Abstract
OBJECTIVES:
Apremilast, proven to be effective against psoriasis, has many side effects at the standard dose of 30 mg, impacting adherence. Hence, we aimed to compare the lower doses (10 mg and 20 mg) to the 30 mg apremilast dose. Primary objectives were to compare psoriasis area and severity index (PASI) 75 response and adverse events (AEs) in apremilast 30 mg versus 20 mg, and 30 mg versus 10 mg from baseline to 16th week.
METHODS:
In this randomized, active-controlled trial, 124 patients with mild to moderate psoriasis were randomized (1:1:1 ratio) to apremilast 10 mg, 20 mg, or 30 mg twice daily for 16 weeks. Efficacy parameters were evaluated at 16th week, and safety was monitored every 2 weeks.
RESULTS:
At week 16, PASI 75 response was comparable between apremilast 30 mg (31.7%) and 20 mg (28.6%) (P = 0.756), but significantly higher than 10 mg (9.8%) (P = 0.014). Apremilast 30 mg and 20 mg demonstrated comparable static physician global assessment 0/1 responses (39% vs. 31%, P = 0.441), whereas 30 mg significantly outperformed 10 mg (12.2%, P = 0.005). Common AEs observed in all groups were nausea and headache. Apremilast 30 mg exhibited significantly more AEs than 20 mg (P = 0.023) and 10 mg (P = 0.001).
CONCLUSION:
Apremilast 20 mg demonstrated comparable efficacy with significantly fewer side effects than the 30 mg dose in mild-to-moderate psoriasis, while apremilast 10 mg showed no significant improvement in efficacy compared to the 30 mg dose.
Keywords: Apremilast, dermatology, psoriasis, randomized trial
Introduction
Psoriasis, a chronic immune-mediated inflammatory disorder, is characterized by irregular keratinocyte proliferation, encompassing both innate and adaptive immunity.[1] Prevalence of psoriasis is 2%–4% in the Western population and 3% in >20 years old adults in the United States.[2,3] In India, psoriasis has a prevalence of 0.44%–2.8%, predominantly in the third or fourth decade of life. Familial predisposition is present in one-third of individuals having a first-degree relative with psoriasis. Onset and exacerbation of psoriasis are influenced by an array of environmental factors, psychological and physiological stressors.[4] Non-dermatologic manifestations include psoriatic onychodystrophy affecting 80%–90% of psoriasis patients, and psoriatic arthritis (PsA), which develops on average 12 years after onset of skin lesion.[4] Psoriasis patients face an increased risk of comorbidities such as immune-mediated inflammatory conditions, malignancy, obesity, metabolic syndrome, and depression. The impact on quality of life (QOL) by psoriasis surpasses that of life-threatening chronic diseases.[4]
Apremilast, a phosphodiesterase-4 (PDE-4) inhibitor, hinders the cyclic adenosine monophosphate (cAMP) conversion to AMP, leading to intracellular cAMP accumulation. The selective inhibition of PDE-4 on the innate immune response reduces the production of inflammatory mediators, resulting in decreased inflammatory response.[5] Apremilast has demonstrated efficacy in psoriasis treatment in the standard dose of 30 mg. Common adverse effects due to apremilast include gastrointestinal symptoms, such as diarrhea and nausea, along with other adverse effects, including headache, upper respiratory tract infection (URTI), vomiting, and fatigue.[5]
Kavanaugh et al. and Edwards et al. observed a high proportion of patients on both apremilast 20 mg BD (twice daily) and 30 mg BD achieving reduction from baseline in psoriasis area and severity index (PASI) 75 score compared to placebo.[6,7] Despite the efficacy of apremilast, its standard 30 mg BD dosing regimen poses challenges due to frequent side effects, thereby reducing treatment adherence and overall therapeutic success. The UNVEIL study by Strober et al. revealed that the apremilast 30 mg group experienced more adverse events (AEs) than the placebo group.[8] Our study aimed to address this issue by exploring lower doses (10 mg and 20 mg) of apremilast, assessing their efficacy and safety compared to the standard 30 mg regimen. The current literature lacks studies on the impact of reduced apremilast concentrations. Hence, we intended to bridge this knowledge gap and provide valuable insights into the potential benefits of lower doses of apremilast.
Subjects and Methods
This randomized, parallel group, active-controlled, open-label trial was conducted in a tertiary healthcare centre in India with the aim to compare the efficacy and safety of apremilast 10 mg and 20 mg to the standard 30 mg dose among patients with mild to moderate psoriasis. Psoriasis patients of both sex and age 18–65 years with PASI < 10,[9] body surface area (BSA) < 10%,[10] and willing to provide written informed consent were included in the trial. Exclusion criteria included pregnant and lactating women, pustular psoriasis, PASI > 10, BSA > 10%, any significant medical (recent myocardial infarction, congestive heart failure, chronic renal failure, chronic liver disease) and surgical conditions, patients with significant hepatic impairment, renal insufficiency, and known hypersensitivity to apremilast.
