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. 2017 Jan 20;9(2):45–53. doi: 10.1177/1759720X16673786

Apremilast in the treatment of psoriatic arthritis: a perspective review

Michael Reed 1, David Crosbie 2,✉
PMCID: PMC5315225  PMID: 28255338

Abstract

Apremilast is an orally-active small molecule which inhibits phosphodiesterase-4 (PDE4). Clinical trials have demonstrated its efficacy and safety in psoriatic arthritis (PsA) and psoriasis. Established therapeutic options have variable effectiveness across the different domains of psoriatic disease. Whilst biologic therapies have proven to be of significant benefit to many patients, not all patients respond, and others are not eligible or do not tolerate biologic therapy. We review the mechanism of action, pharmacokinetics and clinical trial data with regards to both efficacy and safety for apremilast and consider where this new treatment may be positioned in the treatment of PsA.

Keywords: apremilast, PALACE, psoriasis, psoriatic arthritis

Introduction

Psoriatic arthritis (PsA) is an inflammatory arthritis recognized since the early 19th century [Alibert, 1818]. It was defined as discrete from rheumatoid disease in the 1970s with five clinical disease patterns: distal, oligoarticular, polyarticular, primarily axial, and arthritis mutilans [Wright and Moll, 1971]. It is estimated to have a prevalence of 0.3–1.0% [Gladman et al. 2005], affecting up to 30% of patients with cutaneous psoriasis [Zachariae, 2003].

In addition to inflammatory arthritis, PsA can affect the skin, nails, synovial sheaths of tendons, entheses, and soft tissue of the digits. The clinical manifestations are a result of periosteal reaction and enthesitis, [Olivieri et al. 1997; Ritchlin et al. 2009]. Inflammation of an entire digit (dactylitis) is a typical clinical feature of PsA which has been shown by magnetic resonance imaging scans to be a result of both tenosynovitis and synovitis [Olivieri et al. 1997].

The clinical heterogeneity of PsA makes early diagnosis challenging. Typically, in the early phases of PsA, patients have fewer tender or swollen joints than with other forms of inflammatory arthritis [Caso et al. 2014]. In addition, there tends to be low or normal serum inflammatory markers. Presence of enthesitis, dactylitis, inflammatory back pain or previous or current episodes extra-articular features such as uveitis can help in identifying PsA [Caso et al. 2014].

PsA can be a serious condition with joint destruction, disability [Gladman et al. 1990] and impairment of quality of life [Husted et al. 2001]. Increased mortality has been identified [Gladman et al. 1998] with an increased prevalence of metabolic syndrome, type 2 diabetes mellitus, obesity, hyperlipidemia, hypertension and cardiovascular disease observed [Mallbris et al. 2006; Zhu et al. 2012].

Classification criteria have been developed to assist in case definition with the CASPAR (ClASsification criteria for PsA) criteria [Taylor et al. 2006] which have being validated with a specificity of 98.2% and sensitivity of 99.1% [Tillett et al. 2012]. To meet the CASPAR criteria, a patient must have inflammatory articular disease (joint, spine, or entheseal) with three or more points from five categories, with current psoriasis assigned a score of 2 and all other features assigned a score of 1: (1) evidence of current psoriasis, a personal history of psoriasis, or a family history of psoriasis; (2) typical psoriatic nail dystrophy including onycholysis, pitting, and hyperkeratosis observed on current physical examination; (3) a negative test result for the presence of rheumatoid factor; (4) either current dactylitis, defined as swelling of an entire digit, or a history of dactylitis recorded by a rheumatologist; (5) radiographic evidence of juxtaarticular new bone formation, appearing as ill-defined ossification near joint margins (but excluding osteophyte formation) on plain radiographs of the hand or foot [Taylor et al. 2006].

