Efficacy and safety of apremilast and phototherapy versus phototherapy only in psoriasis vulgaris

Abstract Phototherapy and apremilast (oral phosphodiesterase‐4 inhibitor) are well‐known in the treatment of moderate to severe psoriasis vulgaris. However, current evidence on the efficacy and safety of their combination is not sufficient. This multicenter, randomized controlled study compared the efficacy and safety between phototherapy as monotherapy and phototherapy and apremilast as combination therapy in patients with psoriasis vulgaris. Patients with moderate to severe psoriasis vulgaris were assigned to combination (n = 29) and monotherapy (n = 13) groups. All patients underwent an 8‐week phototherapy regimen comprising irradiation with narrowband UV‐B. The patients in the combination group were also administered 10 mg to 60 mg of oral apremilast. We evaluated the improvement percentage based on the Psoriasis Area and Severity Index (PASI) score from baseline to week 8. Additionally, we evaluated the percentage of patients who achieved ≥75% improvement; changes in body surface area (BSA) and scores of EuroQol 5‐dimensions 5‐level, Dermatology Life Quality Index, and visual analog scale for pruritis from baseline to 4 and 8 weeks; and adverse events. Compared with the monotherapy group, the combination group had significantly lower PASI scores at 4 and 8 weeks and more patients who achieved a PASI score improvement of ≥75% at 8 weeks. Both groups exhibited a significant decrease in BSA; at 8 weeks, no significant difference was observed between the two groups, although the combination group tended toward a greater reduction in BSA. The intergroup differences in the changes at the three time points were not significant. Adverse events were more frequent in the combination group than in the monotherapy group. Our findings suggest that an 8‐week combined apremilast and phototherapy regimen may not be adequate in patients for improvements in their subjective assessment of psoriasis, and longer treatment periods may be necessary.

controlled study compared the efficacy and safety between phototherapy as monotherapy and phototherapy and apremilast as combination therapy in patients with psoriasis vulgaris. Patients with moderate to severe psoriasis vulgaris were assigned to combination (n = 29) and monotherapy (n = 13) groups. All patients underwent an 8-week phototherapy regimen comprising irradiation with narrowband UV-B. The patients in the combination group were also administered 10 mg to 60 mg of oral apremilast. We evaluated the improvement percentage based on the Psoriasis Area and Severity Index (PASI) score from baseline to week 8. Additionally, we evaluated the percentage of patients who achieved ≥75% improvement; changes in body surface area (BSA) and scores of EuroQol 5-dimensions 5-level, Dermatology Life Quality Index, and visual analog scale for pruritis from baseline to 4 and 8 weeks; and adverse events. Compared with the monotherapy group, the combination group had significantly lower PASI scores at 4 and 8 weeks and more patients who achieved a PASI score improvement of ≥75% at 8 weeks. Both groups exhibited a significant decrease in BSA; at 8 weeks, no significant difference was observed between the two groups, although the combination group tended toward a greater reduction in BSA. The intergroup differences in the changes at the three time points were not significant. Adverse events were more frequent in the combination group than in the monotherapy group. Our findings suggest that an 8-week combined apremilast and phototherapy regimen may not be adequate in patients for improvements in their subjective assessment of psoriasis, and longer treatment periods may be necessary.

K E Y W O R D S
apremilast, phosphodiesterase-4 inhibitor, phototherapy, psoriasis, Psoriasis Area and Severity Index

