and inflammatory papules and pustules. In addition to the physical manifestations, rosacea may contribute to lower self-esteem, thereby having significant psychosocial implications.¹ Some patients do not respond to conventional treatments for rosacea or are unable to tolerate the adverse effects; therefore, effective new therapies are needed. We sought to investigate the safety and efficacy of apremilast, an oral phosphodiesterase 4 inhibitor, for the treatment of moderate to severe inflammatory rosacea. Apremilast modulates multiple proinflammatory and anti-inflammatory pathways through targeted phosphodiesterase type 4 inhibition, including augmenting interleukin 10 production, which in turn suppresses other proinflammatory cytokines.^2,3 Inhibitors of phosphodiesterase type 4 have been tested for treatment of many inflammatory dermatologic diseases⁴ but never for rosacea.

In this investigator-initiated, open-label pilot study, 10 patients with moderate to severe inflammatory rosacea were administered apremilast, 20 mg orally twice daily, for 12 weeks. The inclusion criteria for enrollment were age of 18 to 75 years and moderate to severe erythematotelangiectatic and papulopustular rosacea defined as a minimum of 10 papules and pustules, the presence of moderate to severe erythema, and the presence of telangiectasias. Patients avoided known triggers of rosacea or treatments that might affect rosacea severity. Extensive exclusion criteria were also used in screening. The study population included 3 men and 7 women (age range, 39 to 74 years). Patients were seen between May 5, 2010, and November 20, 2012. This study was approved by the institutional review board of Columbia University, and written informed consent was obtained from all patients.

All patients received active drug. Visits occurred at baseline, every 2 weeks during treatment (weeks 2, 4, 6, 8, 10, and 12), and 1 month after discontinuation of treatment (week 16). Safety factors were assessed at each visit. Patients acclimatized for at least 15 minutes before being examined.

Statistical analyses were performed via paired t tests and powered to 80% to detect changes greater than 1 SD in all reported variables. The primary end point was also analyzed via Wilcoxon signed rank tests to compare median values.

The primary end point was the total number of papulopustular lesions at baseline compared with the end of treatment and with follow-up 1 month after treatment. Secondary outcomes assessed drug toxicity as well as efficacy as defined by changes in the telangiectasia counts, chromometer readings,⁵ and ratings on the Physician Global 7-Point Assessment, Patient Global Assessment, Physician Overall Erythema Severity, and physician-rated variable scales. When baseline scores were compared with those at the end of treatment, there was a statistically significant improvement in ratings on the Physician Global 7-Point Assessment (t statistic = −2.86, P = .02), Physician Overall Erythema Severity (t statistic = −4.85, P = .001), erythematotelangiectatic rating (t statistic = −3.67, P = .005), and nontransient erythema (t statistic = −2.45, P = .04) (Table and Figure). When baseline ratings were compared with those at follow-up 1 month after discontinuation of treatment, measures that reached statistical significance were Physician Overall Erythema Severity (t statistic = −3.0, P = .02) and nontransient erythema (t statistic = −2.45, P = .04) (Table and Figure). None of the remaining comparisons reached statistical significance, including the primary end point of papule and pustule count, which was additionally analyzed by the Wilcoxon signed rank test to compare median values (Figure and the eTable and eFigure in the Supplement). Comparisons of chromometer readings also were not significant (data not shown).

Apremilast was well tolerated. Few patients experienced adverse effects; the most common event was minor infection, including urinary tract infections and upper respiratory tract infections (2 patients each). No adverse effects required treatment alteration or discontinuation.

These results support further investigation of treatment with apremilast in rosacea, in particular, to perhaps fill a gap for the treatment of the erythematous component of rosacea, which has historically been refractory to other therapies. Although brimonidine tartrate is used topically for this indication, adverse effects are common⁷ and alternative therapies are still needed. An overall trend toward improvement was observed, and 3 of 4 measures of erythema showed significant improvement, two of which were durable 1 month after treatment. Although the primary end point of papule and pustule count did not reach statistical significance, other important measures of improvement were statistically significant. The limitations of this study include the small sample size and the absence of a control arm.

Apremilast may represent a novel alternative treatment for rosacea and rosacea-associated erythema. Larger randomized clinical studies are needed to more adequately evaluate the drug’s efficacy and safety.

Corresponding Author: Julian Mackay-Wiggan, MD, MS, Department of Dermatology, Columbia University, 161 Ft Washington Ave, 12th Floor, New York, NY 10032 (jc299@columbia.edu).

Accepted for Publication: December 8, 2013.

Published Online: July 23, 2014. doi:10.1001/jamadermatol.2013.10526.

Author Contributions: Dr Mackay-Wiggan had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Mackay-Wiggan.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Thompson, Furniss, Mackay-Wiggan.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Thompson, Zhao, Chakraborty.

Obtained funding: Mackay-Wiggan.

Administrative, technical, or material support: Thompson.

Study supervision: Mackay-Wiggan.

Conflict of Interest Disclosures: Dr Mackay-Wiggan reports receiving a research grant from Celgene Corporation. No other disclosures were reported.

Funding/Support: This study was funded in its entirety by an investigator-initiated research grant from Celgene Corporation.

Role of the Sponsor: Celgene Corporation reviewed the manuscript but had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: Julissa Borbon, BA, supported the work of this trial by serving as our administrative coordinator; Grace Ulerio, BA, and Carol Coppola, RN, by serving as our clinical coordinators; and Jackleen Marji, MD, PharmD, by serving as our clinical research fellow (all are with Columbia University). None received direct financial compensation; funds were paid to Columbia University to cover study costs.