Background
Psoriasis is a chronic inflammatory disease that affects approximately 1% to 3% of the worldwide population [
1,
2]. Individuals with psoriasis report impaired health-related quality of life (HRQOL), ranging from physical discomfort and limitations in activities of daily living to psychosocial problems and emotional distress [
3‐
7]. Furthermore, the severity of psoriasis symptoms, and pruritus in particular, has been linked to the degree of HRQOL impairment [
3,
4].
Many therapies for psoriasis treatment improve HRQOL [
8‐
10]. Despite this, each therapy’s benefit can be compromised by poor tolerability, adverse events, and route of administration (particularly injection/infusion reactions) [
11,
12]. These limitations underscore the persistent unmet need for additional treatment options for psoriasis [
13]. As new therapies become available for managing psoriasis, it is important to evaluate their impact on patient-reported HRQOL.
Research over the past decade in inflammatory diseases such as psoriasis has focused upon modulation of cyclic adenosine monophosphate (cAMP), a naturally occurring intracellular secondary messenger that maintains immune homeostasis by modulating production of pro-inflammatory and anti-inflammatory cytokines [
14,
15]. Phosphodiesterase 4 (PDE4) is a cAMP-specific PDE and the dominant PDE in inflammatory cells. PDE4 inhibition elevates intracellular cAMP, which in turn down-regulates the inflammatory response [
16‐
19]. Apremilast (CC-10004; Celgene Corporation, Summit, NJ, USA) is a small molecule that specifically inhibits PDE4, thereby elevating intracellular cAMP levels. Elevated intracellular cAMP reduces pro-inflammatory mediators, such as tumor necrosis factor-α, interleukin-23, and interferon-γ, and increases production of anti-inflammatory mediators, such as interleukin-10 [
18]. Clinical studies have demonstrated the efficacy and tolerability of apremilast in moderate to severe psoriasis and psoriatic arthritis (PsA) [
20‐
22].
In this phase IIb, multicenter, randomized, controlled trial (RCT), orally administered apremilast (10 mg BID, 20 mg BID, or 30 mg BID) resulted in dose-dependent efficacy for the treatment of moderate to severe plaque psoriasis [
20]. A significantly greater proportion of patients receiving apremilast 20 mg (28.7%) and 30 mg BID (40.9%) achieved ≥75% mean reductions from baseline in Psoriasis Area and Severity Index (PASI-75) scores compared with placebo (
P<0.001) after 16 weeks of treatment [
20]. Reductions in baseline PASI scores were evident by week 2, with a separation across doses observed by weeks 2 to 4; improvements were maintained over 24 weeks' treatment. Significant improvements in pruritus visual analog scale (VAS), static Physician’s Global Assessment, and body surface area (BSA) scores were also reported. It is hypothesized that clinical improvements would be accompanied by improvements in patient-assessed HRQOL. This report summarizes the impact of apremilast on patient-reported outcomes (PROs) over the initial 16-week placebo-controlled treatment phase of this trial.
Discussion
In this RCT, patients with moderate to severe plaque psoriasis reported impairments in disease-specific and generic measures of HRQOL at baseline, evidenced by mean DLQI scores >10 and SF-36 MCS scores 0.5 SDs below US age-/gender-matched norms. Statistically significant and clinically meaningful improvements in SF-36 MCS and domain scores were reported by patients treated with apremilast, most evident in the 20- and 30-mg BID dose groups, mirrored by decreases in disease-specific DLQI and pruritus VAS scores. In contrast, patients receiving placebo reported little change or deterioration from baseline in HRQOL. Correlations between SF-36 MCS, BP, and VT scores and DLQI were moderate and, in general, statistically significant. Correlations between SF-36 scores and pruritus VAS were moderate to low, indicating that they measure different impacts of the disease and highlighting the value in assessing efficacy using multiple instruments.
Interpretation and implications
Growing evidence clearly shows that impairments in HRQOL are a large component of the disease burden imposed by psoriasis. These results are in line with national survey findings that show the majority of individuals with psoriasis experience emotional as well as physical disease-related problems [
34]. In that survey, 63% of respondents reported that psoriasis impacts their emotional well-being, marked by feelings of helplessness, anger, embarrassment, and frustration. Given the generally high level of emotional distress patients report regarding psoriasis symptoms, it is important to describe the potential impact of treatment on emotional functioning. Emotional distress has been linked to onset of psoriasis flares, more severe symptoms, and presence of lesions in visible locations [
3,
35] and may contribute to heightened risk of major depressive disorder, often seen in this patient population [
5,
6,
36]. This trial contributes to other RCT data demonstrating that efficacious treatment of moderate to severe psoriasis results in improvements in HRQOL [
7‐
9,
37,
38]. Consistent with findings from other studies [
7], psoriasis appears to have relatively greater impact on mental health rather than physical domains, as patients report larger decrements in RE and SF and to a lesser degree BP domains. This suggests that the impact of physical well-being on mental health might well depend on the nature of the physical impairment, as skin disease may have a disproportionately large effect on mental functioning and ensuing HRQOL whereas joint disease in PsA has more impact on PF, BP, and VT domains. These data demonstrate moderate correlations between improvements in disease-specific functioning, based on DLQI, and broader improvements in SF-36 MCS scores and BP, SF, and RE domains. This likely reflects improvements in painful psoriatic plaques and/or joint pain associated with comorbid PsA, although only a minority of patients reported the presence of arthritis. The ability to measure treatment efficacy based on broader generic instruments has implications when considering comparisons with normative populations as well as across disease states. Disease-associated decrements in HRQOL reported by patients with psoriasis indicate that a multipronged approach could enhance assessment of treatment effectiveness. This approach should encompass clinical signs and symptoms, as well as patient-reported HRQOL, using both disease-specific and generic instruments.