| INTRODUC TI ON
Inflammatory cytokines, mainly tumor necrosis factor α (TNFα); interleukin (IL) 1, IL-6, IL-8, and IL-36; and T helper 17-related cytokines (IL-17, IL-22, and IL-23) are involved in the pathogenesis of psoriasis. 1 The production of inflammatory cytokines is suggested to involve intracellular signaling through the nuclear factor kappa B transcription factor. 2 Patients with mild to moderate psoriasis are topically treated with corticosteroids and active vitamin D3 derivatives. Systemic treatment is usually considered for patients with moderate to severe psoriasis, and it includes oral medications 3,4 such as apremilast, cyclosporine, and etretinate and phototherapies, such as narrowband UV-B (NB-UVB), excimer light, and psoralen UV-A. 5 Biologics may be used in conjunction with these treatments in severe cases or refractory sites.
Apremilast, a small-molecule oral phosphodiesterase-4 (PDE4) inhibitor that regulates a network of inflammatory and antiinflammatory mediators in cells, was first approved overseas in 2014 and in December 2016 in Japan. Apremilast is effective in moderate to severe plaque psoriasis (psoriasis vulgaris) that has not responded adequately to topical and other treatments. 6 By inhibiting PDE4, apremilast suppresses the inflammatory response by increasing intracellular cyclic adenosine monophosphate levels and regulating the expression of inflammatory cytokines and chemokines, such as TNFα, IL-23, CXCL9, and CXCL10. [7][8][9] The combination of cyclosporine and phototherapy is not usually recommended because of the immune suppressive capacity of cyclosporine. Although the combination of biologics and phototherapy is not currently recommended for psoriasis, targeted phototherapy with biologics may be indicated for psoriatic lesions that persist after treatment 5 ; adalimumab (a biologic preparation) with phototherapy has been reported to be highly effective. 10 On the basis of the different action mechanisms of apremilast and phototherapy, their combined use is expected to exhibit increased efficacy.
We compared the efficacy and safety of the combination therapy-apremilast and phototherapy-with those of the monotherapy-phototherapy-in patients with psoriasis vulgaris.

| Study design and treatment
This was a multicenter, randomized, open-label, parallel-group, active-controlled study conducted at four institutions between November 9, 2018, and February 14, 2020. The study was con- With body surface area (BSA) as an allocation factor, stratified permuted block randomization was used to allocate the patients to the combination therapy group, apremilast and phototherapy, or monotherapy group, phototherapy only, in a 2:1 ratio. Apremilast was orally administered as 10 mg (in the morning), 20 mg (morning: 10 mg, evening: 10 mg), 30 mg (morning: 10 mg, evening: 20 mg), 40 mg (morning: 20 mg, evening: 20 mg), 50 mg (morning: 20 mg, evening: 30 mg) on days 1, 2, 3, 4, and 5, respectively, followed by 60 mg daily since day 6 (morning: 30 mg, evening: 30 mg). NB-UVB (311 ± 2 nm) was administered twice a week per the phototherapy guidelines for psoriasis. 5,11 The initial dose was 50% of the minimal erythema dose or 0.3 to 0.5 J/cm 2 . The dose increment was 0.05 to 0.1 J/cm 2 each time as required, with a maximum dose of 1.5 J/cm 2 .
The treatment period was 8 weeks, and usefulness was evaluated 4 weeks after the first dose.

| Patients
The inclusion criteria comprised the following: (1) age 20 to 80 years; (2) diagnosis of moderate to severe psoriasis vulgaris (BSA or Static Physician's Global Assessment [sPGA] score of ≥5% or ≥3, respec- and (11) ineligibility as determined by the physician.

| Study evaluations
The primary efficacy end point was the improvement rate according     The BSA change rate did not significantly differ between the two groups at 8 weeks, but the decrease in BSA in the combination therapy group tended to be greater.

| Statistical analysis
The rate of sPGA 0/1 achievement, in which the sPGA score was 0 or 1 at each evaluation time, tended to be higher at 4 weeks and significantly higher at 8 weeks in the combination therapy group than in the monotherapy group (p < 0.05) (Figure 4).   (Table 2) and a significantly higher PASI improvement in the PPS (Table 3). In the combination therapy group, there was no effect of the percentage of BSA on PASI improvement, but in the monotherapy group, the higher the percentage of BSA, the lower the PASI improvement.

| Quality of life
The magnitude of changes in the EQ-5D-5L scores did not differ significantly between the two groups at weeks 4 and 8 ( Figure 5).
The DLQI and VAS scores for itchiness did not differ between the two groups in terms of a change from baseline to each evaluation time; however, these scores tended to decrease in the combination therapy group (Table 4).