Primary outcomes were the percentage of patients achieving PASI 75 in apremilast 30 mg versus 20 mg and 30 mg versus 10 mg from baseline to week 16, and the safety profile. Secondary outcomes included the percentage of PASI 90, percentage of PASI 50, change in visual analogue scale (VAS) scores,[11] change in dermatology life quality index (DLQI),[10] percentage of static physician global assessment (sPGA) score 0 or 1,[12] change in sPGA scores, erythema scaling induration (ESI) score,[13] change in PsA response criteria (PsARC),[14] change in nail psoriasis severity index (NAPSI) score,[10] difference in lipid parameters and tolerability profile using Common Terminology Criteria for AEs version 5.0 (CTCAE v5.0)[15] in apremilast 30 mg versus apremilast 20 mg and apremilast 30 mg versus 10 mg at 16th week.
Following the institutional ethics committee approval (AIIMS/IEC/2022/4083) and trial registration in the Clinical Trials Registry-India (CTRI/2022/09/045573), 124 patients were enrolled after obtaining written informed consent. Patients were randomized using variable block randomization generated in R software in a 1:1:1 ratio to receive apremilast 10 mg, apremilast 20 mg, or apremilast 30 mg, twice daily for 16 weeks. Allocation concealment involved telephonically contacting a healthcare professional for each recruitment who remained blinded to patient recruitment and assessment till the completion of the study. To reduce GI side effects from apremilast, a gradual titration schedule was followed, starting with 10 mg on Day 1, incrementally reaching 20 mg twice daily and 30 mg twice daily by Day 4 and 6, respectively [Supplementary Figure 1 (35.7KB, jpg) ]. Efficacy parameters, including PASI, VAS, DLQI, sPGA, NAPSI, ESI, and PsARC, were measured at baseline and during each follow-up (1st, 2nd, 3rd, and 4th month). Additionally, lipid profiles were assessed at baseline and 4th month. AEs and CTCAE v5.0 were recorded every 2 weeks through telephonic communication and at the time of each follow-up. Non-responsive patients after 16 weeks of trial were treated with methotrexate.
Statistical analysis
Assuming a proportion of 12% and 40% of patients reaching PASI 75 in the standard and apremilast treatment groups, with an alpha error of 5% and 80% power based on Reich et al.,[16] sample size was estimated to be 37 per group. Thus, a total of 123 patients were needed, assuming 10% drop out rate. Due to the nature of variable block randomization, we totally recruited 124 patients in our study. The Statistical Package for the Social Sciences (SPSS) Statistics, Version 21, IBM Corporation, Armonk, New York was used for data analysis. Missing data were imputed using serial mean method and normality of data distribution was assessed using Kolmogorov–Smirnov test. Descriptive statistics were reported as mean ± standard deviation (SD) for continuous variables and as number or percentage for categorical data. Paired t-test was used to assess within-group comparisons for apremilast dose groups, and unpaired t-test for between-group comparisons. Categorical data were analysed using Chi-square test or fisher exact test, as applicable. P < 0.05 was considered statistically significant.
Results
Upon screening 210 individuals for eligibility, 124 patients were randomized to receive apremilast 10 mg (41 patients), 20 mg (42 patients), or 30 mg (41 patients) twice daily for 16 weeks from March 2022 to November 2023. Figure 1 depicts the CONSORT flow chart of the trial. Baseline characteristics of participants in the three groups were statistically comparable with P > 0.05 [Table 1].
Figure 1.
CONSORT flow chart. n = Number of patients
Table 1.