The different domains and therapeutic options are well described in the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) recommendations [Coates et al. 2016]. There are several existing therapeutic options for the treatment of PsA. These include conventional disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, leflunomide, ciclosporin and sulphasalazine [Joshi and Dhaneshwar, 2014]. The emergence of biologic therapies has proven to be efficacious in PsA providing clinicians with more treatment options. These include tumour necrosis factor (TNF)-α inhibitors (TNFis) [Joshi and Dhaneshwar, 2014; Caso et al. 2016] as well as emerging drugs such as the fully human monoclonal interleukin (IL)12/23 antibody, ustekinumab and the IL17-targeting secukinumab [Caso et al. 2016]. However, not all patients are suitable for, respond to, or tolerate the available treatments.

Apremilast is an oral phosphodiesterase-4 (PDE4) inhibitor which regulates inflammatory mediators [Schafer, 2012]. It has been shown in a randomized controlled trial to be efficacious in the treatment of moderate-to-severe plaque psoriasis [Papp et al. 2012]. In this paper, we review the data with regards to its use in patients with PsA.

Apremilast mechanism of action and pharmacokinetics

Apremilast is a novel small molecule that specifically inhibits intracellular PDE4. This enzyme is a member of the class of phosphodiesterases (PDEs) which are responsible for the hydrolysis of cyclic adenosine monophosphate (cAMP), an intracellular second messengers with multiple roles in eukaryotic cells. Various types of PDEs exist, with different expression in different cell types. PDE4 is expressed widely in haematopoietic cells, as well as some nonhaematopoietic cells such as keratinocytes [Houslay and Adams, 2003]. cAMP influences a network of proinflammatory and anti-inflammatory mediators [Taskén and Aandhl, 2004]. PDE4 inhibition produces increased cAMP levels in immune and nonimmune cells, which alters the expression of various downstream cascades, thus modifying inflammatory responses. Apremilast alters a wide array of inflammatory mediators involved in psoriasis and PsA. The effects of PDE4 inhibition include decreases in the expression of inducible nitric oxide synthase and IL23 and increases in levels of the anti-inflammatory cytokine IL10 [Schafer, 2012]. In addition, apremilast has been shown to reduce TNF-α production by human synovial cells in vitro [McCann et al. 2010].

In murine models of arthritis, apremilast significantly reduced clinically evident arthritis and histopathological change in a dose-dependent manner. Treated mice were found to have reduced levels of synovial hyperplasia, synovial inflammatory infiltrate, pannus formation, cartilage erosion and subchondral bone destruction [McCann et al. 2010].

Pharmacokinetic studies in healthy adult volunteers suggest apremilast is rapidly absorbed, with plasma Tmax values ⩽ 2 h [Hoffmann et al. 2011]. Only 4% of apremilast is excreted unchanged in faeces suggesting absorption of the vast majority of the apremilast oral dose. Elimination half-lives of apremilast and its major metabolites ranged from 7–16 h. Some of the metabolites of apremilast have slightly longer half-lives but the majority of circulating apremilast metabolites were substantially (>50-fold) less active in their anti-PDE4 activity than apremilast [Hoffmann et al. 2011]. The predominant clearance pathway for apremilast was cytochrome P450-mediated metabolism. The absorbed drug was also extensively metabolized via multiple additional pathways (O-demethylation, O-deethylation, N-deacetylation, hydroxylation, glucuronidation or hydrolysis), with the predominant circulating and excreted metabolite formed via O-demethylation followed by glucuronidation. Based on the PDE4 and TNF-α inhibitory effects of the metabolites, it is unlikely that metabolites contribute appreciably to the pharmacological activity of apremilast [Hoffmann et al. 2011]. A study of PsA and rheumatoid arthritis patients, where apremilast was given alone or in combination with methotrexate, found no differences in pharmocikinetic profiles between the two groups [Liu et al. 2014].

