Apremilast in the Treatment of Psoriasis and Psoriatic Arthritis

Melinda Gooderham, MD, MSc, FRCPC^1,3 and Kim Papp, MD, PhD, FRCPC^2,3

¹Skin Centre for Dermatology, Peterborough, ON, Canada
²K. Papp Clinical Research, Waterloo, ON, Canada
³Probity Medical Research, Waterloo, ON, Canada

ABSTRACT
Phosphodiesterase 4 (PDE4) is a key enzyme in the regulation of immune responses of inflammatory diseases through degradation of the second messenger, cyclic adenosine 3′,5′-monophosphate (cAMP). Apremilast, a selective PDE4 inhibitor, has been shown to reduce the production of pro-inflammatory cytokines by increasing intracellular levels of cAMP and promoting the production of anti-inflammatory cytokines. The efficacy and safety of apremilast in the treatment of psoriasis and psoriatic arthritis has been
demonstrated in phase 2 and 3 studies and will be reviewed here. Across all studies, treatment was generally well-tolerated with some mild gastrointestinal complaints that occurred early and resolved over time, resulting in few drop-outs. Meaningful changes in dactylitis and enthesitis were also observed. Routine monitoring is not required given the absence of drug associated physiologic,
biochemical, and haematological changes. Apremilast proves to be a new promising systemic therapy for treating psoriatic disease.

Key Words:
psoriasis, chronic plaque psoriasis, apremilast, PDE4 inhibitors, psoriatic arthritis, immunology, inflammation

Introduction

Psoriasis is a disease complex involving skin, joints, and possibly the bowel.¹ Each manifestation of the psoriasis disease complex is expressed through an inflammatory, immune-mediated process. This has been described in the skin,² joints³ and bowel⁴. Therefore, interference in the immunological pathways common to psoriasis and psoriatic arthritis (PsA) could demonstrate clinical improvement of both. Recent clinical studies have shown precise blockade of phosphodiesterase 4 (PDE4) to be effective in the treatment of psoriasis⁵ and PsA^6,7.

PDE4 belongs to the phosphodiesterase family of
enzymes involved in the breakdown of cyclic adenosine
3′,5′-monophosphate (cAMP).^8,9 cAMP is a secondary messenger central for immune response regulation, and the inhibition of its breakdown leads to a cascade of cellular events resulting in a reduction of inflammatory mediators such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-23, as well as production of anti- inflammatory cytokines such as IL-10.^8,9

PDE4, found in cells of the immune system and keratinocytes, is the key enzyme responsible for cAMP breakdown. Through their cAMP-blocking actions, PDE4 inhibitors can prolong or enhance the effects of cAMP resulting in the reduction of both T-helper 1 (Th1) and Th2 immune responses.¹⁰ PDE4 is
expressed selectively in immune cells and plays a central role in the activation of these cells, which are upregulated in chronic plaque psoriasis and other inflammatory conditions such as PsA.⁹ Inhibition of PDE4 leads to an increase in the intracellular cAMP concentration, thereby reducing the production of inflammatory mediators and increasing anti-inflammatory mediators.^8,11 PDE4
inhibitors and their immune-modulating effects are currently under investigation in a variety of inflammatory conditions such as asthma, chronic obstructive pulmonary disease (COPD), atopic
dermatitis, psoriasis and PsA.^8-10

PDE4 Inhibitor in the Treatment of Psoriasis

The PDE4 inhibitor, apremilast (CC-10004, Otezla™), has been shown to block the production of interferon (IFN)-gamma, TNFalpha, IL-12 and IL-23 – the pro-inflammatory cytokines that play a major role in the pathogenesis of psoriasis. Apremilast, through its action to increase intracellular cAMP concentration,
demonstrated a range of anti-inflammatory effects on a variety of cell lines in vitro, ¹² reduction in the psoriasiform response in a preclinical model of psoriasis in vivo, as well as biologic activity
in a pilot study in humans¹³.