Apremilast clinical data
As described in a separate report [
20], the primary results of this study demonstrate the efficacy and tolerability of apremilast 20 and 30 mg BID over 24 weeks in patients with moderate to severe plaque psoriasis, including significant improvements in PASI, pruritus, static Physician’s Global Assessment, and BSA scores. The most frequently reported adverse events were headache, nausea, vomiting, nasopharyngitis, and upper respiratory tract infection. The majority of adverse events (>96%) were mild or moderate in severity, and rates of discontinuations due to adverse events were generally low (≈10%). Gastrointestinal events were generally transient. Importantly, no opportunistic infections were reported, and no serious infections were considered related to apremilast [
20].
The tolerability findings are important in their relationship to the improved HRQOL seen in this study. While improvement in the severity of disease can be expected in most cases to improve HRQOL, there are some instances in which tolerability and safety issues may abrogate this benefit. The results of the current analysis indicate that this was not the case with apremilast. While the most commonly reported adverse events were related to gastrointestinal complaints and headache, this did not appear to outweigh the benefit of therapy, and resulted in an overall improvement in HRQOL.
On the basis of phase II findings, further examination of the efficacy and safety of apremilast for the treatment of psoriasis is underway in phase III studies. The ESTEEM (
E fficacy and
S afety
T rial
E valuating the
E ffects of apre
M ilast in psoriasis) clinical trial program includes two 52-week RCTs, each with a 16-week placebo-controlled phase, randomized withdrawal phase for PASI responders, and long-term, open-label extension to assess the efficacy, tolerability, and effects of apremilast on HRQOL in patients with moderate to severe plaque psoriasis. Recently, topline results from the ESTEEM 1 trial were presented [
39]. At week 16, a significantly greater proportion of patients receiving apremilast 30 mg BID achieved PASI-75 (33.1%) and PASI-50 (58.7%) compared with placebo (5.3% and 17.0%;
P<0.0001 for both). Apremilast was also associated with significant improvements in static Physician’s Global Assessment, pruritus VAS, and DLQI as well as difficult-to-treat nail and scalp psoriasis. Apremilast was well-tolerated and no new safety or laboratory signals were detected. Additional results are anticipated. In addition, apremilast is currently being investigated in phase III clinical trials for the treatment of PsA and ankylosing spondylitis.
Limitations
The study enrolled patients with moderate to severe plaque psoriasis and results may not be applicable to patients with other forms of psoriasis. This report is based on PROs after 16 weeks of treatment, although a separate publication indicates that improvements with active therapy are generally maintained over 24 weeks of treatment [
20]. Ongoing phase III studies are expected to yield valuable information.
Competing interests
VS has been a consultant to and member of scientific advisory boards for Abbott Immunology, Alder Biopharmaceuticals, Amgen, BiogenIdec, BMS, Celgene Corporation, Galderma, Idera, Incyte, Janssen, MedImmune, Novartis, Pfizer Inc, Regeneron, Rigel, Roche, Sanofi, and UCB. DF has served as an investigator for Amgen, Celgene Corporation, Janssen, Pfizer Inc, and Roche, and as a paid advisor for Amgen, Janssen, MedImmune, and Rigel. CH, RMD, and RMS are employees of Celgene Corporation. KAP has served as an investigator for Abbott, Amgen, Boehringer Ingelheim, BMS, Celgene Corporation, Centocor, Galderma, Isotechnika, Janssen, Leo Pharma, Lilly, MedImmune, Merck, Novartis, and Pfizer Inc; an adviser for Abbott, Amgen, Astellas, BMS, Celgene Corporation, Centocor, Galderma, Incyte, Isotechnika, Janssen, Johnson & Johnson, Lilly, MedImmune, Merck, Novartis, Pfizer Inc, and UCB; and a speaker for Abbott, Amgen, Astellas, Celgene Corporation, Centocor, Isotechnika, Janssen, Novartis, and Pfizer Inc.
Authors’ contributions
All authors had full access to all of the data in the study. VS, DF, CH, RMD, RMS, KAP: Conceived of the study, participated in the design and coordination of the study, and helped to draft the manuscript. CH, RMD, RMS, KAP: Supervised on and performed data analyses and helped to draft the manuscript. VS, CH, RMD, RMS, KAP: Analyzed and interpreted the data and helped to draft the manuscript. VS, DF, CH, RMD, RMS, KAP: All authors had full access to the data and have read and approved the final manuscript.