Efficacy and Safety of Apremilast in Chronic Cutaneous Sarcoidosis

Pentoxifylline, a phosphodiesterase type 4 inhibitor, is reported to be effective for the treatment of sarcoidosis.¹ However, the adverse events associated with this drug have limited its general use. Apremilast is a new phosphodiesterase type 4 inhibitor that blocks the synthesis of proinflammatory cytokines and chemokines, such as tumor necrosis factor, interferon γ, and the interleukins(IL) IL-2, IL-12, and IL-23.² These cytokines are important in the initiation and perpetuation of sarcoidosis.

All the patients included in our trial were required to have active skin lesions consistent with chronic cutaneous sarcoidosis³ and to be receiving systemic therapy for sarcoidosis that was unchanged for the 3 months before the study entry.

An index lesion was determined at baseline for each patient. For patients with more than 1 skin lesion, the lesion with the highest combined score of induration, erythema, desquamation, and area of involvement was designated the index lesion.

Initially, all patients received oral apremilast, 20 mg, twice a day. If adverse events were reported, the dosage was reduced to 20 mg orally once a day. Patients received 12 weeks of treatment and were seen 1 month later.

Skin lesions were assessed in 2 ways: (1) by using the previously described Sarcoidosis Activity and Severity Index (SASI)³ and (2) by comparing photographs of the index lesion initially and at week 12, with the photographs presented in random order.⁴ The scores were subsequently normalized: 1 indicated much better after therapy and 5, much worse after therapy.

Each patient's condition was evaluated at weeks 2, 4, 8, 12, and 16 for adverse events, including changes in liver function test results.

Of 17 patients who provided written consent for participation in the trial, 2 were excluded because of predefined exclusion criteria (1 each for a history of hepatitis C virus and leukopenia). The remaining 15 patents received the drug for the entire study. Individual SASI scores were serially determined by the same investigator for each patient visit in 14 of 15 patients. Apremilast dosage reductions were necessary for 2 patients (1 each for jitteriness and nausea). Both patients completed the study while receiving 20 mg daily without reporting further adverse events.

Of the 15 apremilast-treated patients, 14 were women and 10 were black. All patients were receiving stable systemic therapy, and no patient received topical therapy before or during the study.

Figure 1A shows the change in induration for all 46 lesions after 4 and 12 weeks of therapy. A significant reduction in the induration score was noted at both time points (week 4, P   <  .002; week 12, P   <  .005). Figure 1B demonstrates the change in induration from baseline for the index lesion for all 14 patients whose condition was evaluated. Again, we found a significant decrease in the induration at week 4 (P   <  .05) and week 12 (P   <  .02). Compared with baseline, there was no statistically significant difference in the erythema, desquamation, or area of involvement at week 4 or 12 for all the lesions or for the index lesion.

After 12 weeks of therapy, the normalized mean score was 2 ( “somewhat better after therapy ”) for all 3 photograph readers. Figure 2 shows a pair of photographs that were scored by all 3 readers as 1 ( “much better after therapy ”). There was good correlation between the different readers (Spearman rank correlation, 0.66-0.81; P   <  .02 for all 3 correlations).

Within 3 months after discontinuation of apremilast therapy, 3 patients developed significant worsening of their cutaneous lesions. In all 3 patients, increasing their prednisone dosage only moderately improved these lesions.

To date, there is no consensus regarding the best method to assess response to therapy for cutaneous sarcoidosis. The current study used 2 independent instruments —the SASI score and paired photographs —to objectively report changes in cutaneous lesions. The SASI induration score³ decreased significantly with apremilast therapy (Figure 1). Analysis of paired photographs^4,5 also demonstrated statistically significant improvement. Three patients experienced disease relapse within 3 months of treatment discontinuation.

We found apremilast effective for some patients who had persistent lesions despite multiple systemic treatments. This group of patients has been poorly responsive to most other drugs except for high doses of corticosteroids or the anti –tumor necrosis factor antibody infliximab.⁵ Further studies seem warranted to examine the safety and effectiveness of apremilast for the treatment of chronic cutaneous sarcoidosis.

Correspondence: Dr Baughman, Department of Medicine, University of Cincinnati, 1001 Holmes, Eden Ave, Cincinnati, OH 45267 (bob.baughman@uc.edu).

Accepted for Publication: August 8, 2011.

Published Online: October 17, 2011. doi:10.1001/archdermatol.2011.301

Author Contributions: Drs Baughman, Judson, and Lower and Ms Ingledue had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Baughman, Judson, and Lower. Acquisition of data: Baughman, Judson, Ingledue, and Craft. Analysis and interpretation of data: Baughman, Judson, and Lower. Drafting of the manuscript: Baughman, Judson, Craft, and Lower. Critical revision of the manuscript for important intellectual content: Baughman, Judson, Ingledue, Craft, and Lower. Statistical analysis: Baughman. Obtained funding: Baughman. Administrative, technical, and material support: Baughman, Judson, Ingledue, Craft, and Lower. Study supervision: Baughman, Judson, and Lower.

Funding/Support: This study was supported in part by Celgene.

Role of the Sponsors: The sponsor had no role in the design and conduct of the study; in the collection, analysis, and interpretation of data; or in the preparation, review, or approval of the manuscript.

Trial Registration: clinicaltrials.gov Identifier: NCT00794274

Additional Contributions: Angela Hu, MS, EdM, provided statistical assistance.