Efficacy

A series of phase III studies have been carried out to compare the efficacy of apremilast with placebo in patients with PsA. The PsA Long-term Assessment of Clinical Efficacy (PALACE) trials investigated apremilast at two different doses in patients with active PsA. PALACE 1–3 included patients with active PsA despite prior traditional DMARD or biologic treatment. PALACE 3 included only patients with active psoriatic skin disease as well as PsA. PALACE 4 includes patients with no prior DMARD therapy.

PALACE 1

PALACE 1 was a randomized controlled phase III study of patients with active PsA. Active disease was defined as having three or more swollen joints and three or more tender joints at baseline. All patients met CASPAR criteria for diagnosis of PsA, and all were aged 18 years or above. Patients all had prior, or current, exposure to DMARD therapy. Those on concurrent DMARD had to be on stable dose methotrexate (⩽25 mg weekly), leflunomide (⩽20 mg daily) or sulphasalazine (⩽2G daily) for a minimum of 16 weeks. Patients with prior failure of treatment on biologic therapy were included, but numbers were limited to ⩽10% of the total enrolled. Stable dose oral prednisolone (⩽10 mg/day) or nonsteroidal anti-inflammatory drugs were allowed, providing patients were taking stable doses for >2 weeks.

Exclusion criteria in PALACE 1 included: failure of ⩾3 DMARDs or biologics, any rheumatic condition or autoinflammatory joint disease other than PsA, erythrodermic, guttate, or generalized pustular psoriasis, patients in functional class IV by the American College of Rheumatology (ACR) criteria, patients who had received phototherapy or any other traditional DMARD within 4 weeks of randomization, patients with prior exposure to apremilast, and use of a biologic therapy within ⩽12 weeks of randomization (use of ustekinumab or alefacept ⩽24 weeks of randomization was also an exclusion criteria).

PALACE 1 was carried out across 83 sites in 13 different countries. Patients were randomized 1:1:1 to receive apremilast 20 mg bd, apremilast 30 mg bd or placebo. Randomization was stratified by DMARD use (yes/no). Apremilast dose was titrated, starting on 10 mg daily and increased by 10 mg/day to the target dose.

At week 16, ‘nonresponders’ (defined as those in whom the swollen joint count and tender joint counts had not improved by a minimum of 20%), were entered into the ‘early escape’ arm of the trial. These patients were then randomized to either 20 mg twice daily (bd) apremilast or 30 mg bd apremilast. At week 24, all remaining placebo patients were randomized to either dose of apremilast. From week 24, all patients were then followed up in a 28 week randomized, double-blinded active treatment phase.

Primary outcome was ACR 20 response at week 16. Various secondary outcomes were measured. These included change in HAQ-DI (Health Assessment Questionnaire - Disability Index) from baseline, safety outcomes and measures of enthesitis, dactylitis and psoriasis skin activity.

Results of PALACE 1

A total of 615 patients were screened, of which 504 were randomized. A total of 444 patients (88.1%) completed 24 weeks of the study. 64.9% of patients were on current DMARD therapy (83.5% methotrexate), 23.6% had previous biologic therapy exposure (9.3% were previous biologic failures). There were no significant differences between the three treatment groups at baseline.

At week 16, there were statistically significant improvements in ACR20 response in both apremilast groups compared with placebo. An ACR20 was seen in 19.4% (32/165) in the placebo group whilst it was 31.3% (51/163) (p = 0.014) on apremilast 20 mg bd and 39.8% (64/161) (p = 0.0001) on apremilast 30 mg bd. This was also seen when intention-to-treat analysis was applied (apremilast 20 mg bd 30.4% (51/168) (p = 0.0166), apremilast 30 mg bd 38.1% (64/168) (p = 0.0001), and placebo 19.0% (32/168)). Patterns of a higher absolute ACR20 response were seen in biologic-naïve patients and with the higher apremilast dosage, but no statistical analysis of this was carried out.

