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Research Letter |

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

Bobbye J. Thompson, MD1; Megan Furniss, DO1; Wenjing Zhao, PhD2; Bibhas Chakraborty, PhD2; Julian Mackay-Wiggan, MD, MS1
[+] Author Affiliations
1Department of Dermatology, Columbia University, New York, New York
2Department of Biostatistics, Columbia University, New York, New York
JAMA Dermatol. 2014;150(9):1013-1014. doi:10.1001/jamadermatol.2013.10526.
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Published online

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).

Table Graphic Jump LocationTable.  Physician’s Rating of Nontransient Erythema in 10 Patients
Place holder to copy figure label and caption
Figure.
Rosacea Severity Over Time in 10 Patients

A, Physician Global 7-Point Assessment. Possible ratings were 0, clear; 1, minimal; 2, mild; 3, mild to moderate; 4, moderate; 5, moderate to severe; and 6, severe rosacea. B, Patient Global Assessment. Possible ratings were 0, absent; 1, mild; 2, moderate; and 3, severe rosacea. This assessment uses the standard grading system from the Report of the National Rosacea Society Expert Committee on the classification and staging of rosacea.6 C, Physician Overall Erythema Severity ratings illustrate the shift from mostly moderate erythema to mostly mild erythema. This scale is somewhat restrictive because mild is defined as “slight erythema” and moderate as “pronounced erythema” without a choice in between. At baseline, 1 patient was rated as having mild erythema on the Physician Overall Erythema Severity measure but as having moderate erythema on other measures.

Graphic Jump Location

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.

Garnis-Jones  S.  Psychological aspects of rosacea. J Cutan Med Surg. 1998;2(suppl 4):16-19.
PubMed
Schafer  PH, Parton  A, Gandhi  AK,  et al.  Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis. Br J Pharmacol. 2010;159(4):842-855.
PubMed   |  Link to Article
Seldon  PM, Giembycz  MA.  Suppression of granulocyte/macrophage colony-stimulating factor release from human monocytes by cyclic AMP–elevating drugs: role of interleukin-10. Br J Pharmacol. 2001;134(1):58-67.
PubMed   |  Link to Article
Samrao  A, Berry  TM, Goreshi  R, Simpson  EL.  A pilot study of an oral phosphodiesterase inhibitor (apremilast) for atopic dermatitis in adults. Arch Dermatol. 2012;148(8):890-897.
PubMed   |  Link to Article
Fadzil  MH, Ihtatho  D, Affandi  AM, Hussein  SH.  Area assessment of psoriasis lesions for PASI scoring. J Med Eng Technol. 2009;33(6):426-436.
PubMed   |  Link to Article
Wilkin  J, Dahl  M, Detmar  M,  et al; National Rosacea Society Expert Committee.  Standard grading system for rosacea: report of the National Rosacea Society Expert Committee on the classification and staging of rosacea. J Am Acad Dermatol. 2004;50(6):907-912.
PubMed   |  Link to Article
Mirvaso (brimonidine) topical gel [package insert]. Fort Worth, TX: Galderma Laboratories; August 2013. http://www.galdermausa.com/PI/MirvasoPI.pdf. Accessed May 26, 2014.

Figures

Place holder to copy figure label and caption
Figure.
Rosacea Severity Over Time in 10 Patients

A, Physician Global 7-Point Assessment. Possible ratings were 0, clear; 1, minimal; 2, mild; 3, mild to moderate; 4, moderate; 5, moderate to severe; and 6, severe rosacea. B, Patient Global Assessment. Possible ratings were 0, absent; 1, mild; 2, moderate; and 3, severe rosacea. This assessment uses the standard grading system from the Report of the National Rosacea Society Expert Committee on the classification and staging of rosacea.6 C, Physician Overall Erythema Severity ratings illustrate the shift from mostly moderate erythema to mostly mild erythema. This scale is somewhat restrictive because mild is defined as “slight erythema” and moderate as “pronounced erythema” without a choice in between. At baseline, 1 patient was rated as having mild erythema on the Physician Overall Erythema Severity measure but as having moderate erythema on other measures.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable.  Physician’s Rating of Nontransient Erythema in 10 Patients

References

Garnis-Jones  S.  Psychological aspects of rosacea. J Cutan Med Surg. 1998;2(suppl 4):16-19.
PubMed
Schafer  PH, Parton  A, Gandhi  AK,  et al.  Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis. Br J Pharmacol. 2010;159(4):842-855.
PubMed   |  Link to Article
Seldon  PM, Giembycz  MA.  Suppression of granulocyte/macrophage colony-stimulating factor release from human monocytes by cyclic AMP–elevating drugs: role of interleukin-10. Br J Pharmacol. 2001;134(1):58-67.
PubMed   |  Link to Article
Samrao  A, Berry  TM, Goreshi  R, Simpson  EL.  A pilot study of an oral phosphodiesterase inhibitor (apremilast) for atopic dermatitis in adults. Arch Dermatol. 2012;148(8):890-897.
PubMed   |  Link to Article
Fadzil  MH, Ihtatho  D, Affandi  AM, Hussein  SH.  Area assessment of psoriasis lesions for PASI scoring. J Med Eng Technol. 2009;33(6):426-436.
PubMed   |  Link to Article
Wilkin  J, Dahl  M, Detmar  M,  et al; National Rosacea Society Expert Committee.  Standard grading system for rosacea: report of the National Rosacea Society Expert Committee on the classification and staging of rosacea. J Am Acad Dermatol. 2004;50(6):907-912.
PubMed   |  Link to Article
Mirvaso (brimonidine) topical gel [package insert]. Fort Worth, TX: Galderma Laboratories; August 2013. http://www.galdermausa.com/PI/MirvasoPI.pdf. Accessed May 26, 2014.

Correspondence

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eTable. Papule and Pustule Counts During Treatment

eFigure. Papule and Pustule Counts Over Time

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