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Study | ONLINE FIRST

A Pilot Study of an Oral Phosphodiesterase Inhibitor (Apremilast) for Atopic Dermatitis in Adults FREE

Aman Samrao, MD; Trista M. Berry, BS; Renato Goreshi, MD; Eric L. Simpson, MD, MCR
[+] Author Affiliations

Author Affiliations: Departments of Dermatology, University of California, Los Angeles (UCLA), Los Angeles (Dr Samrao), and Oregon Health and Science University, Portland (Drs Samrao, Goreshi, and Simpson and Ms Berry). Dr Samrao is now with Division of Dermatology, Harbor-UCLA Medical Center, Torrance. 


Arch Dermatol. 2012;148(8):890-897. doi:10.1001/archdermatol.2012.812.
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Published online

Objective To investigate the preliminary safety and efficacy of apremilast, an oral phosphodiesterase 4 inhibitor, for atopic dermatitis.

Design This investigator-initiated, open-label pilot study evaluated 2 doses of apremilast in patients with atopic dermatitis. Differential gene analysis was performed from peripheral whole blood using data before and after treatment.

Setting University-based dermatology clinical research unit.

Patients Sixteen adult patients with atopic dermatitis.

Intervention A specific phosphodiesterase 4 inhibitor, apremilast.

Main Outcome Measures The primary outcome was incidence of adverse events. Secondary outcomes included the differences in pruritus, Dermatology Life Quality Index (DLQI), and Eczema Area and Severity Index (EASI) scores between the baseline visit and end-of-study visit for each cohort.

Results The group receiving apremilast, 20 mg twice daily, displayed a significant reduction from baseline of pruritus (P = .02) and the DLQI (P = .003) at 3 months. The group receiving apremilast, 30 mg twice daily, displayed a significant reduction of the EASI (P = .008) and the DLQI (P = .01) at 3 months. At 6 months, there was a significant reduction of the EASI (P = .002), the visual analog scale (P = .03), and the DLQI (P = .03). Gene ontologic analyses comparing baseline with samples during treatment revealed alterations in immune response pathways, especially those related to cyclic adenosine monophosphate–mediated signaling.

Conclusions These results support further development of apremilast for treatment of atopic dermatitis. Larger randomized controlled studies are needed to more adequately evaluate both safety and efficacy. Limitations include the small sample size and absence of a control.

Trial Registration clinicaltrials.gov Identifier: NCT01393158

Figures in this Article

Moderate to severe atopic dermatitis (AD) often cannot be adequately controlled with topical agents. Consequently, many patients with AD are treated with systemic corticosteroids, cyclosporine, azathioprine, and methotrexate that carry the risks associated with immunosuppression or can lead to end-organ damage.1 A safe, effective systemic therapy for patients with AD is greatly needed. It has been known since the 1980s that leukocytes from patients with AD display elevated phosphodiesterase (PDE) activity compared with normal controls, which leads to leukocyte hyperactivity and inflammation.24Quiz Ref IDThere are 11 different human PDE isoenzymes in the human body known to date. PDE type 4 (PDE4) is one of the major PDEs expressed in leukocytes.3,5 Inhibitors of PDE4 cause accumulation of intracellular cyclic adenosine monophosphate (cAMP), which in turn activates protein kinase A (PKA) and other downstream effectors, resulting in inhibition of proinflammatory cytokine transcription and other cellular responses, such as neutrophil degranulation, chemotaxis, and adhesion to endothelial cells.6

Inhibitors of PDE have been developed, and they provide clinical benefit in patients with AD when used topically,79 although no compounds have been brought to the marketplace. Oral inhibitors of PDE4 have been studied for treatment of asthma, chronic obstructive pulmonary disease, psoriasis, and psoriatic arthritis, but not for AD.10 Apremilast is a novel oral agent that modulates multiple anti-inflammatory pathways through targeted PDE4 inhibition. Apremilast has pharmacodynamic properties with potential therapeutic benefit for treating inflammatory disorders that involve elevated serum cytokine levels. In human cellular models, apremilast inhibited production of inflammatory mediators such as tumor necrosis factor (TNF), interleukin 12 (IL-12), IL-2, interferon γ (IFN-γ), IL-5, IL-8, leukotriene B4 (LTB4), and the adhesion molecule CD18/CD11b (Mac-1) (Figure 1). In addition, apremilast is known to augment IL-10 production, which is a known suppressor of other proinflammatory chemokines.11,12 To assess the safety and efficacy, and possible mechanism of action of apremilast in AD, we conducted an open-label prospective trial of apremilast in 16 adult patients with moderate to severe AD.