Improvements in HAQ-DI were also seen with apremilast. For the per protocol population, mean absolute reduction in HAQ-DI at week 16 was −0.09 [ standard error (SE) 0.04] for placebo. For apremilast 20 mg it was −0.20 (SE 0.04) and for apremilast 30 mg −0.25 (SE 0.04). Results were very similar in the intention-to-treat population [placebo −0.09 (SE 0.04), apremilast 20 mg −0.20 (SE 0.04), apremilast 30 mg −0.24 (SE 0.04)]. Measurements of minimum clinically important differences (MCIDs) in HAQ-DI of >0.13 and >0.30 showed improvements in the apremilast 30 mg group over placebo but not in the apremilast 20 mg group (MCID > 0.13: placebo 28.8%, apremilast 20 mg 44.8%, apremilast 30 mg 50.3%, MCID > 0.30: placebo 27.3%, apremilast 20 mg 33.7%, apremilast 30 mg 39.8%).

In patients with enthesitis at baseline, the mean change from baseline on the Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) was also recorded at week 24. This was found to be significantly greater than placebo in the apremilast 30 mg group (−1.7 versus −0.8, p = 0.0334) but not in the apremilast 20 mg group (−1.6 versus −0.8,p = 0.0678). The percentage achieving a MASES score of 0 at week 24 was significantly greater in both the apremilast 30 mg group [36/107 (33.6%)] and the apremilast 20 mg group [32/100 (32.0%)] than placebo [14/97 (14.4%)].

In patients with baseline dactylitis, there was a statistically nonsignificant observation of a greater proportion achieving a dactylitis score of 0 at 24 week in the apremilast 30 mg group (31/65, 47.7%) and apremilast 20 mg group (29/57, 50.9%) than placebo (27/66, 40.9).

In those with baseline psoriasis affecting >3% of body surface area, a greater proportion of patients in both apremilast groups achieved PASI-50 and Psoriasis Area and Severity Index (PASI)-75 responses than the placebo group (apremilast 20 mg 33.8% PASI-50, 17.6% PASI-75; apremilast 30 mg 50.6% PASI-50, 21.0% PASI-75; placebo 18.5% PASI-50, 4.6% PASI-75.) At both drug doses, both outcomes were statistically significantly different from placebo [Kavanaugh et al. 2015]

PALACE 1 long-term follow up

Patients entered into PALACE 1 have been followed up for up to 2 years. Results of 52 and 104-week outcomes have been presented.

Of the 444 patients who completed the 24 weeks of the initial trial, 428 entered the next phase of the trial and 373 (87.1%) of these completed 52 weeks. Half of participants received each of the doses of apremilast used in the initial trial.

At week 52, ACR20 responses were seen in 54.6% for apremilast 20 mg bd, and 63.0% for apremilast 30 mg bd. Therefore, in those who continued treatment, ACR20 responses were maintained. Results for mean change in HAQ-DI were also comparable [−0.37 (SE 0.48) for apremilast 20 mg and −0.32 (SE 0.55) for apremilast 30 mg], and minimum significant improvements in HAQ-DI. Improvements in enthesitis scores, dactylitis scores and PASI-50 and PASI-75 were also maintained to week 52.

PALACE 1 was continued as an open-label follow up to complete 2 years. A total of 285 of the original patients randomized completed 2 years of follow up (144 on apremilast 30 mg, 173 on apremilast 20 mg). In those who completed the second year, ACR20 responses were 60.9% (84/138) for apremilast 20 mg and 65.3% for apremilast 30 mg (94/144). ACR50 responses (32.4% apremilast 20 mg, 34.0% apremilast 30 mg) and ACR70 responses (16.5% apremilast 20 mg, 19.6% apremilast 20 mg) were also comparable between the two doses.

At week 104, mean changes in swollen joint count and tender joint count were also reported with both groups (mean 77.3% decrease Swollen Joint Count (SJC) and 71.0% decrease Tender Joint Count (TJC) with apremilast 30 mg, mean 67.7% decrease SJC and 67.1% decrease TJC with apremilast 20 mg). HAQ-DI responses at week 52 were also maintained to week 104 (−0.41 with apremilast 30 mg and −0.31 with apremilast 20 mg) [Mease et al. 2015].

