10.5826/dpc.1202a76
Introduction: Drug survival is an indirect measure of efficacy and safety and its post-marketing assessment using real-life data is invaluable.
Objectives: To investigate the survival of apremilast in a cohort of psoriasis patients treated with apremilast in a Greek hospital.
Methods: A retrospective cross-sectional study examined adult psoriasis patients receiving apremilast (March 2016 to January 2021). Primary endpoint was the cumulative survival probability at 52 weeks. Kaplan-Meier analysis was used to calculate survival probability. Cox regression analysis was performed to investigate potential risk factors for apremilast discontinuation.
Results: 102 patients (29.4% females) with a mean age of 55.94 years (Standard Deviation 15.21) were included. 65 patients (63.7%) had discontinued treatment by lock date: 19 (18.6%) due to lack of efficacy, 24 (23.5%) due to loss of efficacy, 15 (14.7%) due to adverse reactions, and 7 (6.86%) due to other reasons. Cumulative survival probability at 52 weeks was 52.1%. Median survival time for all reasons for discontinuation was 58 weeks 95%Confidence Interval (40.02, 75.98).
Conclusions: Approximately half of patients remained on apremilast after a year of treatment. Secondary drug failure was the most common reason for discontinuation.
&nbsp;
text/xml
2160-9381
1907
en
Efstratios Vakirlis
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
Greece
Apremilast survival and reasons for discontinuation in psoriasis: five-year experience from a Greek tertiary care centre
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2022-05-02
2021-07-25
2022-05-02
2022-05-24
e2022076
Dermatol Pract Concept
Introduction: Drug survival is an indirect measure of efficacy and safety and its post-marketing assessment using real-life data is invaluable.
Objectives: To investigate the survival of apremilast in a cohort of psoriasis patients treated with apremilast in a Greek hospital.
Methods: A retrospective cross-sectional study examined adult psoriasis patients receiving apremilast (March 2016 to January 2021). Primary endpoint was the cumulative survival probability at 52 weeks. Kaplan-Meier analysis was used to calculate survival probability. Cox regression analysis was performed to investigate potential risk factors for apremilast discontinuation.
Results: 102 patients (29.4% females) with a mean age of 55.94 years (Standard Deviation 15.21) were included. 65 patients (63.7%) had discontinued treatment by lock date: 19 (18.6%) due to lack of efficacy, 24 (23.5%) due to loss of efficacy, 15 (14.7%) due to adverse reactions, and 7 (6.86%) due to other reasons. Cumulative survival probability at 52 weeks was 52.1%. Median survival time for all reasons for discontinuation was 58 weeks 95%Confidence Interval (40.02, 75.98).
Conclusions: Approximately half of patients remained on apremilast after a year of treatment. Secondary drug failure was the most common reason for discontinuation.
&nbsp;
Efstratios Vakirlis
2022/05/02
10.5826/dpc.1202a76
e2022076
First Department of Dermatology and Venereology, School of Medicine, Aristotle University, Thessaloniki, Greece
2160-9381
Greece
en
e2022076
Apremilast survival and reasons for discontinuation in psoriasis: five-year experience from a Greek tertiary care centre
https://dpcj.org/index.php/dpc/article/download/1907/1554
                    Dermatology Practical & Conceptual


         Apremilast Survival and Reasons for
   Discontinuation in Psoriasis: Five-Year Experience
          From a Greek Tertiary Care Centre
    Elena Sotiriou1, Aikaterini Tsentemeidou1, Nikolaos Sideris1, Aimilios Lallas1, Nikolaos
                      Kougkas2, Dimitrios Ioannides1, Efstratios Vakirlis1


1 First Department of Dermatology and Venereology, School of Medicine, Aristotle University, Thessaloniki, Greece
2 Fourth Department of Internal Medicine, Aristotle University of Thessaloniki, Greece.