| Safety
Adverse events were more frequent in the combination therapy group (56 adverse events in 19 patients) than in the monotherapy group (seven adverse events in four patients) ( Table 5).
In addition, three serious adverse events (ileus, goiter, and complete atrioventricular block) were reported in two patients in the combination therapy group, whereas two serious adverse events (septic shock and liver cancer) were reported in one patient in the monotherapy group. A total of 29 adverse drug reactions were reported in 14 patients in the combination therapy group only; however, these were not considered as serious.

| DISCUSS ION
Several studies have demonstrated only moderate efficacy of apremilast monotherapy for psoriasis vulgaris. In two studies in which a 16-week treatment with apremilast monotherapy was administered,  Phototherapy is an effective and relatively reasonable treatment for psoriasis vulgaris with few adverse events. NB-UVB is particularly effective for the treatment of psoriasis, with rapid lesion clearance, fewer excessive erythema episodes, and longer remission periods. 5  first treated with phototherapy. 18 In another study, the Treg cell levels were analyzed in 68 patients before and after phototherapy. 19 Although the Treg cell levels were not increased by phototherapy in any of the 68 patients, they were significantly increased in patients who initially had <4.07% Treg cells, which was defined as the mean in the controls. Assessment of the Treg cell function before and after phototherapy revealed a significantly lower Treg cell function ratio in patients with psoriasis than in age-matched controls before therapy, which was significantly increased  following phototherapy, thereby restoring Treg cell function to almost normal levels. These findings suggest that successful phototherapy not only increases the Treg cell levels but also restores its function. 19 Phototherapy has many advantages in the treatment of psoriasis, but continued use is inconvenient because the effects of the therapy appear only after a long time, and patients are required to frequently visit the clinic for irradiation. Therefore, the combination of phototherapy with other modalities should be considered. In this study, the combination of apremilast and phototherapy demonstrated sufficient therapeutic effects in psoriasis despite the reduced frequency of visits to the clinic, which may have considerable implications in clinical practice.
We compared the efficacy and safety of apremilast and phototherapy combination therapy with those of phototherapy as monotherapy in patients with moderate to severe psoriasis vulgaris. The primary end point was PASI improvement from baseline to 8 weeks; the combination of apremilast and phototherapy achieved a higher rate of improvement than with monotherapy. Moreover, if the analysis set was the PPS, the PASI improvement rate was significantly higher in the combination therapy group than in the monotherapy group when the missing values were supplemented with or without LOCF.
In the combination therapy group, the BSA percentage at baseline did not affect the PASI improvement rate; however, in the monotherapy group, the PASI improvement rate decreased when the baseline percentage of BSA was higher. This may indicate that monotherapy is not sufficiently effective in patients with a high BSA ratio at the start of the treatment and that the effects of apremilast complement the limitations of the phototherapy monotherapy with NB-UVB.
The PASI score, change from baseline, and rate of change in the BSA improved over time in both of the treatment groups, suggesting that phototherapy as monotherapy and in combination with apremilast is effective in the treatment of psoriasis vulgaris. The rates of PASI75 achievement and sPGA0/1, which are frequently used as end points in clinical trials, tended to be higher at 4 weeks and significantly higher at 8 weeks in the combination therapy group than in the phototherapy monotherapy group, suggesting that combined treatment with apremilast and phototherapy may be effective against psoriasis over a shorter period.
In the present study, the EQ-5D-5L, DLQI (indicators of the patient's quality of life), and VAS (an indicator of itchiness) scores did not differ significantly between the two groups but tended to decrease in the combination therapy group. These findings suggest that an 8-week treatment regimen may not be sufficient in patients for an improvement in their subjective assessment of psoriasis, and longer treatment periods may be necessary.
Our findings indicate that phototherapy as monotherapy was insufficient in patients with high baseline BSA, and concomitant administration of apremilast improved the outcomes. However, an 8- week treatment regimen, may be insufficient for inducing subjective improvement.