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Figure 1. The role of phosphodiesterase type 4 (PDE4) in inflammation. An overview of the proposed mechanism of action in various cell types derived from in vivo studies. CCL indicates C-C motif ligand; CXCL, C-X-C motif ligand; GM-CSF, granulocyte macrophage colony-stimulating factor; HLA-DR, human leukocyte antigen-DR; ICAM-1, intercellular adhesion molecule-1; IFN, interferon; IL, interleukin; iNOS, inducible nitric oxide synthase; LTB4, leukotriene B4; Mac-1, adhesion molecule CD18/CD11b; NK, natural killer; and TNF, tumor necrosis factor. (Figure reproduced with permission from Celgene Corp.)

CLINICAL METHODS

This study was approved by the Oregon Health and Science University (Portland) institutional review board, and informed consent was obtained from all patients. This was an investigator-initiated, open-label pilot study examining 2 doses of apremilast, N -{2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethyl]-1,3-dioxoisoindolin-4-yl}acetamide (S-enantiomer) for adult AD. A total of 16 patients with moderate to severe AD were treated with apremilast in 2 different cohorts. Cohort 1 consisted of 6 adult patients treated with apremilast, 20 mg twice a day, for a total of 3 months. At the conclusion of this cohort, the US Food and Drug Administration (FDA) approved a higher dose and longer treatment course for apremilast. Thus, a second cohort was initiated. Cohort 2 consisted of 10 adult patients treated with apremilast, 30 mg twice a day, for a total of 6 months. A diagnosis of AD was determined by the Hanifin-Rajka criteria.13 The primary outcome for the study was incidence of adverse events (AEs), with secondary outcomes focusing on disease severity measures and peripheral whole-blood gene expression changes.

Efficacy of apremilast was assessed at each study visit using the Eczema Area and Severity Index (EASI),14 Dermatology Life Quality Index (DLQI), investigator global assessment (IGA), and the visual analog scale (VAS) for pruritus.

Patients were monitored for AEs and improvement in eczema as determined by the EASI, DLQI, and VAS for pruritus at 1 week, 2 weeks, 4 weeks, and every 4 weeks thereafter in cohort 1 and at 2 weeks, 4 weeks, and every 4 weeks thereafter in cohort 2. After the last dose of medication, patients in both cohorts were asked to return for a 4-week follow-up visit.

To participate in the study, patients must have met the following inclusion criteria: age of at least 18 years at time of consent, disease severity of at least 6 on the Rajka-Langeland15 severity scoring system, EASI score of at least 11, and be a candidate for or previously receiving systemic therapy. In addition, patients were required to remain on a stable regimen of triamcinolone acetonide ointment, 0.1%, for 2 weeks prior to the start of the study and throughout the trial. Most patients applied the ointment twice a day 2 times a week. No other topical therapy except emollients was allowed.

Patients were excluded if they had a history of active mycobacterial infection with any species (including Mycobacterium tuberculosis) within 3 years prior to the screening visit, latent or incompletely treated M tuberculosis infection, as indicated by a positive purified protein derivative skin test. Patients were not allowed to participate in the trial if they had had at least 3 major bacterial infections resulting in hospitalization and/or requiring intravenous antibiotic treatment within the past 2 years; clinically significant abnormality on chest radiography at screening; use of any investigational medication or systemic medication within 4 weeks prior to the start of the study drug or 5 pharmacokinetic/pharmacodynamic half-lives (whichever was longer); any clinically significant abnormality on 12-lead electrocardiogram at screening; a history of congenital or acquired immunodeficiency; positive results at screening for antinuclear antibody, hepatitis B surface antigen or hepatitis B core antibody, or antibodies to hepatitis C; a history of human immunodeficiency virus infection; malignant disease or a history of malignant disease (except for treated [ie, cured] basal cell skin carcinomas > 3 years prior to screening); systemic corticosteroid–dependent asthma; or active infection of any type at the time of enrollment.