Baseline characteristics of the study
| Apremilast 30 mg (N=41), mean±SD | Apremilast 20 mg (N=42), mean±SD | Apremilast 10 mg (N=41), mean±SD | P | |
|---|---|---|---|---|
| Age (years) | 38.3±13.5 | 35.7±15.7 | 38.2±16.2 | 0.677 |
| Malea | 32 (78) | 30 (71.4) | 30 (73.2) | 0.776 |
| Femalea | 9 (22) | 12 (28.6) | 11 (26.8) | |
| Duration of psoriasis (years) | 6.5±5.8 | 4.9±4.3 | 4.2±4.9 | 0.107 |
| Body surface area (m2) | 3.8±1.8 | 4±1.8 | 4.2±2 | 0.626 |
| Koebner phenomenona | 26 (63.4) | 23 (54.8) | 24 (58.5) | 0.725 |
| Nail involvementa | 21 (51.2) | 20 (47.6) | 22 (53.7) | 0.858 |
| Scalp involvementa | 27 (65.9) | 24 (57.1) | 23 (56.1) | 0.612 |
| Joint involvementa | 5 (12.2) | 6 (14.3) | 7 (17.1) | 0.923 |
| Lipid profile (mg/dL) | ||||
| Total cholesterol | 187.14±11.5 | 191.31±14.29 | 187.73±11 | 0.254 |
| Triglycerides | 136.67±24.55 | 130.24±12.17 | 134±13.48 | 0.43 |
| HDL cholesterol | 52.48±8.17 | 53±12.85 | 53.78±13.57 | 0.882 |
| LDL cholesterol | 114.61±12.23 | 113.98±13.43 | 114.07±11.38 | 0.969 |
| VLDL cholesterol | 30.22±5.98 | 30.83±5.13 | 31.12±4.76 | 0.735 |
| Efficacy parameters | ||||
| PASI | 4.8±2.2 | 4.6±1.5 | 4.7±1.3 | 0.883 |
| ESI | 4.88±1.65 | 5.33±1.57 | 5.34±1.59 | 0.327 |
| sPGA | 2.76±0.43 | 3±0.58 | 3.02±0.47 | 0.051 |
| VAS | 6.24±1.24 | 6.05±1.13 | 6.10±1.22 | 0.741 |
| NAPSI | 18.86±11.94 | 19.60±16.62 | 15.95±9.19 | 0.621 |
| DLQI | 19.83±4.90 | 19.17±3.60 | 18.61±3.80 | 0.413 |
aFrequency (%). Values are represented as mean±SD or frequency (%). DLQI=Dermatology Life Quality Index, ESI=Erythema Scaling Induration score, HDL=High density lipoprotein, LDL=Low density lipoprotein, NAPSI=Nail Psoriasis Severity Index, N=Total number of patients in each group, n=Number of patients, PASI=Psoriasis area and severity index score, SD=Standard deviation, sPGA=Static physician’s global assessment, VAS=Visual Analogue Scale, and VLDL=Very LDL
Efficacy results
PASI scores
Apremilast at 30 mg versus 20 mg demonstrated statistically comparable efficacy in achieving PASI 75 response (31.7% vs. 28.6%, P = 0.756), whereas the 10 mg group showed significantly lower PASI 75 against the 30 mg group (9.5%, P = 0.014) [Table 2 and Supplementary Figure 2 (44.1KB, jpg) ] in mild-to-moderate psoriasis. Similarly, apremilast 30 mg versus 20 mg showed comparable PASI 90 (24.4% vs. 16.7%, P = 0.383) and PASI 50 (56.1% vs. 57.1%, P = 0.92) responses. The 10 mg group had a significantly lower PASI 90 (7.3%, P = 0.034) and PASI 50 (26.8%, P = 0.007) responses compared to the 30 mg group.
Table 2.
Comparison of psoriasis area and severity index score (PASI) 75, PASI 90, PASI 50, Static physician’s global assessment 0/1 and Psoriatic Arthritis Response Criteria responses achieved at 16th week in three groups
| Parameters | Apremilast 30 mg (N=41), frequency (%) | Apremilast 20 mg (N=42) frequency (%) | P (two-sided) for 30 mg versus 20 mga | Apremilast 10 mg (N=41), frequency (%) | P (two-sided) for 30 mg versus 10 mga |
|---|---|---|---|---|---|
| PASI 75 | 13 (31.7) | 12 (28.6) | 0.756 | 4 (9.5) | 0.014 |
| PASI 90 | 10 (24.4) | 7 (16.7) | 0.383 | 3 (7.3) | 0.034 |
| PASI 50 | 23 (56.1) | 24 (57.1) | 0.92 | 11 (26.8) | 0.007 |
| sPGA 0/1 | 16 (39) | 13 (30.9) | 0.441 | 13 (12.2) | 0.005 |
| PsARCb | 3 (60) | 3 (50) | 1.00 | 0 | 0.045 |
aIntergroup comparisons for individual parameters carried out by Chi-square test or Fisher’s exact test, as applicable, bNumber of patients for PsARC are 5, 6, and 7 in 30 mg, 20 mg, and 10 mg groups, respectively. Values are represented as frequency and percentage. N=Number of patients, PASI=Psoriasis Area and Severity Index score, PsARC=Psoriatic Arthritis Response Criteria, sPGA=Static physician’s global assessment
Static physician global assessment scores
No significant difference in sPGA 0/1 response was observed between apremilast 30 mg (39%) and 20 mg (30.9%) groups (P = 0.441). However, apremilast 30 mg differed significantly from 10 mg (12.2%) group (P = 0.005) in achieving sPGA 0/1 response. Refer Table 2 and Supplementary Figure 3a (76.1KB, jpg) -c (76.1KB, jpg) for the comparison of PASI 90, PASI 50, and sPGA 0/1 responses between the groups at 16th week, respectively. Statistically significant improvement in psoriasis using sPGA score from baseline (P = 0.001) was observed in the 30 mg and 20 mg groups, but not the 10 mg group (P = 0.691). Comparison of apremilast 30 mg and 20 mg groups showed a negligible mean difference of − 0.07 (95% confidence interval [CI] −3.27–0.19) with P = 0.61. While a significant mean difference of 1.12 (0.72–1.52) was observed (P = 0.001) between the 30 mg and 10 mg groups.
