Apremilast is an oral phosphodiesterase-4 inhibitor with immunomodulatory activity that partially blocks the expression of proinflammatory cytokines and induces the expression of anti-inflammatory cytokines with a pathogenic role in psoriasis. It is indicated for the treatment of moderate to severe psoriasis1 and psoriatic arthritis and has acceptable short- and long-term safety and tolerability profiles. Nevertheless, because the patients studied in the pivotal clinical trials of apremilast had a very specific profile, similar to that of candidates for biologic therapy,2,3 little is known about real-world usage, such as the identification of candidates for treatment or the correct positioning of the drug in relation to conventional and biologic therapies. Consensus-based recommendations based on expert opinions and developed using rigorous, validated methodologies serve as useful guidelines for such situations and provide experts with valuable information on the use of apremilast in everyday clinical practice.4

To complement the existing evidence on the use of apremilast, a group of experts came together to evaluate clinical scenarios and aspects of treatment for which the information in the literature was considered to be lacking.

The efficacy of apremilast in the treatment of moderate to severe plaque psoriasis has been evaluated in several phase II and III randomized clinical trials.

In the phase III ESTEEM 1 and 2 trials,2,3 one-third of patients in the apremilast arm achieved PASI-75 by week 16 compared with 6% in the placebo arm. Half of the patients maintained this response at week 50, and over 75% maintained a reduction in PASI of 70% or greater.

Outcomes from clinical trials, however, even when significant, do not necessarily reflect the use of conventional new-generation drugs such as apremilast in real-world clinical practice.

The expert panel agreed that apremilast was most likely to be successful in patients with stable, moderate psoriasis. There are, however, no clear or agreed-on definitions of moderate psoriasis. The 2011 American Academy of Dermatology guidelines of care for the management of psoriasis and psoriatic arthritis defined 3 categories of psoriasis according to percentage of body surface area (BSA) affected and considered that patients with a BSA involvement of between 5% and 10% had moderate psoriasis.8

In a survey of US dermatologists, Knuckles et al.9 found that most dermatologists considered a median BSA of 5% to 10% to indicate moderate psoriasis, although cutoff scores mentioned varied considerably. Llamas-Velasco et al.10 proposed that moderate psoriasis should be defined by either a PASI score of less than 7 and a DLQI score of at least 5 or a PASI score of between 7 and 15 regardless of DLQI; these latter scores overlap with scores indicating candidacy for biologic therapy. The prospective LAPIS-PSO study of 500 patients treated with apremilast in routine care found that patients were more likely to achieve PASI-75 or a physician global assessment score of 0 or 1 (PGA 0/1) when their baseline PASI was lower than that in the ESTEEM 1 and 2 trials.11,12 Papadavid et al., 13 in a series of 51 patients with a mean PASI score of 10.8 treated in everyday practice, reported a PASI-75 rate of 59.3% at week 16. Aragón-Miguel et al.14 and Lukoviek et al.15 also reported lower PASI scores (9.37 and 9.01, respectively) in real-life settings. Finally, in the real-world APRIL study,16 patients still on apremilast 6 months after initiating treatment had a lower mean baseline PASI score than those who discontinued treatment due to a lack of response (9.4 vs. 11.8).

Most of the members of the expert panel considered that apremilast is an appropriate option for patients in whom conventional treatment fails or is contraindicated, and that it should ideally precede biologic therapy. This treatment profile differs to that of the pivotal trials, where most patients had severe, extensive psoriasis that was often refractory to biologic therapy. The outcomes could therefore vary. In the ESTEEM-2 study, for example, PASI-75 rates were significantly lower in patients who had been previously treated with biologics (22.8%) than in patients who had never been treated with systemic therapy, whether biologic (31.9%) or conventional (33.3%).3

In addition, patients still on apremilast after 6 months had on average been treated with fewer systemic treatments (mean, 1.47) and biologic therapies (0.20) than those no longer taking apremilast (1.96 and 0.70, respectively). Twenty-seven percent of patients in this group had received biologic therapy. Apremilast was clearly positioned by the panel as a conventional therapy in psoriasis, which seems reasonable considering both its chemical nature and effectiveness and safety profile. However, because of its price, similar to that of drugs in the biologics segment, access to this drug has been strongly shaped by reimbursement policies.17 Despite the above considerations, it should be recalled that there are no clinical trial data for the specific use of apremilast in moderate psoriasis.