STATISTICAL ANALYSIS

A sample size of 10 patients was initially determined to provide adequate preliminary data regarding the safety of apremilast in this patient population. The patient number was increased to 16 when a new cohort (cohort 2) was started to examine a higher dose of apremilast that was approved by the FDA for study. Intent-to-treat analyses were performed using the last observation carried forward method for patients who discontinued the study or who required potent topical steroid rescue. For per-protocol analyses, only patients with available data were included. This analysis included the scores in patients who required potent topical steroid rescue. We used t tests for analyses of continuous variables.

MICROARRAY ANALYSES

As an exploratory end point to potentially identify immune pathways affected by apremilast, peripheral whole blood was obtained for differential gene expression analyses at baseline and after 3 (cohort 1) and 6 (cohort 2) months of treatment to determine apremilast's potential mechanism of action in patients with AD. RNA isolation and microarray analyses were performed in the Oregon Health and Science University Gene Microarray Shared Resource.16 Total RNA was isolated from PAXGene tubes using the PAXGene Blood RNA Isolation kit (QIAGEN Inc). RNA quantity was measured by spectrophotometric analysis; RNA quality was evaluated by size analysis on the Bioanalyzer 2100 (Agilent Technologies Inc). All samples passed RNA quality assessment review.

RNA samples were labeled using the Ovation WTA Pico Amplification and Labeling System (NuGEN Technologies Inc). Fifty nanograms of each sample were amplified with the Ovation WTA Pico kit, converted to sense complementary DNA (cDNA) with the WT-Ovation Exon Module, version 1, kit, and labeled with the Encore Biotin Module kit. Hybridization and array processing were performed as described in the NuGEN Encore Biotin Module User Guide (http://www.nugeninc.com/tasks/sites/nugen/assets/File/user_guides/userguide_encore_biotin.pdf). Two micrograms of each labeled cDNA target were hybridized with the GeneChip Human Gene 1.0 ST array (Affymetrix) and scanned on the Affymetrix GeneChip 3000 Scanner. The array image was processed with Affymetrix Command Console (version 3.1.1). Data were normalized using the robust multichip average method.17

Differential expression analyses were performed on 16 paired samples. All putatively differentially expressed genes were based on false discovery rate–adjusted P values < .05. Based on the putative differentially expressed gene list, both enriched pathways and functional gene ontologic characteristics were identified (P < .05 for hypergeometric test) in the GoStats package within the Bioconductor statistical programming environment (http://www.bioconductor.org).

Sixteen patients with moderate to severe AD were included in this open-label study. Patients were divided into 2 cohorts. The 6 patients in cohort 1 received apremilast, 20 mg twice daily for 3 months, and the 10 patients in cohort 2 received apremilast, 30 mg twice daily, for a total of 6 months. Population demographics are shown in Table 1. Almost all patients had received systemic therapy in the past. In cohort 1, 3 patients had an IGA of severe disease, and 1 patient had an IGA of very severe disease. In cohort 2, 8 of 10 had moderate disease, and 2 of 10 had severe disease as measured by the IGA.

ADVERSE EVENTS

Quiz Ref IDNausea was the most common AE and seemed to be dose related (33% in cohort 1, 90% in cohort 2). In all patients the nausea was rated as mild and improved over the course of the study. Other AEs were rated as mild, with the exception of herpes zoster, and improved over the course of the study (eTable). Only 1 patient (patient 5) was withdrawn from the study owing to an AE, the onset of herpes zoster after 2 weeks of taking apremilast, 20 mg twice daily (eTable). Two patients in cohort 2 (patients 11 and 12) required rescue with clobetasol propionate, 0.05%, ointment once daily for 1 week, owing to a disease flare. Patient 11 required the rescue medication after 2 months, and patient 12 required rescue medication after 4 months.