To date, apremilast has been evaluated in a number of phase 2^14-16 and phase 3 clinical trials (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1 and 2), demonstrating efficacy in psoriasis^17,18 and PsA^6,7,19-21. Another phase 3b study evaluating the efficacy and safety of apremilast, compared with etanercept and placebo in patients with moderate to severe plaque psoriasis, is ongoing (ClinicalTrials.gov Identifier: NCT01690299).

Apremilast Use in Psoriasis

Results from Phase 2 Studies in Plaque Psoriasis

Apremilast demonstrated efficacy in phase 2 clinical trials.^14-16 In a 12-week, phase 2, randomized, placebo-controlled trial in 259 patients, apremilast 20 mg twice daily (BID) achieved a Psoriasis
Area and Severity Index (PASI)-75 in 24.4% of patients vs. 10.3% in the placebo group. A dose-response was observed with a mean percent reduction in PASI from baseline of 17.4%, 30.3% and 52.1% for placebo, apremilast 20 mg once daily (OD) and apremilast 20 mg BID, respectively.¹⁴

Efficacy of apremilast was also shown in the phase 2b doubleblind, randomized, placebo-controlled crossover trial in 352 patients, which compared apremilast 10 mg, 20 mg, 30 mg or placebo BID for 16 weeks, at which point patients receiving placebo were then randomized to 20 mg or 30 mg BID up to 24 weeks. Primary endpoint of PASI-75 at 16 weeks was 11% for 10 mg, 29% for 20 mg, and 41% for 30 mg BID vs. 6% of patients on placebo.¹⁵

Treatment with apremilast also resulted in significant
improvement on patient-reported quality of life outcomes, with particular benefit noted at the 30 mg BID dose.¹⁶ Adverse effects were mild to moderate, and included headache, nausea, urinary tract infection (UTI) and diarrhea. No significant changes in laboratory values were observed in any of the trials.

Results from Phase 3 Studies in Plaque Psoriasis

The efficacy and safety of apremilast 30 mg BID was evaluated in two phase 3 randomized, placebo-controlled studies ESTEEM 1¹⁷ and ESTEEM 2¹⁸. The efficacy and safety of apremilast compared with etanercept and placebo in patients with moderate to severe plaque psoriasis is being evaluated in a phase 3b study (NCT01690299).

In ESTEEM1, 844 patients with moderate to severe plaque
psoriasis (PASI ≥12, Body Surface Area [BSA] ≥10%, static Physician’s Global Assessment [sPGA] ≥3) were randomized 2:1 to apremilast 30 mg BID (n=562) or placebo (n=282). At Week 16, all patients in the placebo group were switched to apremilast 30 mg BID through Week 32. At Week 32, all patients in the apremilast 30 mg BID group who achieved PASI-75 were
randomized (1:1, blinded) to continue apremilast 30 mg BID or receive placebo. Upon loss of PASI-75, patients who were rerandomized to placebo resumed apremilast 30 mg BID.¹⁷

In ESTEEM 2, 413 patients with moderate to severe psoriasis (PASI ≥12, BSA ≥10%, and sPGA ≥3) were randomized to placebo (n=138) or apremilast 30 mg BID (n=275) through Week 16. As in ESTEEM 1, at Week 16, all patients receiving placebo were switched to apremilast 30 mg BID through Week 32, followed by a randomized withdrawal phase through Week 52. At Week 32, all patients in the apremilast 30 mg BID group who achieved PASI-50 were randomized (1:1, blinded) to
continue apremilast 30 mg BID or receive placebo. Upon loss of PASI-50, patients who were re-randomized to placebo resumed apremilast 30 mg BID.¹⁸

Patients re-started apremilast at the time of loss of effect, defined as time of loss of 75% (ESTEEM 1) and 50% (ESTEEM 2) of the PASI improvement obtained at Week 32 compared with baseline, but no later than Week 52. Patients initially on placebo or randomized to apremilast 30 mg BID who did not attain a PASI-75 or PASI-50, in ESTEEM 1 and ESTEEM 2, respectively, were
able to add topicals and/or ultraviolet B (UVB) phototherapy at Week 32 at the discretion of the investigator.^17,18 Study design of ESTEEM clinical trial program is shown in Figure 1.