PALACE 2

PALACE 2 was a randomized controlled trial with an identical design to PALACE 1.

A total of 488 patients were enrolled and 484 received at least one dose of the study drug, 159 were randomized to placebo, 163 to apremilast 20 mg bd and 162 to apremilast 30 mg bd. As with PALACE 1 those on placebo were re-randomized at week 16 (‘early escape’) or at week 24, to either dose of apremilast.

Results were presented at the ACR Meeting in October 2013 [Cutolo et al. 2013].

At week 16, there were statistically significant improvements in ACR20 response in both apremilast groups compared with placebo. ACR20 was seen in 19.5% in the placebo group. It was 38.4% (p = 0.0002) on apremilast 20 mg bd and 34.4% (p = 0.0024) on apremilast 30 mg bd.

A total of 237 patients completed 1 year on apremilast. At week 52, ACR20 response was achieved in 52.9% of patients on apremilast 20 mg bd, and in 52.6% of those on apremilast 30 mg bd. The patients who continued treatment for 1 year maintained their ACR20 responses. Results for mean change in HAQ-DI were also comparable [−0.192 from baseline (SE 0.573) for apremilast 20 mg and −0.330 (SE 0.509) for apremilast 30 mg]. Improvements in enthesitis scores, dactylitis scores and PASI-50 and PASI-75 were also maintained to week 52.

No new safety signals were identified and the study is planned to run for up to 4.5 years to assess the long-term safety aspects.

PALACE 3

PALACE 3 was a randomized controlled trial with almost identical design to that of PALACE 1 and 2. For enrolment to PALACE 3, patients had to fulfill criteria for PALACE 1 and 2 but were also required to have ⩾1 psoriasis plaque measuring ⩾2 cm in diameter. All other inclusion and exclusion criteria were identical to PALACE 1.

A total of 505 patients were enrolled, 169 were randomized to apremilast 20 mg bd, 167 to apremilast 30 mg bd, and 169 to placebo. As with PALACE 1 and PALACE 2, those on placebo were re-randomized at week 16 (‘early escape’) or week 24, to either dose of apremilast.

Results at week 52 and week 104 were presented to the European League Against Rheumatism (EULAR) in 2015. ACR20 responses with apremilast 20 mg were 56.4% at 52 weeks and 63.2% at week 104. With apremilast 30 mg, these were 61.3% and 66.5% respectively. Mean % change in SJC and TJC also fell in both groups. With apremilast 20 mg the decrease in SJC was −63.8% at 1 year and −72.6% at 2 years. For apremilast 30 mg, −57.6% at 1 year and −74.7% at the end of year 2. The results for TJC were −51.3% at 1 year and −59.2% at 2 years for apremilast 20 mg and −55.3% at 1 year and −66.5% at 2 years for apremilast 30 mg.

Improvements in PASI-50 and PASI-75 for those patients with significant psoriasis (n = 186) were also reported. (PASI-50 54.0% for apremilast 20 mg and 54.5% for apremilast 30 mg, at week 52). These improvements were sustained at week 104. As with PALACE 1, improvements in HAQ-DI were seen at both doses. Mean change −0.33 on apremilast 20 mg and −0.35 on apremilast 30 mg at week 52. At week 104, results were similar (−0.36 for apremilast 20 mg, −0.41 for apremilast 30 mg) [Edwards et al. 2015].

PALACE 4

PALACE 4, the last of the four placebo-controlled randomized controlled trials carried out for apremilast, included only patients who had not taken traditional DMARD therapy in the past. It was therefore a study comparing apremilast with placebo in DMARD and biologic-naïve PsA patients.