EFFICACY AT 3 MONTHS IN COHORTS 1 AND 2

In both cohorts 1 and 2, a trend toward improvement was seen in all outcomes (Figure 2). Quiz Ref IDIntent-to-treat analyses performed at 3 months revealed significant reduction of itch from baseline (VAS) and improvement in quality of life (DLQI) in cohort 1 (P = .02 and P = .003, respectively). Disease severity (EASI) and quality of life (DLQI) improved in cohort 2 (P = .008 and P = .01, respectively). Statistically significant clinical improvement in AD was noted within the first 2 weeks of study drug in cohort 2 (P = .03). Patients experienced an average reduction in itch of 49% using a VAS, from a mean baseline of 62.3 mm to 30.5 mm in cohort 1 and a 25% reduction in cohort 2, from 45.8 mm to 32.4 mm (Figure 3). The EASI scores reduced an average of 19% in cohort 1 from a mean baseline of 30.9 to 22.1 and an average of 39% in cohort 2, from a mean baseline of 21.4 to 13.2 (Figure 2) at 3 months. The DLQI scores reduced an average of 55% in cohort 1, from a mean baseline of 14.2 to 6.2 (Figure 4) and an average of 58% in cohort 2, from a mean baseline of 10.1 to 3.8. In cohort 1, patients reported a statistically significant decline in pruritus within the first 2 weeks of use (P = .045) with a trend for a decline in pruritus in cohort 2 (P = .06) (Figure 3). In cohort 1, 1 of 6 patients reduced their IGA score by 1 U (eg, from very severe to severe) (Figure 5). Two of 10 patients in cohort 2 reduced their IGA score by 1 U (Figure 6). No patient in either cohort reached an IGA score of clear or almost clear at the 3-month time point. One patient achieved an IGA score of mild in cohort 2. More detailed information regarding cohort 2 responses for each outcome is shown in Figures 7, 8, and 9.

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Figure 2. Mean Eczema Area and Severity Index (EASI) scores per cohort at different time points with error bars representing standard deviations.

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Figure 3. Mean visual analog scale (VAS) scores for pruritus at different time points with error bars representing standard deviations.

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Figure 4. Mean Dermatology Life Quality Index (DLQI) scores per cohort at different time points with error bars representing the standard deviations.

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Figure 5. Distribution of investigator global assessment (IGA) scores in cohort 1 (pretreatment and posttreatment with apremilast, 20 mg twice a day).

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Figure 6. Distribution of investigator global assessment scores at 3 months in cohort 2 (pretreatment and posttreatment with apremilast, 30 mg twice a day).

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Figure 7. Percentage change in Dermatology Life Quality Index (DLQI) scores in cohort 2 (apremilast, 30 mg twice a day) from baseline and at 3 months and at 6 months.

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Figure 8. Percentage change in Eczema Area and Severity Index (EASI) in cohort 2 (apremilast, 30 mg twice a day) from baseline and at 3 months and at 6 months.

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Figure 9. Percentage change in visual analog scale in cohort 2 (apremilast, 30 mg twice a day) from baseline and at 3 months and at 6 months.

EFFICACY AT 6 MONTHS IN COHORT 2

Evaluation of cohort 1 was concluded at 3 months; consequently, no 6-month data were available for that cohort. Statistically significant improvement was seen in all outcomes at 6 months in cohort 2 (Figures 3, 4, and 10). Intent-to-treat analyses revealed significant reduction in EASI, from 21.1 to 11.6 (P = .002); VAS, from 45.8 mm to 25.3 mm (P = .03); and the DLQI, from 10.1 mm to 4.2 mm (P = .03). Per protocol, EASI reduced from 21.1 to 10.4 (P = .001), VAS from 45.8 to 22.7 (P = .01), and DLQI from 10.1 to 4.0 (P = .02). The number of patients who improved or worsened with the different outcomes is shown in Figures 7, 8, and 9. Five patients (50%) improved at least 1 U in the IGA at 6 months. Four of these 5 reached an IGA of mild, and 1 achieved an IGA of almost clear (Figure 11). More detailed information regarding cohort 2 responses for each outcome is shown in Figures 7, 8, and 9.

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Figure 10. Visual analog scale (VAS), Dermatology Life Quality Index (DLQI), and Eczema Area and Severity Index (EASI) scores at day 1- and 6-month visits in cohort 2 (apremilast, 30 mg twice a day). Means with standard deviation errors are shown. < .05 for all comparisons.