Figure 1. ESTEEM 1 and 2 study design^{17, 18}

^aDoses of apremilast were titrated during the first week of administration.
^bA responder was defined as a patient achieving ≥PASI-75 (ESTEEM 1) or ≥PASI-50 (ESTEEM 2) at Week 32.
^cIn ESTEEM 1, patients were switched to apremilast at the time of loss of PASI-75, but no later than Week 52. In ESTEEM 2, patients were switched to apremilast at
time of loss of effect, defined as time of loss of 50% of the PASI improvement obtained at Week 32 compared with baseline, but no later than Week 52.
^dAt Week 32, patients will have the option of adding topical and/or UVB therapy. The decision may be made at Week 32 only, but does not need to be initiated at
this visit. T = topicals; P = UVB phototherapy.

Figure 2A and 2B. PASI-75 (primary endpoint), PASI-50, and sPGA response at Week 16^17,18

Patients achieving PASI-75, PASI-50, and sPGA response with apremilast 30 mg BID vs. placebo. A. Response at Week 16 in ESTEEM 1. B. Response at Week 16 in
ESTEEM 2. sPGA score of clear (0) or almost clear (1) with at least a 2-point reduction from baseline. *P

Significant improvements with apremilast 30 mg BID were
observed at Week 16 for PASI-75 (a reduction of ≥75% in PASI scores) and sPGA scores. In ESTEEM 1, significantly more patients in the apremilast group achieved PASI-75 (33.1%), PASI-50 (58.7%) and sPGA 0-1 (21.7%) vs. placebo (*P<0.0001, all),17 and in ESTEEM 2, patients treated with apremilast achieved PASI-75 (28.8%), PASI-50 (55.5%) and sPGA 0-1 (20.4%) vs. placebo (*P<0.0001, all)18. (Figure 2)

Improvements with apremilast 30 mg BID were also seen in the Nail Psoriasis Severity Index (NAPSI-50), scalp PGA (ScPGA 0-1), Palmoplantar Psoriasis Physician’s Global Assessment (PPPGA), Dermatology Life Quality Index (DLQI), and pruritus scores on the Visual Analogue Scale (VAS).^17,18

More patients treated with apremilast 30 mg BID achieved NAPSI-50 response at Week 16 vs. placebo. In ESTEEM 1, 33.3% of patients in the apremilast group achieved NAPSI-50 response vs. 14.9% with placebo (P<0.0001),¹⁷ and in ESTEEM 2, 44.6% of patients in the apremilast 30 mg BID group achieved NAPSI-50
vs. 18.7% with placebo (P<0.0001)¹⁸.

As well, a higher proportion of patients in the apremilast 30 mg BID group achieved ScPGA 0-1 (Clear-Minimal) at Week 16 vs. those in the placebo group. In ESTEEM 1, 46.5% in the apremilast group vs. 17.5% with placebo (P<0.0001),¹⁷ and in ESTEEM 2, 40.9% of patients in the apremilast group achieved ScPGA 0-1 vs. 17.2% with placebo (P<0.0001)¹⁸. In ESTEEM 2, 65.4% of patients treated with apremilast 30 mg BID achieved PPPGA 0-1 (Clear-Minimal) vs. 31.3% of patients treated with placebo.¹⁸ PPPGA 0-1 was not reported in ESTEEM 1.¹⁷

Apremilast 30 mg BID was associated with a significantly higher proportion of patients who achieved minimum clinically important difference (MCID) in DLQI and pruritus VAS from baseline at Week 16. Over 90% of patients receiving apremilast 30 mg BID, who were PASI-75 responders at Week 16, achieved MCID in DLQI and pruritus VAS. In ESTEEM 1, 70.2% of patients in the apremilast group achieved a MCID DLQI response vs. 33.5% with placebo (P<0.0001),^17,22 and in ESTEEM 2, 70.8% of patients treated with apremilast achieved a MCID DLQI response vs. 42.9% with placebo (P<0.0001)²³. For pruritus VAS, 70.6% of patients in ESTEEM 1 treated with apremilast achieved MCID vs. 33.7% with placebo (P<0.0001) in ESTEEM 1.²²