Key words: psoriasis, apremilast, survival, discontinuation, Greece
Citation: Sotiriou E, Tsentemeidou A, Sideris N, et al. Apremilast survival and reasons for discontinuation in psoriasis: five-year experience
from a Greek tertiary care centre. Dermatol Pract Concept. 2022;12(2):e2022076. DOI: https://doi.org/10.5826/dpc.1202a76
Accepted: December 7, 2021; Published: January 2022
Copyright: ©2022 Sotiriou et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-
NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use,
distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing interests: None.
IRB approval: Ethics committee of The Hospital of Venereal and Dermatologic Diseases of Thessaloniki, Greece.
Authorship: All authors have contributed significantly to this publication
Corresponding author: Aikaterini Tsentemeidou, MS. First Department of Dermatology and Venereology, School of Medicine, Aristotle
University, Thessaloniki, Greece. Email: ktsenteme@gmail.com




  ABSTRACT              Introduction: Drug survival is an indirect measure of efficacy and safety and its post-marketing as-
                        sessment using real-life data is invaluable.
                        Objectives: To investigate the survival of apremilast in a cohort of psoriasis patients treated with
                        apremilast in a Greek hospital.
                        Methods: A retrospective cross-sectional study examined adult psoriasis patients receiving apremi-
                        last (March 2016 to January 2021). Primary endpoint was the cumulative survival probability at
                        52 weeks. Kaplan-Meier analysis was used to calculate survival probability. Cox regression analysis
                        was performed to investigate potential risk factors for apremilast discontinuation.
                        Results: One hundred and two patients (29.4% females) with a mean age of 55.9 years (standard de-
                        viation 15.21) were included. Sixty-five patients (63.7%) had discontinued treatment by lock date: 19
                        (18.6%) due to lack of efficacy, 24 (23.5%) due to loss of efficacy, 15 (14.7%) due to adverse reactions,
                        and 7 (6.9%) due to other reasons. Cumulative survival probability at 52 weeks was 52.1%. Median
                        survival time for all reasons for discontinuation was 58 weeks (95% Confidence Interval 40.02, 75.98).
                        Conclusions: Approximately half of patients remained on apremilast after 1 year of treatment. Sec-
                        ondary drug failure was the most common reason for discontinuation.




Original Article | Dermatol Pract Concept. 2022;12(2):e2022076                                                                               1
                         Take-home message
                          • Psoriasis treatment with biologics and small-molecule agents is of finite duration, most often due
                            to efficacy-related reasons.
                          • Apremilast survival was investigated in a real-life setting. Cumulative survival probability at 24, 52 and
                            208 weeks was 69.3%, 52.1% and 28.1%, respectively. Nineteen (18.6%), 24 (23.5%) and 15 (14.7%)
                            patients discontinued apremilast due to lack of efficacy, loss of efficacy and adverse reactions, respectively.




Introduction                                                             Index (PASI) score (PASI75) at weeks 16, 24, 52, 104 and
                                                                         156 as well as mean/median drug survival for all reasons
Apremilast (Otezla®, Amgen) is an orally administered                    for discontinuation and stratified for specific reason (lack of
PDE4 inhibitor, whose efficacy and tolerability for the                  and loss of efficacy, adverse events, other). Gender, age, body
treatment of moderate-to-severe plaque psoriasis was in-                 mass index (BMI, kg/m2), presence of scalp and nail psoria-
vestigated in the ESTEEM phase III trials [1,2]. Psoriasis               sis, presence of psoriatic arthritis, diabetes, hyperlipidaemia,
treatment with biologics and small-molecule agents is of                 hypertension and cardiovascular disease, as well as previous
finite duration, most often due to efficacy-related reasons              treatment with biologics were tested as potential predictors
[3] The probability that psoriasis patients will stay on a               for drug discontinuation.
biologic treatment for ≥3 years is 53%-58% [4]. Anti-drug                    Treatment was considered discontinued if patients
antibodies, genomic and transcriptomic parameters as well                stopped receiving apremilast tablets. Reasons for discontin-
as non-compliance could possibly explain this phenome-                   uation were primary drug failure (no ≥50% improvement
non [4,5]. Forty-five of 382 (11.78%) ESTEEM 2 partic-                   in baseline PASI – PASI50 – by week 24), secondary drug
ipants, who received apremilast, discontinued treatment                  failure (loss of achieved efficacy at two consecutive visits),
due to lack of efficacy by week 52 [2]. Long-term (≥156                  adverse events and personal/other reasons. Patients lost
weeks) pooled data from the two ESTEEM trials showed                     to follow-up were considered to have discontinued treat-
that 34.7% of participants receiving apremilast discontin-               ment. Sequential recruitment of all eligible treated patients
ued treatment due to lack of efficacy, which was the most                was performed to limit selection bias. The study protocol
common reason for treatment cessation [6]. Drug survival                 adhered to the Declaration of Helsinki and was approved
– time from initiation to discontinuation of treatment – can             by the Ethics Committee of the First Dermatology Depart-
be used as a surrogate measure for drug efficacy and toler-              ment, Aristotle University, Thessaloniki, Greece. Signed in-
ability [4]. As everyday practice may differ from the setting            formed consent was obtained by all participating patients.
of clinical trials, real-world data is invaluable.                           SPSS software version 25 (IBM Corp.) was used to per-
                                                                         form all statistical analyses. Qualitative variables were de-