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Figure 11. Distribution of investigator global assessment (IGA) scores at 6 months in cohort 2 (pretreatment and posttreatment with apremilast, 30 mg twice a day).

POST HOC EFFICACY ANALYSES ON COHORTS COMBINED

Post hoc intent-to-treat analyses performed on combined data from both cohorts were performed to improve the power of our analyses. The data from both cohorts combined showed statistically significant improvement in all outcomes. The EASI score was reduced from a mean baseline of 24.8 to 16.2 (P = .002), the VAS was reduced from a mean baseline of 52.0 mm to 31.7 mm (P = .003), and the DLQI was reduced from a mean baseline of 11.6 to 4.7 (P = .001). Post hoc per-protocol analyses, which included data from all patients who were able to finish the study, also revealed significance in all outcomes (EASI, P = .001; VAS, P = .007; DLQI, P = .001).

PERIPHERAL BLOOD GENE EXPRESSION ANALYSIS

Quiz Ref IDIn cohort 1, gene expression data revealed significant differential expression of the cAMP response element binding (CREB) pathway (P = 3.19 × 10−4) and BAD (bcl-2 antagonist of cell death) phosphorylation pathway (P = 2.54 × 10−3). In addition, gene ontologic analyses of biological processes revealed significant differential expression of chemokine-mediated signaling (P = 9.5 × 10−6), IL-12 signaling (P < .05), cytoskeleton remodeling (P < .05), and regulation of immune complex clearing by monocytes and macrophages (P = 1.9 × 10−6) (Table 2). In cohort 2, there was significant differential expression of CCR3 signaling in eosinophils (P = 5.497 × 10−2).

Apremilast seemed to be a safe and tolerable systemic therapy in our small cohort of adult patients with AD, with nausea being the most common AE. The clinical responses seen at 6 months with apremilast (>50% improvement in EASI) are similar to responses seen with immunosuppressant medications currently used in treating AD.1 While this pilot study was uncontrolled and open label, the efficacy data suggest that apremilast provided clinically meaningful improvement in several disease parameters. Combined, these data support the development of a future controlled study for moderate to severe AD in adults. Given the lack of any FDA-approved systemic medications for AD, the further development of candidate drugs for this condition is greatly needed.

Current therapy for moderate severe disease in AD includes phototherapy, methotrexate, azathioprine, cyclosporine, and mycophenolate.1 Phototherapy, while safe and effective, is limited by its inconvenience for the patient. Cyclosporine is the best studied and most effective systemic therapy for AD but is limited by nephrotoxicity.18 Mycophenolate may be a safer option than cyclosporine, but in a recent comparison trial with cyclosporine, patients receiving mycophenolate sodium required several oral steroid rescues.19 Methotrexate and azathioprine are both limited by their relatively modest efficacy (<50% reduction in EASI at 12 weeks in 1 recent comparative study20) and their potential for hepatic and hematologic toxic reaction. In the current study, the reduction in EASI scores seen at the 6-month time point would suggest the efficacy of apremilast to be on par with the responses seen with traditional agents. Quiz Ref IDAn advantage of apremilast over these other agents is the lack of end-organ toxicity. The data thus far with apremilast suggest no significant renal, hepatic, or hematologic toxic reaction concerns. Randomized, placebo-controlled studies are needed to determine more accurate estimates of efficacy and safety in this population.

The mechanism by which apremilast may work in AD is not known, although it has many anti-inflammatory effects. By blocking PDE4 activity, apremilast affects several cell types in the immune system, including monocytes, dendritic cells, neutrophils, T cells, natural killer cells, and macrophages. Because immune cells in AD are known to have elevated PDE activity,24 we hypothesized that apremilast would reverse this abnormality unique to AD and return immune cells to a less active state. Specifically, apremilast may improve AD by way of inhibiting the expression of T-cell cytokines previously reported to be increased in AD such as IFN- γ, TNF, Il-5, IL-13, and IL-17.