Time to loss of PASI improvement and PASI-75 response
were also evaluated at 52 weeks in ESTEEM 1. Of the patients re-randomized to placebo, 70.3% regained PASI-75 response after re-initiation of treatment with apremilast 30 mg BID. The duration of re-treatment ranged from 3.4-22.1 weeks.¹⁷ The median time to loss of PASI-75 response was 5.2 and 15.7 weeks for patients re-randomized to placebo and apremilast 30 mg BID, respectively. For the subgroup of patients who received apremilast 30 mg BID from Day 0 and continued on therapy, with PASI-75 responders at Week 32, there was a mean percent change from baseline in PASI score of -80% at Week 52.¹⁷

Safety and Tolerability Profile

Apremilast demonstrated an acceptable safety profile and was generally well-tolerated for up to 52 weeks in the treatment of plaque psoriasis. Most adverse events (AEs) were mild or moderate in severity. Discontinuation rates for diarrhea and nausea were each <2% in the apremilast 30 mg BID group through Week 52. The most frequently reported AEs during the
placebo-controlled period and apremilast-exposure period were diarrhea, upper respiratory tract infection (URTI), nausea, nasopharyngitis, tension headache, and headache.²⁴

In ESTEEM 1, apremilast 30 mg BID was generally welltolerated for up to 52 weeks with no increase in the incidence of AEs over time. Serious AEs – including serious infections, malignancies, and cardiovascular events – and laboratory value changes were not significantly affected, which is consistent with prior apremilast trials. AEs in ≥5% reported during Weeks 0-16 and over the entire apremilastexposure period (Weeks 0-52) of either placebo or apremilasta 30 mg BID group are shown in Table 1.¹⁷

In ESTEEM 2, the majority of AEs were mild or moderate in severity and discontinuation rates due to AEs during Weeks 0-16 were low (placebo: 5.1%; apremilast: 5.5%). In patients receiving apremilast, diarrhea and nausea were mostly mild in severity, with the highest incidence during the first week of dosing, generally resolving within 1 month, with few patients reporting use of concomitant medications. Serious AEs – including serious infections, malignancies, and cardiovascular events – and laboratory value changes again were consistent with prior apremilast studies; laboratory values were not significantly changed and serious AEs were low across treatment groups. AEs
reported during Weeks 0-16 in ≥5% are presented in Table 2.¹⁸

	Placebo-Controlled Period Weeks 0-16		Apremilast-Exposure Period Weeks 0-52
Patients (%)	Placebo n=282	Apremilast 30 mg BID n=560	Apremilast 30 mg BID n=804
Diarrhea	7.1	18.8	18.7
Upper respiratory tract infection	7.4	10.2	17.8
Nausea	6.7	15.7	15.3
Nasopharyngitis	8.2	7.3	13.4
Tension headache	4.3	7.3	9.6
Headache	4.6	5.5	6.5
Table 1. Adverse events ≥5% any treatment group in ESTEEM 117The apremilast-exposure period (Weeks 0-52) included all patients who received apremilast 30 mg BID, regardless of when treatment was initiated. Exposure-adjusted incidence rate (EAIR) per 100 patient-years is defined as 100 times the number (n) of patients reporting the event divided by patientyears within the phase (up to the first event start date for patients reporting the event).17

 

	Placebo-Controlled Period Weeks 0-16
Patients (%)	Placebo n=136	Apremilast 30 mg BID n=272
Nausea	6.6	18.4
Diarrhea	5.9	15.8
Vomiting	3.7	5.1
Nasopharyngitis	4.4	7.4
Tension headache	1.5	7.4
Headache	0.7	6.3
Psoriasis	5.1	1.5
Table 2. Adverse events ≥5% any treatment group in ESTEEM 218