Erythema scaling induration and visual analogue scale scores
Both the apremilast 30 mg (P = 0.001) and 20 mg (P = 0.001) groups demonstrated statistically significant improvement in psoriasis measured using ESI scores from baseline to 16th week. In contrast, the 10 mg group showed no significant change in ESI (P = 0.736). Comparing the change in ESI score between apremilast 30 mg and 20 mg group showed only a minimal mean difference of 0.08 (95% CI: −0.62–0.77) with P value of 0.83, whereas 30 mg had a significant mean difference of 3.05 (2.24–3.86) with P value of 0.001 against 10 mg group. Clinical images of patients at baseline and 16th week in different doses of apremilast are illustrated in Figure 2. Apremilast 30 mg (P = 0.001) and 20 mg (P = 0.001) groups showed statistically significant improvement in psoriasis using the VAS score from baseline, but not the 10 mg group (P = 0.94). Apremilast 30 mg showed no significant improvement in change in VAS than the 20 mg group (P = 0.164). While apremilast 30 mg exhibited a significant change in VAS at 16th week than 10 mg group (P = 0.001) [Supplementary Tables 1 and 2].
Figure 2.
Clinical images of patients at baseline and 16th week in different doses of apremilast. (a) Psoriatic lesion in a patient in apremilast 30 mg group at baseline, (b) Improvement in the psoriatic lesion observed at 16th week in the same patient in 30 mg group, (c) Psoriatic lesions in a patient in apremilast 20 mg group at baseline, (d) Improvement in those psoriatic lesions observed at 16th week in the same patient of 20 mg group. (e) Psoriatic lesions in a patient in apremilast 10 mg group at baseline, (f) Improvement in the same psoriatic lesions observed at 16th week for that patient of 10 mg group
Supplementary Table 1.
Mean change in Visual Analogue Scale, Static Physician’s Global Assessment Erythema Scaling Induration, Nail Psoriasis Severity Index, and Dermatology life quality index after 16 weeks of treatment in Apremilast 30 mg and 20 mg groups from baseline
| Parameters | Apremilast 30 mg (N=41) | Apremilast 20 mg (N=42) | Apremilast 30 mg versus Apremilast 20 mg | |||||
|---|---|---|---|---|---|---|---|---|
|
|
|
|
||||||
| 0 week | 16 weeks | Mean change, mean±SD (P)€ | 0 week | 16 weeks | Mean change, mean±SD (P)€ | Mean difference (95% CI) | P (two-sided)¶ | |
| VAS | 6.24±1.24 | 2.49±0.77 | 3.75±1.09* (0.001) | 6.05±1.13 | 2.6±0.90 | 3.44±0.89* (0.001) | 0.31 (−0.13–0.75) | 0.164 |
| sPGA | 2.76±0.43 | 1.56±0.59 | 1.19±0.55* (0.001) | 3±0.58 | 1.74±0.54 | 1.26±0.62* (0.001) | −0.07 (−3.27–0.19) | 0.61 |
| ESI | 4.88±1.65 | 1.92±0.75 | 2.95±1.84* (0.001) | 5.33±1.57 | 2.45±0.90 | 2.88±1.27* (0.001) | 0.08 (−0.62–0.77) | 0.83 |
| NAPSIΩ | 18.86±11.94 | 9.14±6.40 | 9.45±6.81* (0.001) | 19.60±16.62 | 9.99±9.26 | 9.60±8.55* (0.001) | 0.11 (−4.75–4.96) | 0.96 |
| DLQI | 19.83±4.90 | 9.7±3.01 | 10.12±3.08* (0.001) | 19.17±3.60 | 9.78±2.29 | 9.39±2.87* (0.001) | 0.73 (−0.57–2.03) | 0.27 |
*Statistically significant difference, €Intragroup comparisons for individual parameters carried out by Paired t-test, ¶Intergroup comparisons for individual parameters carried out by Student’s t-test, ΩNumber of patients for NAPSI are 21 and 20 in 30 mg and 20 mg groups, respectively. N=Number of patients, SD=Standard deviation, CI=Confidence interval, VAS=Visual Analogue Scale, sPGA=Static Physician’s Global Assessment, ESI=Erythema Scaling Induration score, NAPSI=Nail Psoriasis Severity Index, DLQI=Dermatology life quality index
Supplementary Table 2.