A total of 527 patients were recruited (175 received apremilast 20 mg bd, 176 apremilast 30 mg bd, and 176 received placebo). As with PALACE 1–3, placebo patients were switched to either dose of apremilast at weeks 16 or 24.

Endpoints measured at week 52, showed ACR20 response with apremilast 30 mg was achieved in 58.0% (119/205). With apremilast 20 mg bd, ACR20 was achieved in 55.4% (107/193). Follow up to week 104 showed this response rate was maintained (61.4% with apremilast 30 mg and 64.2% with apremilast 20 mg). Mean percentage improvement in SJC was −70.5% at week 52 and −77.2% at week 104 with apremilast 20 mg bd. With apremilast 30 mg bd, it was −76.1% and −79.8%, respectively. TJC reduced by a mean of −52.8% at 1 year and −60.9% at 2 years with apremilast 20 mg. With apremilast 30 mg, the mean change was −59.4% at year 1 and −64.0% at end of year 2.

HAQ-DI improvements were similar at the two doses. With 20 mg bd dose, the mean improvement was −0.28 at week 52 and −0.33 at week 104. With apremilast 30 mg, the change was −0.35 at 1 year and −0.38 at 2 years.

PALACE 4 also reported sustained responses in PASI 50/PASI 75, as well as enthesitis scores and dactylitis scores. For those with baseline enthesitis, the percentage achieving a MASES score of 0 was 39.4% at 52 weeks and 58.3% at week 104 (apremilast 20 mg bd). For apremilast 30 mg, the percentage achieving a 0 score was 51.2% at week 52 and 61.4% at week 104 [Wells et al. 2015].

The PALACE study groups have also presented results on work productivity measures in the patients recruited to PALACE 1–3. This was based on data collected using the work limitations questionnaire (WLQ). Recruits completed this questionnaire including questions regarding their employment across four domains: physical demands, mental demands, time management, and output demands. At week 16, where the primary outcomes were measured, there were significant improvements from baseline seen in both apremilast groups. This improvement was found to be sustained at week 52 [Zhang et al. 2015].

Safety profile of apremilast

In PALACE 1 there was a low incidence of adverse events (AEs) and most AEs were mild or moderate. Discontinuation in the trial due to AEs was 6.0% (10/168) in the apremilast 20 mg group, 7.1% (12/168) in the apremilast 30 mg group, and 4.8% (8/168) in the placebo group. The only AEs reported in >5% of patients in any treatment group were: diarrhoea, nausea, headache and upper respiratory tract infections.

Discontinuation due to gastrointestinal AEs was rare (1.8% (3/168) with apremilast 20 mg, 4.2% (7/168) with apremilast 30 mg and 2.4% (4/168) with placebo). Reported diarrhoea occurred in 51 patients (56 events) on apremilast. Median onset was 9 days after starting the drug and median duration was 29.5 days. There were 59 events of nausea in 47 patients. Median onset was 10 days and median duration 17 days.

Few serious AEs (SAEs) occurred. There were 4 serious infections: 2 occurred on placebo and 2 in the apremilast 30 mg group (1 pneumonia and 1 clostridium gastrointestinal infection). All four patients continued in the study. There were 2 myocardial infarctions (1 on placebo, 1 on apremilast 20 mg), 2 malignancies (1 placebo, 1 apremilast 30 mg). Overall, one patient died during the study (apremilast 20 mg group). The cause of death was multi-organ failure secondary to pre-existing vitamin B12 deficiency and was considered unrelated to the study medication by the investigator. There were no case cases of tuberculosis (new or reactivation), lymphoma or vasculitis.

There were few blood screening abnormalities detected. Of note, leucopaenia (white cell count falling below normal laboratory range) occurred in 0.6% with placebo, 2.6% on apremilast 20 mg and 1.3% with apremilast 30 mg.