Objectives                                                               scribed through relative frequencies. We used Shapiro-Wilk
                                                                         test to check for normal distribution of quantitative variables.
This study was conducted to investigate the survival of                  Mean, standard deviation (SD) and 95% confidence interval
apremilast in a cohort of patients treated for psoriasis in a            (CI) were used in case of normal distribution, whereas me-
real clinical setting.                                                   dian and interquartile range were used in the opposite case. A
                                                                         two-tailed significance level of <0.05 was set. Kaplan-Meier
                                                                         analysis was used to calculate survival probability. Study
Methods                                                                  event was drug discontinuation due to any reason or loss to
A retrospective cross-sectional study was performed. Data                follow-up. Patients still on treatment were censored at the last
was retrieved from the psoriasis archives of the 1 Dermatol-
                                                       st                available follow-up visit. Univariate and multivariate Cox re-
ogy Department, Aristotle University, Thessaloniki, Greece.              gression analysis were performed to investigate potential risk
All adult patients with any type of psoriasis, who had re-               factors for apremilast discontinuation (hazard ratio, signifi-
ceived at least one dose of apremilast from March 2016 until             cance level set at P ≤0.05). Akaike information criterion was
January 2021, were eligible for inclusion in the study. Dos-             used to choose the best-fitting model for survival prediction.
ing followed summary of product characteristics. Primary
endpoint was cumulative survival probability at 52 weeks.
                                                                         Results
Secondary endpoints were cumulative survival probability at
weeks 24, 104, 156, and 208, percentage of patients achiev-              Out of 2313 psoriasis patients registered in the psoriasis ar-
ing 75% reduction in their baseline Psoriasis Area Severity              chives, 110 patients were potentially eligible for inclusion. Six



2                                                                             Original Article | Dermatol Pract Concept. 2022;12(2):e2022076
patients did not give consent for study participation and 2           while 4 (3.92%) were lost to follow-up. Cumulative survival
patients were excluded due to incompletely recorded data.             probability at 24, 52, 104, 156, and 208 weeks was 69.3%,
We included 102 patients in our analysis (29.4% females,              52.1%, 39.8%, 31.2%, and 28.1%, respectively (Figure 1).
70.6% males) with various types of psoriasis and a mean age           Mean survival time per reason for discontinuation and PASI75
of 55.94 years (SD 15.21). Patient baseline characteristics are       achievement rates are presented in Table 1. Median survival
presented in Table 1. Patients were followed-up for a total           time for all reasons for discontinuation was 58 weeks (95%
of 26,826 patient-weeks. Sixty-five patients (63.7%) had dis-         CI 40.02, 75.98). The only covariate found able to predict
continued treatment by lock date: 19 (18.6%) due to lack of           drug survival was the combination of cardiovascular disease
efficacy, 24 (23.5%) due to loss of efficacy, 15 (14.7%) due to       and diabetes, which was associated with 78% less likelihood
adverse reactions, 3 (2.94%) due to other/personal reasons,           of apremilast discontinuation (hazard ratio 0.22, P = 0.035).