Mean change in Visual Analogue Scale, Static Physician’s Global Assessment, Erythema Scaling Induration, Nail Psoriasis Severity Index, and Dermatology Life Quality Index after 16 weeks of treatment in Apremilast 30 mg and 10 mg groups from baseline
| Parameters | Apremilast 30 mg (N=41) | Apremilast 10 mg (N=41) | Apremilast 30 mg versus apremilast 10 mg | |||||
|---|---|---|---|---|---|---|---|---|
|
|
|
|
||||||
| 0 week | 16 weeks | Mean change, mean±SD (P)€ | 0 week | 16 weeks | Mean change, mean±SD (P)€ | Mean difference (95% CI) | P (two-sided)¶ | |
| VAS | 6.24±1.24 | 2.49±0.77 | 3.75±1.09* (0.001) | 6.10±1.22 | 6.61±2.01 | −0.51±1.91 (0.94) | 4.27 (3.58–4.95)* | 0.001 |
| sPGA | 2.76±0.43 | 1.56±0.59 | 1.19±0.55* (0.001) | 3.02±0.47 | 2.95±1.02 | 0.07±1.17 0.691) | 1.12 (0.72–1.52)* | 0.001 |
| ESI | 4.88±1.65 | 1.92±0.75 | 2.95±1.84* (0.001) | 5.34±1.59 | 5.44±1.84 | −0.97±1.84 (0.736) | 3.05 (2.24–3.86)* | 0.001 |
| NAPSIΩ | 18.86±11.94 | 9.14±6.40 | 9.45±6.81* (0.001) | 15.95±9.19 | 16.31±8.96 | −0.35±2.53 (0.512) | 10.07 (6.96–13.19)* | 0.001 |
| DLQI | 19.83±4.90 | 9.7±3.01 | 10.12±3.08* (0.001) | 18.61±3.80 | 18.53±4.62 | 0.073±3.89 (0.905) | 10.04 (8.50–11.59)* | 0.001 |
*Statistically significant difference, €Intragroup comparisons for individual parameters carried out by Paired t-test, ¶Intergroup comparisons for individual parameters carried out by Student’s t-test, ΩNumber of patients for NAPSI are 21 and 22 in 30 mg and 10 mg groups, respectively. N=Number of patients, SD=Standard deviation, CI=Confidence interval, VAS=Visual Analogue Scale, sPGA=Static Physician’s Global Assessment, ESI=Erythema scaling induration score, NAPSI=Nail Psoriasis Severity Index, DLQI=Dermatology Life Quality Index
Psoriatic arthritis response criteria and nail psoriasis severity index
When comparing the apremilast 30 mg and 20 mg groups, the proportion of participants who achieved PsARC were 60% and 50%, respectively (P = 1.00), while none in the 10 mg group attained remission (P = 0.045) [Table 2 and Supplementary Figure 3d (76.1KB, jpg) ]. Both apremilast 30 mg (P = 0.001) and 20 mg (P = 0.001) groups demonstrated statistically significant improvements from baseline in nail conditions as assessed by change in NAPSI scores at 16th week, while the 10 mg group showed no significant improvement (P = 0.512). Apremilast 30 mg had no significant change in NAPSI compared to 20 mg group at 16th week (P = 0.96). However, a significant change in NAPSI was observed in the 30 mg group than the 10 mg group (P = 0.001) [Supplementary Tables 1 and 2].
Quality of life (dermatology life quality index) and lipid profile
Apremilast 30 mg (P = 0.001) and 20 mg (P = 0.001) had significant improvement of QOL assessed using DLQI at 16th week, while patients from 10 mg group (P = 0.905) showed no significant improvement of QOL. Similar to the other efficacy parameters, the 30 mg group showed significant improvement of QOL than 10 mg (P = 0.001), but not against the 20 mg group (P = 0.27) when assessed with the change in DLQI from baseline to 16th week. The lipid parameters such as total cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, and very low-density lipoprotein, showed no significant change from baseline at 16th week in all three groups. Furthermore, the mean difference of apremilast 30 mg versus 20 mg, and 30 mg versus 10 mg groups showed no significant change in lipid parameters [Supplementary Tables 3 and 4].
Supplementary Table 3.