Weight loss was observed with apremilast treatment. Mean (SD) weight change at 24 weeks was 0.19 (2.6) kg with placebo (n = 166). With apremilast 20 mg it was −1.29 (3.4) kg (n = 166), and with apremilast 30 mg −0.97 (2.8) kg (n = 168) [Kavanaugh et al. 2014].

Longer-term safety data from PALACE 1

In following up patients included in the active treatment phase of PALACE 1, low levels of AEs were recorded. Rates of discontinuation due to AEs were <10% in all treatment groups. The vast majority of reported AEs were mild or moderate in severity.

Gastrointestinal AEs were infrequently reported (<2% discontinued due to diarrhoea or nausea). Between weeks 24–52, 7 patients reported nausea (5 apremilast 20 mg, 2 apremilast 30 mg) and 5 reported diarrhoea (2 apremilast 20 mg, 3 apremilast 30 mg). Reported events of diarrhoea typically occurred within 2 weeks of starting treatment and resolved within 4 weeks.

There were few SAEs. No SAE was reported in >1 patient, with the exception of myocardial infarction (MI) which occurred in 2 patients. The one patient that was initially in the placebo group, switched to apremilast 20 mg and after 62 days (day 231 of trial) suffered an MI. The other patient was randomized to apremilast 20 mg and suffered an MI on day 39. Neither cardiac event was considered to be related to the study treatment.

There was one SAE of nausea in the apremilast 30 mg group. Of patients treated with apremilast from baseline, there were 5 SAEs between weeks 24–52 (1 case each of endometriosis and appendicitis with apremilast 20 mg, and single cases of gastroenteritis, MI and osteoarthritis with apremilast 30 mg.) At week 52, there had only been 5 SAEs related to infections. During weeks 0–24, there was 1 pneumonia, and 1 gastrintestinal clostridium infection (both apremilast 30 mg), and during weeks 24–52, 1 pneumonia and 1 appendicitis (both apremilast 20 mg), and 1 episode of gastroenteritis on apremilast 30 mg. There was 1 case of skin cancer. There were no cases of tuberculosis or lymphoma reported.

There were 6 discontinuations due to SAEs; 2 in the placebo group (abnormal thinking, prostate carcinoma); 1 in the apremilast 20 mg group due to MI; 3 in the apremilast 30 mg group (deep vein thrombisos and acute hypertension, hypertensive crisis, and gastrointestinal clostridial infection).

Blood monitoring over 52 weeks of apremilast treatment identified no significant problems. There were two patients noted to have elevations in alanine aminotransferase and 2 had falls in haemoglobin on apremilast 30 mg but changes were small.

Weight loss was observed in patients on apremilast at 52 weeks. The decrease in weight from baseline was 1.6% on apremilast 20 mg (1.8% at 24 weeks) and 2.0% on apremilast 30 mg (1.8% at week 24). Mean change in weight was −1.79 kg on apremilast 30 mg bd. Those with a weight loss of >5% from baseline, were 17.2% on apremilast 30 mg and 15.8% on apremilast 20 mg [Adebajo et al. 2015]

PALACE 1–3 pooled safety data

Safety data pooled across the three studies PALACE 1, 2, 3 have been presented [Mease et al. 2015]. This included 1493 patients, including 501 patients who took apremilast 20 mg and 497 patients who took apremilast 30 mg. It was calculated that this incorporated an exposure of 1209.3 patient years during weeks 0–52, and 907.7 patient years for weeks 52–104.

In weeks 0–52, the only AEs seen in ⩾5% patients were diarrhoea, nausea, headache, upper respiratory tract infection and nasopharyngitis. In weeks 52–104, none were seen in ⩾5% of patients. The most frequent AEs were diarrhoea (2.9%), nausea (1.8%) and headache (3.0%).

Most AEs were mild. Severe AEs were rare. In weeks 0–52, SAEs were 7.6% in apremilast 30 mg and 6.0% with apremilast 20 mg. In weeks 52–104, rates of SAEs were 4.6% on apremilast 30 mg, and 5.7% on apremilast 20 mg. In weeks 52–104, rates of discontinuation due to AEs was low (2.3%). There were no events of tuberculosis.