The expert panel considered that treatment effectiveness should be measured not just by objective indicators of complete or near-complete response (absolute PASI scores), but by a combination of indicators and other factors, in particular overall patient-reported satisfaction, tolerability, and safety. They also considered that a leeway of 24 weeks could be left before deciding whether or not to continue with treatment. This recommendation is in contrast to the treatment goals established in the clinical trials of apremilast, highlighting the challenges that lie ahead in terms of determining treatment goals and follow-up intervals for patients with psoriasis and also highlighting the role of patient empowerment in terms of the consideration of patient-reported outcome measures.18 Nonetheless, this recommendation also complicates the objective comparison of the drug’s effectiveness—and efficiency—relative to other treatments on the market.

Despite the limited evidence available, the expert panel considered that apremilast is a useful option for treating refractory disease in difficult-to-treat areas (palms/soles, nails, and scalp). This recommendation is supported by observations (limited by patient numbers) from phase II and III clinical trials.19–21 In the observational LAPIS-PSO study, 62% of patients treated with apremilast in routine care achieved nail PASI-50 after 4 months; in the same period, approximately 60% achieved scalp PGA 0/1 and almost 70% achieved palmoplantar PGA 0/111,22 (Appendix B Table S2. See supplementary material).

In the only randomized trial to specifically evaluate the efficacy of apremilast in palmoplantar psoriasis, Bissonnette et al.19 found no significant differences in PGA 0/1 between patients treated with apremilast and placebo after 16 weeks (4%, P = .1595). Nonetheless, 24% of patients treated with apremilast achieved this goal by week 32. In addition, patients in the apremilast arm performed better in terms of PASI-75 (22% vs. 8% for placebo, P = .0499) and DLQI (−4.3 [5.1] vs.−0.8 [4.5], P =  .0004) scores. In the STYLE study, the first phase III multicenter, placebo-controlled, randomized clinical trial to evaluate the efficacy and safety of apremilast in patients with moderate to severe plaque psoriasis of the scalp, 43.4% of patients in the treatment arm versus 13.8% in the placebo arm achieved the primary endpoint, which was scalp PGA 0/1 with an improvement of 2 points or more from baseline to week 16.23

The panel considered that the concomitant presence of psoriatic arthritis constituted an additional reason to use apremilast, particularly in patients with moderate psoriasis, joint involvement, or dactylitis. The phase III PALACE-1-3 clinical trial assessed the efficacy of apremilast in the treatment of psoriatic arthritis.24–26 After 16 weeks of treatment, 40% of patients in the apremilast arm (30 mg twice daily) versus 20% of those in the placebo arm achieved a 20% or greater improvement in American College of Rheumatology response criteria.

Over 70% of patients treated with apremilast maintained this response in the long term (260 weeks).

Approximately 55% and 80% of patients who achieved complete resolution of enthesitis and dactylitis, respectively, remained stable on 30 mg of apremilast administered twice a day.26

Overall, the panel members considered safety to be one the most attractive attributes of apremilast. The most common adverse effects (affecting ≥ 5% of patients) are summarized in Appendix B Table S3 of the supplementary material.27,28 In the pooled safety analysis of the ESTEEM 1 and 2 trials, the incidence of adverse effects at 156 weeks was not significantly higher than that observed after 1 year for cardiovascular events (exposure-adjusted incidence rate of 0.5/100 patient-years), malignancies (1.2/100 patient-years), depression (1.8/100 patient-years), and suicide attempts (0.1/100 patient-years).28 Data from the observational LAPIS-PSO study, which analyzed 500 patients, suggested that the overall incidence of adverse events might be lower in routine care than in clinical trial settings.