Apremilast Use in Psoriatic Arthritis

Results from Phase 3 Studies in Psoriatic Arthritis

The efficacy and safety of apremilast were evaluated in the phase 3 Psoriatic Arthritis Long-term Assessment of Clinical Efficacy (PALACE) clinical trial program studies in patients with PsA.^6,7,9,19-21

The key inclusion criteria in PALACE 1 and 2 were adults with a documented diagnosis of PsA at baseline (duration ≥6 months; met the Classification Criteria for Psoriatic Arthritis [CASPAR] criteria), ≥3 swollen and ≥3 tender joints despite past or current disease-modifying antirheumatic drugs (DMARDs) and/or biologics.^6,7,9,19 In PALACE 3, in addition to the above inclusion criteria for PALACE 1 and 2, patients also had to have at least one psoriatic lesion ≥2 cm, and PALACE 4 was in DMARD and/or biologics naïve patients.^20,21 Study design for the PALACE clinical trial program is shown in Figure 3.²⁰

Figure 3. PALACE Study Design^6,7,19-21

Note: Plasma samples for the biomarker assay were obtained at baseline and Weeks 4, 16, 24, and 40.
*All doses were titrated over the first week of treatment.
§Patients whose swollen and tender joint counts had not improved by ≥20% at Week 16 were considered non-responders and were required to be re-randomized
(1:1) to apremilast 20 mg BID or 30 mg BID if they were initially randomized to placebo. Apremilast-treated patients continued on their initial apremilast dose.
‡At Week 24, all remaining placebo patients were re-randomized to apremilast 20 mg BID or 30 mg BID.

 

The results of a 24-week placebo-controlled phase of PALACE 1 have been published, as well as the 52-week period results, and will be presented here.^6,7 Patients with active PsA (n=504) were randomized (1:1:1) to placebo, apremilast 20 mg BID or apremilast 30 mg BID. At Week 16, patients without ≥20% reduction in swollen and tender joint counts were required to
be re-randomized equally to either apremilast dose if initially randomized to placebo or remained on their initial apremilast dose. Patients on background concurrent DMARDs continued stable doses. Primary outcome was the proportion of patients achieving 20% improvement in modified American College of Rheumatology 20% improvement criteria (ACR20) at Week 16. ^6,7

At Week 16, significantly more patients receiving apremilast 20 mg BID (30.4%; P=0.0166) and 30 mg BID (38.1%; P=0.0001) achieved an ACR20 response vs. placebo (19.0%).⁷ At Week 24, a significantly greater proportion of patients receiving apremilast 20 mg BID and 30 mg BID achieved ACR20, ACR50 and ACR70 vs. placebo, and these response rates were maintained in the active treatment groups (P≤0.0001 vs. placebo, all). An ACR20 response of 45.3% was observed at Week 24 in patients treated with apremilast 30 mg BID independent of their response at Week 16.⁷ At Week 52, ACR20 response was observed among patients receiving apremilast continuously for 52 weeks (n=254) in 63.0% (20 mg BID) and 54.6% (30 mg BID) of patients.⁷

Patients who continued receiving apremilast through Week 52 demonstrated sustained rates of ACR20 response over 52 weeks. At Week 52, 63.0% of patients who received apremilast 20 mg BID from baseline and 54.6% who received 30 mg BID achieved an ACR20. ACR50 and ACR70 responses were observed in 24.8% and 15.4% of patients receiving apremilast 20 mg BID and 24.6% and
13.8% of patients receiving apremilast 30 mg BID, respectively.⁷

Patients treated with apremilast had a statistically significant improvement in physical function, as measured by changes from baseline in Health Assessment Questionnaire–Disability Index
(HAQ-DI) score (P=0.0004 vs. placebo) and the 36-Item ShortForm Health Survey v2 Physical Functioning domain score (P=0.0001 vs. placebo). Significant improvements were also seen in most ACR component scores, particularly swollen and tender joint counts and patient assessment of pain (P placebo).⁶