Mean change in lipid profiles after 16 weeks of treatment in Apremilast 30 mg and 20 mg groups from baseline
| Parameters | Apremilast 30 mg (N=41) | Apremilast 20 mg (N=42) | Apremilast 30 mg versus apremilast 20 mg | |||||
|---|---|---|---|---|---|---|---|---|
|
|
|
|
||||||
| 0 week | 16 weeks | Mean change, mean±SD (P)€ | 0 week | 16 weeks | Mean change, mean±SD (P)€ | Mean difference (95% CI) | P (two- sided)¶ | |
| TC | 187.14±11.5 | 197.43±9.63 | −0.29±5.31 (0.728) | 191.31±14.29 | 191.3±13.31 | 0.009±4.26 (0.989) | −0.29 (−2.39–1.79) | 0.777 |
| TG | 136.67±24.55 | 136.68±24.55 | −1.55±8.09 (0.228) | 130.24±12.17 | 131.25±12.23 | −1.01±3.69 (0.082) | −0.53 (−3.27–2.20) | 0.699 |
| HDL | 52.48±8.17 | 52.58±6.83 | −0.09±4.09 (0.885) | 53±12.85 | 53.35±12.47 | −0.35±3.95 (0.567) | 0.26 (−1.49–2.02) | 0.769 |
| LDL | 114.61±12.23 | 115.62±12.11 | −1.01±5.13 (0.215) | 113.98±13.43 | 114.6±12.63 | −0.62±5.01 (0.424) | −0.39 (−2.60–1.83) | 0.730 |
| VLDL | 30.22±5.98 | 30.18±5.72 | 0.04±2.77 (0.920) | 30.83±5.13 | 31.75±5.48 | −0.92±3.2 (0.07) | 0.96 (−0.35–2.27) | 0.147 |
€Intragroup comparisons for individual parameters carried out by Paired t-test, ¶Intergroup comparisons for individual parameters carried out by Student’s t-test. N=Number of patients, SD=Standard deviation, CI=Confidence interval, TC=Total cholesterol, TG=Triglyceride, HDL=High density lipoprotein, LDL=Low density lipoprotein, VLDL=Very LDL
Supplementary Table 4.
Mean change in lipid profiles after 16 weeks of treatment in Apremilast 30 mg and 10 mg groups from baseline
| Parameters | Apremilast 30 mg (N=41) | Apremilast 10 mg (N=41) | Apremilast 30 mg versus apremilast 10 mg | |||||
|---|---|---|---|---|---|---|---|---|
|
|
|
|
||||||
| 0 week | 16 weeks | Mean change, mean±SD (P)€ | 0 week | 16 weeks | Mean change, mean±SD (P)€ | Mean difference (95% CI) | P (two- sided)¶ | |
| TC | 187.14±11.5 | 197.43±9.63 | −0.29±5.31 (0.728) | 187.73±11 | 187.09±11.28 | 0.63±2.2 (0.072) | −0.92 (−2.70–0.86) | 0.306 |
| TG | 136.67±24.55 | 136.68±24.55 | −1.55±8.09 (0.228) | 134±13.48 | 134.79±12.98 | −0.79±4.61 (0.282) | −0.76 (−3.65–2.13) | 0.602 |
| HDL | 52.48±8.17 | 52.58±6.83 | −0.09±4.09 (0.885) | 53.78±13.57 | 54.6±12.55 | −0.81±4.85 (0.288) | 0.72 (−1.25–2.69) | 0.468 |
| LDL | 114.61±12.23 | 115.62±12.11 | −1.01±5.13 (0.215) | 114.07±11.38 | 113.19±11.57 | 0.88±5.24 (0.287) | −1.89 (−4.17–0.39) | 0.102 |
| VLDL | 30.22±5.98 | 30.18±5.72 | 0.04±2.77 (0.920) | 31.12±4.76 | 30.6±4.4 | 0.53±2.58 (0.199) | −0.48 (−1.66–0.69) | 0.417 |
€Intragroup comparisons for individual parameters carried out by Paired t-test, ¶Intergroup comparisons for individual parameters carried out by Student’s t-test. N=Number of patients, SD=Standard deviation, CI=Confidence interval, TC=Total cholesterol, TG=Triglyceride, HDL=High density lipoprotein, LDL=Low density lipoprotein, VLDL=Very LDL
Safety results
Mild and moderate AEs were significantly prevalent in the apremilast 30 mg group (39%) compared to the 20 mg group (16.7%) (P = 0.023). Vomiting was reported by 12.2% in apremilast 30 mg group, contrasting with no reports in the 20 mg group (P = 0.02). However, nausea, diarrhoea, and headache were statistically comparable between the 30 mg and 20 mg groups. Apremilast 30 mg group also had significantly more AEs overall and for individual AEs when compared to the 10 mg group. No severe or serious AEs were reported in any of the groups. Table 3 and Supplementary Figure 4 (41.5KB, jpg) represent the AEs reported between the groups during the study period. As per CTCAE v5.0, in the 30 mg group, all reported cases of nausea and diarrhea were of Grade 1 (mild) severity, whereas vomiting reported by two patients was Grade 2 (moderate) and three experienced Grade 1 severity. Among the 6 patients who reported headache, one had Grade 2, whereas the remaining had Grade 1 severity in the 30 mg group. In apremilast 20 mg group, six patients reported nausea of Grade 1 severity, one patient reported diarrhoea of Grade 1, and two patients reported headache of Grade 1 severity. For the apremilast 10 mg Group, 2 patients reported nausea of Grade 1 severity [Supplementary Figure 5 (39.1KB, jpg) ].