Unfortunately, whole-blood RNA profiling in this study failed to identify gene pathways that were replicated in both study cohorts, although significant changes in gene expression were found in some pathways that may be relevant to AD. The CREB pathway had significant differential expression in cohort 1. CREB is a transcription factor with multiple downstream effects on gene expression in various cell types. CREB has been shown to be both anti-inflammatory and proinflammatory in immune and epithelial cells.21CREB is activated by phosphorylation by various kinases, 1 of which being PKA.22 PKA is directly influenced by increased levels of intracellular cAMP, as would be seen with a PDE4 inhibitor.22 The role of the CREB pathway in AD is unknown at this time. The BAD phosphorylation pathway also had significant differential expression in cohort 1. The unphosphorylated form of BAD is well known to be a proapoptotic factor by binding to bcl-2, consequently inhibiting its anti-apoptotic action.23 One of PKA's many targets is BAD, which effectively inactivates the pathway.24 Interestingly, increased levels of bcl-2 have been shown in patients with AD treated with UV light, inferring that bcl-2 may have a role in AD.25 Finally, IL-12 and CCR3 signaling pathways were also found to be significant. CCR3 is a chemokine receptor for eotaxin—a chemokine found to be elevated in the lesional skin of patients with AD.26 Likewise, elevated expression of IL-12 has been reported in the lesional skin and blood of patients with AD.27,28 Modifications of these immune pathways by apremilast may account for some of the beneficial effect in AD, but more detailed analyses of these pathways are necessary.

Given the drug's broad anti-inflammatory profile, apremilast is being evaluated for activity in various inflammatory skin diseases, such as psoriasis (clinicaltrials.gov: NCT01194219), psoriatic arthritis (clinicaltrials.gov: NCT01172938), and cutaneous lupus (clinicaltrials.gov: NCT00708916). Most recently, a 352-patient, multicenter controlled study was carried out in which patients with psoriasis achieved a significant dose-dependent improvement in disease severity with apremilast therapy, and pivotal phase 3 studies are under way for this disease.

Limitations of the current study include its small sample size and the possibility of bias or confounding. First, patients with severe disease may naturally get better (regression to the mean). Second, patients may adhere to topical treatment regimens better during clinical studies. We attempted to reduce the chance of an effect of the concomitant topical steroid use by ensuring that patients were receiving stable doses of topical steroids 2 weeks prior to study drug initiation. Topical steroid use then continued at a stable dose or could be discontinued.

In summary, our preliminary data indicate that apremilast significantly improves inflammation, pruritus, and quality of life in patients with AD with mild and generally well-tolerated AEs. Larger randomized controlled studies are needed to further assess its safety and efficacy in AD.

Correspondence: Eric Simpson, MD, MCR, Department of Dermatology (CH16D), Oregon Health and Science University, 3303 SW Bond Ave, Portland, OR 97239-4501 (simpsone@ohsu.edu).

Accepted for Publication: March 2, 2012.

Published Online: April 16, 2012. doi:10.1001/archdermatol.2012.812

Author Contributions: Dr Simpson 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: Samrao and Simpson. Acquisition of data: Samrao, Berry, and Simpson. Analysis and interpretation of data: Samrao, Berry, Goreshi, and Simpson. Drafting of the manuscript: Samrao, Berry, Goreshi, and Simpson. Critical revision of the manuscript for important intellectual content: Samrao and Simpson. Statistical analysis: Samrao, Berry, Goreshi, and Simpson. Obtained funding: Simpson. Administrative, technical, and material support: Samrao and Simpson. Study supervision: Simpson.

Financial Disclosure: Dr Simpson has received research grants from Celgene Corp, Abbott Laboratories, Brickell Biotech Inc, Centocor, Galderma, Medicis, Novartis, and Stiefel.

Funding/Support: This study was funded by an investigator-initiated research grant from Celgene Corp. Support was also obtained from the Oregon Clinical and Translational Research Institute grant No. 5 KL2 RR024141-04 from the National Center for Research Resources, a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research.

Role of the Sponsors: The sponsor had no involvement in study design, analysis, or manuscript preparation.

Additional Contributions: Kristina Vartanian, PhD, and Shannon McWeeney, PhD, performed the gene arrays and analyzed the gene expression data. Christine E. Carocci provided editing assistance and Jon M. Hanifin, MD, pioneered the work regarding the role of PDE in AD that inspired the development of this study.