Significant improvements in key secondary measures (physical function, psoriasis) were evident with both apremilast doses compared to placebo (P6 Among patients receiving apremilast continuously for 52 weeks, response was also maintained across secondary outcomes, including measures of PsA signs and symptoms, skin psoriasis severity, and physical function.⁶

In patients with baseline enthesitis, the mean change from baseline in the Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) was significantly higher for apremilast 30 mg BID vs. placebo (P=0.0334), and significantly greater proportions of patients receiving apremilast 20 mg BID (32.0%; P=0.0037) and
30 mg BID (33.6%; P=0.0013) achieved a MASES score of 0 at Week 24 vs. placebo (14.4%). In patients with baseline dactylitis, mean change from baseline in dactylitis severity score was higher with apremilast vs. placebo. Greater proportions of patients with dactylitis achieved scores of 0 at Week 24 with apremilast 20 mg BID (50.9%), apremilast 30 mg BID (47.7%) vs. placebo (40.9%); these differences did not reach statistical significance at Week 24.⁶ At Week 52, in patients with enthesitis and dactylitis at baseline who received apremilast continuously through Week 52, the median change from baseline in MASES at Week 52 was 100% with apremilast 20 mg BID and 66.7% with apremilast 30 mg BID, and a MASES score of 0 was observed in 50.7% (35/69) of patients receiving apremilast 20 mg BID and 38.2% (34/89) receiving apremilast 30 mg BID.⁷

At Week 16, treatment with apremilast was associated with significantly greater reductions (improvements) in HAQ-DI vs. placebo (key secondary endpoint, SE). The mean SE changes from baseline were -0.09 (0.04) (placebo), -0.20 (0.04) (apremilast 20 mg BID; P=0.0252 vs. placebo), and -0.25 (0.04) (apremilast 30 mg BID; P=0.0015 vs. placebo).⁶

As well, HAQ-DI scores were maintained in both apremilast groups over 52 weeks with continued treatment. At Week 52, mean reductions in HAQ-DI score were –0.37 (0.48) with apremilast 20 mg BID and –0.32 (0.55) with apremilast 30 mg BID, with improvements of ≥0.13 observed in 60.0% and 59.8%, respectively, and improvements of ≥0.30 observed in 45.8% and 44.7%, respectively.⁷

The most common AEs in the PALACE 1 trial were gastrointestinal (GI), mild or moderate in severity, occurred early, self-limited, did not recur, and infrequently led to discontinuation (<2.5%) in the apremilast 20 mg BID and 30 mg BID groups through
Week 24. No imbalance in major adverse cardiac events,
serious or opportunistic infections, malignancies or laboratory abnormalities was observed. For an overview of AEs occurring in ≥5% in any treatment group during the placebo-controlled phase (Weeks 0-24) and apremilast exposure period (Weeks 0-52) of PALACE 1 see Table 3. There were no new emergent AEs over the
52-week period.⁷

		Placebo-ControlledPeriod Weeks 0-24			ApremilastExposure Period Weeks 0-52
Patients (%)		Placebo	Apremilast		Apremilast
		n=168	20 mg BID n=168	30 mg BID n=168	20 mg BID n=245	30 mg BID n=245
Diarrhea		2.4	11.3	19.0	11.0	19.0
Nausea		6.5	9.5	18.5	9.8	14.3
Headache		4.8	10.1	10.7	9.0	9.8
Upper respiratory tract infection		3.6	6.0	4.2	7.8	5.7
Nasopharyngitis		3.0	3.6	4.8	6.9	6.5
Table 3. Adverse events ≥5% any treatment group in PALACE 17

Warnings and Precautions: Data from Studies in
Psoriasis and PsA

Weight Decrease

Psoriasis: During the controlled period of the trials, weight decrease between 5%-10% of body weight was reported in 12% of psoriasis patients treated with apremilast 30 mg BID vs. 5% treated with placebo. Weight decrease of ≥10% of body weight occurred in 2% of patients treated with apremilast 30 mg BID vs.
1% in the placebo group. It is recommended that patients treated with apremilast should have their weight monitored.