Table 3.
Comparison of adverse events between apremilast 30 mg, 20 mg, and 10 mg groups
| Apremilast 30 mg (N=41), n (%) | Apremilast 20 mg (N=42), n (%) | P (two-sided) for 30 mg versus 20 mga | Apremilast 10 mg (N=41), n (%) | P (two-sided) for 30 mg versus 10 mga | |
|---|---|---|---|---|---|
| Serious adverse events | 0 | 0 | - | 0 | - |
| Mild and moderate adverse events | |||||
| Overall | 16 (39) | 7 (16.7) | 0.023b | 2 (4.9) | 0.001b |
| Nausea | 12 (29.3) | 6 (14.3) | 0.098 | 2 (4.9) | 0.003b |
| Vomiting | 5 (12.2) | 0 | 0.02b | 0 | 0.021b |
| Diarrhoea | 5 (12.2) | 1 (2.4) | 0.084 | 0 | 0.021b |
| Headache | 6 (14.6) | 2 (4.8) | 0.128 | 0 | 0.011b |
aIntergroup comparisons for individual parameters carried out by Chi-square test or Fishers’ exact test, as applicable, bStatistically significant difference. N=Total number of patients in each group, n=Number of patients with adverse events
Discussion
In this randomized, active-controlled trial, mild-to-moderate psoriasis patients were studied to assess the efficacy and safety of standard dose versus the lower doses of apremilast. Recognizing the potential for a more favourable safety profile, the study explored lower doses (10 mg and 20 mg) to identify whether these reduced concentrations could yield comparable efficacy to the standard 30 mg regimen. Primary endpoints focused on the percentage of patients who achieved PASI 75 from baseline to week 16 and the safety profile of apremilast 30 mg versus 20 mg, and apremilast 30 mg versus 10 mg group. PASI 75, indicative of a 75% reduction in PASI, served as a reliable measure of treatment efficacy.
Kavanaugh et al. and Edwards et al. found significantly higher PASI 75 responses with apremilast 20 mg BD and 30 mg BD versus placebo.[6,7] A meta-analysis by Kang et al. highlighted the better efficacy of apremilast in achieving PASI 75 across 11 trials compared to placebo.[16] Similarly, the LIBERATE trial on moderate-to-severe plaque psoriasis by Reich et al. confirmed better PASI 75 outcomes for apremilast 30 mg and etanercept than placebo.[17] In our study, both 30 mg and 20 mg groups showed comparable PASI 75 improvements at week 16, aligning with the past research on apremilast efficacy across doses. Notably, the 10 mg group lacked significant improvement of psoriasis compared to the 30 mg group, offering insights into dose-dependent efficacy in our mild to moderate psoriasis cohort. ESTEEM trial observed that apremilast 30 mg had significant PASI 50 and PASI 90 responses compared to placebo.[18] Papp et al. reported no significant PASI 90 response with apremilast 20 mg than placebo.[19] While our study found significant PASI 50 and PASI 90 responses in 30 mg than 10 mg, and comparable difference between 30 mg and 20 mg groups.
In a meta-analysis by Kang et al., apremilast showed a higher incidence of treatment-emergent AEs leading to withdrawal compared to placebo.[16] Wells et al. study on active PsA patients reported common AEs as diarrhoea and nausea, in both 30 mg and 20 mg doses, with additional occurrences of headache and URTI in the 30 mg group.[20] The UNVEIL study by Strober et al. noted no serious AEs in the placebo group, while the apremilast 30 mg group experienced four non-treatment-related serious AEs.[8] However, a pooled safety analysis by Mease et al. indicated that apremilast 30 mg group had fewer AEs than the 20 mg group but more than placebo, with similar rates of serious AEs across apremilast doses and placebo.[21] In our study, higher apremilast doses, especially the 30 mg group, showed more frequent AEs such as nausea, vomiting, diarrhoea, and headache, with the findings aligning with previous trials. No serious AEs were reported, highlighting overall apremilast safety. CTCAE v5.0 grading revealed mostly grade 1 AEs across groups, with Grade 2 AEs observed only in the 30 mg group. Nausea induced by apremilast is attributed to both peripheral and central mechanisms, implicating enhanced chemoreceptor trigger zone activity and effects on central neurokinin receptors.[22] The PDE-inhibited effects, likely from increased cAMP, may induce secretory diarrhoea.[23]
In the DISCREET trial, Merola et al. reported over three times more patients achieving sPGA response at week 16 with 30 mg apremilast compared to placebo in genital psoriasis.[24] Similarly, the PROMINENT study by Okubo et al. found 43.7% of sPGA 0/1 response with apremilast 30 mg at 16th week, which was maintained till the 32nd week.[25] In our trial, the 30 mg and 20 mg groups showed no significant difference in achieving sPGA 0/1, but the 30 mg group significantly outperformed the 10 mg group. Both the 30 mg and 20 mg groups also exhibited significant sPGA improvement from baseline, but not the 10 mg group.