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PubMed   |  Link to Article
Schram ME, Roekevisch E, Leeflang MM, Bos JD, Schmitt J, Spuls PI. A randomized trial of methotrexate versus azathioprine for severe atopic eczema.  J Allergy Clin Immunol. 2011;128(2):353-359
PubMed   |  Link to Article
Wen AY, Sakamoto KM, Miller LS. The role of the transcription factor CREB in immune function.  J Immunol. 2010;185(11):6413-6419
PubMed   |  Link to Article
Borrelli E, Montmayeur JP, Foulkes NS, Sassone-Corsi P. Signal transduction and gene control: the cAMP pathway.  Crit Rev Oncog. 1992;3(4):321-338
PubMed
Yang X, Liu L, Sternberg D,  et al.  The FLT3 internal tandem duplication mutation prevents apoptosis in interleukin-3-deprived BaF3 cells due to protein kinase A and ribosomal S6 kinase 1-mediated BAD phosphorylation at serine 112.  Cancer Res. 2005;65(16):7338-7347
PubMed   |  Link to Article
Harada H, Becknell B, Wilm M,  et al.  Phosphorylation and inactivation of BAD by mitochondria-anchored protein kinase A.  Mol Cell. 1999;3(4):413-422
PubMed   |  Link to Article
Breuckmann F, von Kobyletzki G, Avermaete A, Kreuter A, Altmeyer P. Efficacy of ultraviolet A1 phototherapy on the expression of bcl-2 in atopic dermatitis and cutaneous T-cell lymphoma in vivo: a comparison study.  Photodermatol Photoimmunol Photomed. 2002;18(5):217-222
PubMed   |  Link to Article
Yawalkar N, Uguccioni M, Schärer J,  et al.  Enhanced expression of eotaxin and CCR3 in atopic dermatitis.  J Invest Dermatol. 1999;113(1):43-48
PubMed   |  Link to Article
Hamid Q, Naseer T, Minshall EM, Song YL, Boguniewicz M, Leung DYM. In vivo expression of IL-12 and IL-13 in atopic dermatitis.  J Allergy Clin Immunol. 1996;98(1):225-231
PubMed   |  Link to Article
Shida K, Koizumi H, Shiratori I,  et al.  High serum levels of additional IL-18 forms may be reciprocally correlated with IgE levels in patients with atopic dermatitis.  Immunol Lett. 2001;79(3):169-175
PubMed   |  Link to Article

Figures

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Figure 1. The role of phosphodiesterase type 4 (PDE4) in inflammation. An overview of the proposed mechanism of action in various cell types derived from in vivo studies. CCL indicates C-C motif ligand; CXCL, C-X-C motif ligand; GM-CSF, granulocyte macrophage colony-stimulating factor; HLA-DR, human leukocyte antigen-DR; ICAM-1, intercellular adhesion molecule-1; IFN, interferon; IL, interleukin; iNOS, inducible nitric oxide synthase; LTB4, leukotriene B4; Mac-1, adhesion molecule CD18/CD11b; NK, natural killer; and TNF, tumor necrosis factor. (Figure reproduced with permission from Celgene Corp.)

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Figure 2. Mean Eczema Area and Severity Index (EASI) scores per cohort at different time points with error bars representing standard deviations.

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Figure 3. Mean visual analog scale (VAS) scores for pruritus at different time points with error bars representing standard deviations.

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Figure 4. Mean Dermatology Life Quality Index (DLQI) scores per cohort at different time points with error bars representing the standard deviations.

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Figure 5. Distribution of investigator global assessment (IGA) scores in cohort 1 (pretreatment and posttreatment with apremilast, 20 mg twice a day).

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Figure 6. Distribution of investigator global assessment scores at 3 months in cohort 2 (pretreatment and posttreatment with apremilast, 30 mg twice a day).

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Figure 7. Percentage change in Dermatology Life Quality Index (DLQI) scores in cohort 2 (apremilast, 30 mg twice a day) from baseline and at 3 months and at 6 months.

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Figure 8. Percentage change in Eczema Area and Severity Index (EASI) in cohort 2 (apremilast, 30 mg twice a day) from baseline and at 3 months and at 6 months.

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Figure 9. Percentage change in visual analog scale in cohort 2 (apremilast, 30 mg twice a day) from baseline and at 3 months and at 6 months.