Depression was screened for. There was a co-morbid depression in 14.5% at baseline. New events of depression on apremilast were seen in 24 patients (1.7%) in weeks 0–52, and in 15 (1.5%) during weeks 52–104

Safety data from PALACE 4

PALACE 4 reported low levels of AEs and SAEs. Again, diarrhoea and nausea were the two most commonly reported side effects. In the first year of therapy, these were reported in 10.3% of those on apremilast 20 mg and 10.9% of those on 30 mg. For those continuing in the trial for a second year, the rates were very low in year 2 (apremilast 20 mg 2.6% and apremilast 30 mg 1.9%). In PALACE 4, discontinuation due to AEs was rare. With apremilast 20 mg; 5.6% in year 1, 1.7% in year 2. With apremilast 30 mg; 5.2% in year 1, 3.5% in year 2 [Wells et al. 2015]

Comparative efficacy

There has been considerable interest in the comparative efficacy of apremilast versus both traditional DMARD and biologic therapies. An indirect comparison and cost per responder analysis for adalimumab, methotrexate and apremilast in the treatment of methotrexate-naïve patients with PsA has been carried out [Betts et al. 2016]. The number needed to treat (NNT) to achieve an ACR20 response in methotrexate-naïve patients to be 2.63 for adalimumab, 6.69 for apremilast and 8.31 for methotrexate based on data from the Adalimumab Effectiveness in Psoriatic Arthritis (APEPT) trial for adalimumab [Mease et al. 2005], PALACE 4 for apremilast [Wells et al. 2015] and the Methotrexate in Psoriatic Arthritis (MIPA) trial for methotrexate [Kingsley et al. 2012].

In patients with PsA who have an inadequate response to anti-TNF an indirect comparison of the efficacy of apremilast, abatacept, secukinumab and ustekinumab found no significant difference in ACR20 response rate between the agents [Ungprasert et al. 2016].

Cost

Apremilast has a high cost compared with traditional DMARD therapy and is closer in price to the biologic therapies. The incremental costs per ACR20 responder in methotrexate-naïve patients were calculated at USD 45,808 for apremilast compared with USD 3622 for methotrexate and USD 26,316 for adalimumab. The incremental costs per ACR20 responder were USD 222,488 for apremilast versus methotrexate [Betts et al. 2016].

Conclusion

Apremilast has been investigated in the largest clinical trials carried out in PsA and been found to have a favorable safety profile and efficacy across a broad range of the clinical features of psoriatic disease. The efficacy is lower than would be anticipated with biologic therapies with a higher NNT to achieve an ACR20 response compared with adalimumab, but the favourable safety profile demonstrated in the studies would seem to position apremilast as an alternative to biologic therapy in patients perceived to be at high risk of infections or with other caution or contraindication.

Compared to traditional DMARD apremilast has better data to demonstrate efficacy from the clinical studies and has the benefit of not requiring routine therapeutic drug monitoring. Despite this, as it is significantly more expensive than the other current therapies, it would seem likely to remain a second or third line therapy.

The data regarding weight loss is intriguing, we are increasingly concerned about the rates of obesity in patients with psoriatic disease and the association with metabolic syndrome and cardiovascular disease. The suggestion that a therapy could have a positive impact on weight loss raises the hope that this could reduce some of the comorbidities associated with PsA.

Footnotes

Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement: DC has received speaker fees from Celgene within the UK to a total of less tan £3000. MR has no conflicts of interest in preparing this article.

Contributor Information

Michael Reed, Department of Rheumatology, Queen Elizabeth University Hospital, UK.

David Crosbie, Department of Rheumatology, Queen Elizabeth University Hospital, 1345 Govan Road, Glasgow G51 4TF, UK.

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