In the ESTEEM trial, apremilast 30 mg demonstrated a greater mean percentage improvement in NAPSI compared to placebo.[18] Our study showed significant improvements in nail psoriasis from baseline using NAPSI in both apremilast 30 mg and 20 mg over 16 weeks. The apremilast 30 mg group had a significantly better change in NAPSI than 10 mg but not against 20 mg. Kang et al. highlighted the positive impact of apremilast on VAS for pruritus,[17] aligning with our significant improvement in VAS scores for pruritus. Apremilast 30 mg showed better VAS improvement than 10 mg, supporting higher dosage efficacy, while 30 mg and 20 mg groups had similar VAS scores. Papp et al. found significant QOL improvement using DLQI with apremilast than placebo.[26] DLQI and ESI scores significantly improved with 30 mg compared to 10 mg, with no notable difference between 30 mg and 20 mg. PsARC achievement was comparable between 30 mg and 20 mg groups, but 30 mg significantly differed from 10 mg in PsA patients. Lipid profiles showed no significant difference across the treatment groups, consistent with Ferguson et al., indicating that apremilast at various doses do not impact the lipid parameters.[27]
Efficacy parameters in our study demonstrated comparability between 30 mg and 20 mg apremilast doses, suggesting that apremilast 20 mg dose could offer efficacy similar to the standard 30 mg with a potentially more favourable safety profile. While the 10 mg dose had lesser side effects, it did not achieve comparable efficacy. This study adds to the knowledge that the 20 mg apremilast dosage can be a clinically viable, safer alternative for psoriasis treatment. In addition, the lesser efficacy of the 10 mg dose emphasizes the need for personalized treatment approaches. Although the 16-week study had limitations, including potential bias due to open label, our larger sample size provided valuable insights, enhancing the detection of meaningful differences between apremilast doses in psoriasis treatment. Extended studies could offer a more comprehensive understanding of long-term efficacy and safety.
Conclusion
Our study concluded that the apremilast 20 mg dose is a promising alternative to the conventional 30 mg regimen with comparable efficacy and better safety profile for the treatment of mild to moderate psoriasis.
Conflicts of interest
There are no conflicts of interest.
Titration of doses for apremilast 20 mg BD and 30 mg BD dose groups. AM = Ante meridiem (morning), PM = Post meridiem (evening), mg = milligram
Psoriasis area and severity index 75 Response across apremilast dosage groups at week 16. PASI = Psoriasis area and severity index
Psoriasis area and severity index (PASI) 90, PASI 50, static physician global assessment 0/1, and psoriatic arthritis response criteria responses across apremilast dosage groups at week 16. (a) PASI 90 response, (b) PASI 50 response, (c) sPGA 0/1 response, (d) PsARC response. PASI = Psoriasis area and severity index, sPGA = Static physician global assessment, PsARC = Psoriatic arthritis response criteria
Adverse events across apremilast dosage groups
Distribution of adverse events by severity grade (CTCAE v5.0) across apremilast dosage groups
Funding Statement
Nil.
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Titration of doses for apremilast 20 mg BD and 30 mg BD dose groups. AM = Ante meridiem (morning), PM = Post meridiem (evening), mg = milligram
Psoriasis area and severity index 75 Response across apremilast dosage groups at week 16. PASI = Psoriasis area and severity index
Psoriasis area and severity index (PASI) 90, PASI 50, static physician global assessment 0/1, and psoriatic arthritis response criteria responses across apremilast dosage groups at week 16. (a) PASI 90 response, (b) PASI 50 response, (c) sPGA 0/1 response, (d) PsARC response. PASI = Psoriasis area and severity index, sPGA = Static physician global assessment, PsARC = Psoriatic arthritis response criteria
Adverse events across apremilast dosage groups
Distribution of adverse events by severity grade (CTCAE v5.0) across apremilast dosage groups