PsA: During the controlled period of the trials, weight decrease between 5%-10% of body weight was reported in 10% of patients with PsA treated with apremilast 30 mg BID vs. 3.3% of placebo. It is recommended that patients treated with apremilast should have their weight monitored regularly.²⁵

Depression

Psoriasis and PsA: While treatment with apremilast was associated with a risk of depression, data from the clinical trials do not suggest an increase in depression nor suicidal ideation in subjects treated with apremilast vs. placebo.²⁵

Drug Interactions

Psoriasis and PsA: The use of cytochrome P450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) with apremilast is not recommended. It has been shown that the coadministration of strong cytochrome P450 enzyme inducer, rifampin, resulted in a reduction of systemic exposure of apremilast, which may result in a loss of its efficacy.²⁵

Conclusion

Treatment with apremilast demonstrated efficacy in reducing the severity of moderate to severe plaque psoriasis^17,18 and improving signs, symptoms and physical function in PsA.^6,7,19-21 Apremilast demonstrated an acceptable safety profile and was well-tolerated with generally mild GI complaints occurring early in the course of the treatment and resolving with time, and there was no requirement for laboratory monitoring.^6,7,19-21,24 Based on these results, apremilast should be considered as a therapeutic option in the treatment of plaque psoriasis and PsA.

Acknowledgement

The authors gratefully acknowledge the medical editorial support from Flora Krasnoshtein in preparing this manuscript.