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Figure 10. Visual analog scale (VAS), Dermatology Life Quality Index (DLQI), and Eczema Area and Severity Index (EASI) scores at day 1- and 6-month visits in cohort 2 (apremilast, 30 mg twice a day). Means with standard deviation errors are shown. < .05 for all comparisons.

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Figure 11. Distribution of investigator global assessment (IGA) scores at 6 months in cohort 2 (pretreatment and posttreatment with apremilast, 30 mg twice a day).

References

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PubMed   |  Link to Article
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PubMed   |  Link to Article
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PubMed   |  Link to Article
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PubMed   |  Link to Article
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PubMed
Vartanian K, Slottke R, Johnstone T,  et al.  Gene expression profiling of whole blood: comparison of target preparation methods for accurate and reproducible microarray analysis.  BMC Genomics. 2009;10:2
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PubMed   |  Link to Article
Schmitt J, Schmitt N, Meurer M. Cyclosporin in the treatment of patients with atopic eczema: a systematic review and meta-analysis.  J Eur Acad Dermatol Venereol. 2007;21(5):606-619
PubMed
Haeck IM, Knol MJ, Ten Berge O, van Velsen SG, de Bruin-Weller MS, Bruijnzeel-Koomen CA. Enteric-coated mycophenolate sodium versus cyclosporin A as long-term treatment in adult patients with severe atopic dermatitis: a randomized controlled trial.  J Am Acad Dermatol. 2011;64(6):1074-1084
PubMed   |  Link to Article
Schram ME, Roekevisch E, Leeflang MM, Bos JD, Schmitt J, Spuls PI. A randomized trial of methotrexate versus azathioprine for severe atopic eczema.  J Allergy Clin Immunol. 2011;128(2):353-359
PubMed   |  Link to Article
Wen AY, Sakamoto KM, Miller LS. The role of the transcription factor CREB in immune function.  J Immunol. 2010;185(11):6413-6419
PubMed   |  Link to Article
Borrelli E, Montmayeur JP, Foulkes NS, Sassone-Corsi P. Signal transduction and gene control: the cAMP pathway.  Crit Rev Oncog. 1992;3(4):321-338
PubMed
Yang X, Liu L, Sternberg D,  et al.  The FLT3 internal tandem duplication mutation prevents apoptosis in interleukin-3-deprived BaF3 cells due to protein kinase A and ribosomal S6 kinase 1-mediated BAD phosphorylation at serine 112.  Cancer Res. 2005;65(16):7338-7347
PubMed   |  Link to Article
Harada H, Becknell B, Wilm M,  et al.  Phosphorylation and inactivation of BAD by mitochondria-anchored protein kinase A.  Mol Cell. 1999;3(4):413-422
PubMed   |  Link to Article
Breuckmann F, von Kobyletzki G, Avermaete A, Kreuter A, Altmeyer P. Efficacy of ultraviolet A1 phototherapy on the expression of bcl-2 in atopic dermatitis and cutaneous T-cell lymphoma in vivo: a comparison study.  Photodermatol Photoimmunol Photomed. 2002;18(5):217-222
PubMed   |  Link to Article
Yawalkar N, Uguccioni M, Schärer J,  et al.  Enhanced expression of eotaxin and CCR3 in atopic dermatitis.  J Invest Dermatol. 1999;113(1):43-48
PubMed   |  Link to Article
Hamid Q, Naseer T, Minshall EM, Song YL, Boguniewicz M, Leung DYM. In vivo expression of IL-12 and IL-13 in atopic dermatitis.  J Allergy Clin Immunol. 1996;98(1):225-231
PubMed   |  Link to Article
Shida K, Koizumi H, Shiratori I,  et al.  High serum levels of additional IL-18 forms may be reciprocally correlated with IgE levels in patients with atopic dermatitis.  Immunol Lett. 2001;79(3):169-175
PubMed   |  Link to Article

Correspondence

CME


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Samrao A, Berry TM, Goreshi R, Simpson EL. A pilot study of an oral phosphodiesterase inhibitor (apremilast) for atopic dermatitis in adults. Arch Dermatol. Published online April 16, 2012. doi:10.1001/archdermatol.2012.812.

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