The members of the expert panel considered that patients treated with apremilast need less rigorous prescreening and follow-up than patients treated with conventional systemic treatments or biologic therapy. A priori, this could be viewed as offering certain advantages over the standard protocol required for systemic therapies and could lead to greater prescribing of apremilast in centers where it takes time or considerable effort to gain access to conventional systemic treatments and biologic therapy. The summary of product characteristics (SPC) does not mention the need for special tests before or during treatment with apremilast.27

In addition to the contraindications described for apremilast in the SPC, the European S3-Guideline mentions acute, severe infections as an absolute contraindication for apremilast.29 It also includes acute and chronic infections, cancer, lymphoproliferative disorders, and depression as relative contraindications. There is no evidence on the use of apremilast in patients with cancer, as, with the exception of cervical intraepithelial neoplasia and squamous cell carcinoma, malignancy was an exclusion criterion in the clinical trials. Depression, aside from being a common comorbidity in patients with psoriasis,30,31 is listed as a potential adverse effect in the SPC for apremilast. Just over 1% of patients treated with apremilast in the phase III clinical trials and 0.5% of those treated with placebo experienced depression.27

Regarding follow-up recommendations, the panel considered that an annual blood test was sufficient and that other tests or procedures should be performed on an as-needed basis. This consideration is consistent with the recommendations of the European Academy of Dermatology and Venerology.29

The most relevant adverse events associated with apremilast according to the expert panel are gastrointestinal problems, mood changes, and weight loss. Supporting observations in the literature,32 it was agreed that awareness and prompt management of adverse effects can help minimize their impact and enable patients to continue with treatment. Nonetheless, treatment discontinuation due to tolerability problems is likely to be more common in real-world settings than in clinical trials, probably as patients treated in routine practice have access to other treatments. In a series of 77 patients treated with apremilast in a real-world setting, Lee et al.33 reported a treatment discontinuation rate of 23% over a mean period of 123 days, contrasting with the rate of 5.3% reported in the clinical trials. Treatment was stopped in most cases because of adverse effects.

In brief, the clinicians who participated in this study view apremilast as an attractive option for the individualized treatment of psoriasis and consider that objective indicators of effectiveness should be contemplated together with safety, convenience, and patient satisfaction. In particular, they appreciated the versatility of the drug as an option for patients who are not candidates for other treatments as well as its favorable safety profile and positive impact on symptoms, quality of life, and lesions in difficult-to-treat areas. Disadvantages that should be considered include its lower effectiveness compared with other new-generation drugs and certain tolerability aspects that could influence efficiency in this highly competitive setting.

This study highlights the importance of defining moderate psoriasis to enable comparative studies of apremilast and other drugs as well as the need for greater evidence from clinical trials and real-world settings to verify the recommendations of the experts.

Jose Manuel Carrascosa has served as a consultant and speaker, participated in clinical trials, and attended meetings and conferences with financial support from AbbVie, Celgene, Janssen-Cilag, Leo-Pharma, Lilly, Novartis, Pfizer, Biogen, Sandoz, Milan, Sanofi-Aventis, and Almirall.

Mariano Ara has given talks and attended consultancy meetings sponsored by AbbVie, Pfizer, MSD, Janssen, Celgene, Almirall, Amgen, Novartis, Lilly, and Leo.

Pedro Herranz has worked as a consultant/speaker/researcher for AbbVie, Celgene, Lilly, Janssen-Cilag, MSD, Novartis, Pfizer, Regeneron, and Sanofi-Aventis

Isabel Belinchon has participated in clinical trials and received consultancy and speakers’ fees from AbbVie, Janssen, MSD, Pfizer-Wyeth, Leo, Celgene, Novartis, and Lilly.

Marta García-Bustínduy has served as a consultant and speaker, participated in clinical trials, and attended meetings and conferences with financial support from AbbVie, Celgene, Janssen-Cilag, Leo, Lilly, Novartis, MSD, Pfizer-Wyeth, and Sanofi-Aventis.

Celgene provided bibliographic support and collaborated with the organization of working meetings and the design and development of the Delphi study carried out by the independent scientific group. Nobody involved with Celgene participated in the generation of proposals or other content produced by this working group or in the writing of this manuscript.

Celgene provided bibliographic support and collaborated with the organization of working meetings and the design and development of the Delphi study carried out by the independent scientific group.