References

1. Najarian DJ, Gottlieb AB. Connections between psoriasis and Crohn’s disease. J Am Acad Dermatol. 2003 Jun;48(6):805-21; quiz 22-4.
2. Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med. 2009 Jul 30; 361(5):496-509.
3. Ritchlin CT. Pathogenesis of psoriatic arthritis. Curr Opin Rheumatol. 2005 Jul;17(4):406-12.
4. Salari-Sharif P, Abdollahi M. Phosphodiesterase 4 inhibitors in inflammatory bowel disease: a comprehensive review. Curr Pharm Des. 2010 16(33):3661-7.
5. Papp K, Cather JC, Rosoph L, et al. Efficacy of apremilast in the treatment of moderate to severe psoriasis: a randomised controlled trial. Lancet. 2012 Aug 25;380(9843):738-46.
6. Kavanaugh A, Mease PJ, Gomez-Reino JJ, et al. Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Ann Rheum Dis. 2014 Jun;73(6):1020-6.
7. Kavanaugh A, Mease PJ, Gomez-Reino JJ, et al. Longterm (52-week) results of a phase III randomized, controlled trial of apremilast in patients with psoriatic arthritis. J Rheumatol. 2015 Mar;42(3):479-88.
8. Schafer P. Apremilast mechanism of action and application to psoriasis and psoriatic arthritis. Biochem Pharmacol. 2012 Jun 15;83(12):1583-90.
9. Schafer PH, Parton A, Capone L, et al. Apremilast is a selective PDE4 inhibitor with regulatory effects on innate immunity. Cell Signal. 2014 Sep;26(9):2016-29.
10. Baumer W, Hoppmann J, Rundfeldt C, et al. Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis. Inflamm Allergy Drug Targets. 2007 Mar;6(1):17-26.
11. Serezani CH, Ballinger MN, Aronoff DM, et al. Cyclic AMP: master regulator of innate immune cell function. Am J Respir Cell Mol Biol. 2008 Aug;39(2):127-32.
12. Serezani CH, Ballinger MN, Aronoff DM, et al. Cyclic AMP: master regulator of innate immune cell function. Am J Respir Cell Mol Biol. 2008 Aug;39(2):127-32.
13. Gottlieb AB, Strober B, Krueger JG, et al. An open-label, single-arm pilot study in patients with severe plaque-type psoriasis treated with an oral anti-inflammatory agent, apremilast. Curr Med Res Opin. 2008 May;24(5): 1529-38.
14. Papp KA, Kaufmann R, ThaÁi D, et al. Efficacy and safety of apremilast in subjects with moderate to severe plaque psoriasis: results from a phase II, multicenter, randomized, double-blind,placebo-controlled, parallel-group, dose-comparison study. J Eur Acad Dermatol Venereol. 2013 Mar;27(3):e376-83.
15. Papp K, Cather JC, Rosoph L, et al. Efficacy of apremilast in the treatment of moderate to severe psoriasis: a randomized controlled trial. Lancet. 2012 Aug 25;380(9843):738-46.
16. Strand V, Hu A, Day R, Sloan V. P3337: Improved quality of life with apremilast (APR) in the treatment of psoriasis: results from a phase IIb randomized controlled study J Am Acad Dermatol 2011:64(2): AB154. [Poster abstract P3337]. Presented at the American Academy of Dermatology 2011 69th Annual meeting; February 4-8, 2011; New Orleans, LA.
17. Papp K, Reich K, Leonardi C, et al. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate to severe psoriasis: results from the randomized treatment withdrawal phase of a phase 3, randomized, controlled trial (ESTEEM 1). [Poster 8359]. Presented at the 72nd Annual Meeting of the American Academy of Dermatology; March 21-25, 2014; Denver, CO.
18. Paul C, Cather J, Gooderham M, et al. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate to severe psoriasis: 16-week results of a phase 3, randomized, controlled trial (ESTEEM 2). [Poster 8412]. Presented at the 72nd Annual Meeting of the American Academy of Dermatology; March 21-25, 2014; Denver, CO.
19. Cutolo M, Myerson GE, Fleischmann RM, et al. Long-term (52-week) results of a phase 3, randomized, controlled trial of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis (PALACE 2). [Presentation number 815]. Presented at ACR 2013. American College of Rheumatology 2013 Annual Meeting; October 25-31,2013; San Diego, CO.
20. Edwards CJ, Blanco FJ, Crowley J, et al. Long-term (52-Week) Results of a phase 3, randomized, controlled trial of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis and current skin involvement (PALACE 3). [Poster 311]. Presented at ACR 2013 American College of Rheumatology 2013 Annual Meeting; October 25-31,2013; San Diego, CO.
21. Edwards CJ, Wells AF, Adebajo AO, et al. Apremilast, an oral phosphodiesterase 4 inhibitor, is associated with long-term (52-Week) improvements in enthesitis or dactylitis in patients with psoriatic arthritis: results from the PALACE 4 phase 3, randomized, controlled trial. Presented at European League Against Rheumatism Congress; June 1-14, 2014; Paris, France.
22. Armstrong AW, Griffiths CEM, Tencer T, et al. Effect of apremilast on patientreported outcomes in patients with moderate to severe plaque psoriasis in the ESTEEM 1 trial. [Poster P1691]. Presented at: the 23rd Congress of the European Academy of Dermatology and Venereology; October 8-12, 2014; Amsterdam, the Netherlands.
23. Gooderham M, Cather J, Crowley J, et al. Effects of apremilast on healthrelated quality of life in patients with moderate to severe plaque psoriasis: 16-week results from the ESTEEM 2 trial. [Poster P1688]. Presented at the 23rd Congress of the European Academy of Dermatology and Venereology; October 8-12, 2014; Amsterdam, the Netherlands.
24. Reich K, Papp K, Leonardi C, et al. Long-term safety and tolerability of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate to severe psoriasis: results from a phase III, randomized, controlled trial (ESTEEM 1). [Poster 8296]. Presented at the 72nd Annual Meeting of the American Academy of Dermatology; March 21-25, 2014; Denver, CO.
25. Otezla^® (apremilast) [Full Prescribing information]. Summit, NJ: Celgene Corporation; revised December 2014. Available at: http://www.otezla.com/ otezla-prescribing-information.pdf. Accessed August 2, 2015.