                     Table 1. Patient Demographic Characteristics and Apremilast Survival
                                                                   Female                                      Male
 Sex†, n (%)                                                       30 (29.4)                                 72 (70.6)

 Age‡, years(                                            57.1 (12.89, 57.1 – 52.29)               55.17 (16.06, 51.37 – 58.97)

 BMI§ (kg/m2)                                                    27.11 (8.01)                              27.68 (6.63)

 Psoriasis duration§ (years)                                        9 (14)                                    13 (14)

 Baseline PASI§                                                    11 (5.4)                                  11.7 (7.4)

 Psoriatic arthritis†                                              5 (16.7)                                  15 (20.8)

 Scalp psoriasis†                                                  28 (93.3)                                 55 (76.4)

 Nail psoriasis†                                                   13 (43.3)                                 35 (48.6)

 Smoking†                                                          15 (50.0)                                 44 (61.1)

 Comorbidities

 Hypertension†                                                     11 (36.7)                                 23 (31.9)

 Diabetes†                                                         6 (20.0)                                  11 (15.3)

 Hyperlipidemia†                                                   9 (30.0)                                  18 (25.0)

 Obesity†                                                          9 (30.0)                                  24 (33.3)

 Cardiovascular disease†                                           5 (16.7)                                  15 (20.8)

 Median survival time (all reasons for discontinuation)           58 weeks 95%CI (40.02, 75.98)

 Mean survival time in weeks (95% Confidence Interval)

 All reasons for discontinuation                                                 96.75 (78.34, 115.15)

 Due to lack of efficacy                                                        178.06 (159.41, 196.72)

 Due to loss of efficacy                                                        152.35 (130.53, 174.17)

 Due to adverse events                                                          190.59 (174.45, 206.73)

 Due to other reasons (including loss to                                        211.06 (199.08, 223.05)
 follow-up)
                               Week 16            Week 24        Week 52        Week 104                     Week 156

 PASI75¶                        20.80%             46.00%        45.74%          30.33%                       13.20%

†number (percentage). ‡mean (standard deviation, 95% confidence interval). §BMI: Body Mass Index, median (interquartile range). ¶PASI75:
percentage of patients having achieved 75% reduction in their baseline Psoriasis Area Severity Index score.




Original Article | Dermatol Pract Concept. 2022;12(2):e2022076                                                                        3
                                                               APREMILAST SURVIVAL - ALL REASONS FOR DISCONTINUATION
                                                                                                                                           SURVIVAL FUNCTION
                                   1.0                                                                                                     CENSORED




                                   0.8
PROBABILITY OF REMAINING ON DRUG




                                   0.6

                                                                                                                                  0.5

                                   0.4




                                   0.2




                                   0.0

                                          0               50             100             150               200                250

                                                       WEEKS OF APREMILAST TREATMENT UNTIL JANUARY 2021

  Figure 1. Cumulative survival probability of apremilast (Kaplan-Meier survival curve) for all reasons of drug discontinuation. Event: drug
  discontinuation due to any reason or loss to follow-up. Patients still on treatment were censored at the last available follow-up visit.



Conclusions                                                                                    of patients with palmoplantar pustulosis, however, apremi-
                                                                                               last was associated with the longest survival (65 weeks) com-
According to our results, approximately half of psoriasis pa-                                  paring to classic systemic treatments, such as cyclosporine,
tients treated with apremilast remained on treatment after                                     acitretin plus PUVA, methotrexate, acitretin, alitretinoin and
one year and a little more than a quarter of them were still                                   fumaric acid esters [13]. Primary treatment failure was the
receiving the drug after 4 years of treatment. The most com-                                   most common reason for apremilast discontinuation in a
mon reason for discontinuation was secondary drug failure.                                     USA study comparing various biologics and apremilast as
Patients suffering from both diabetes and cardiovascular dis-                                  well as in a smaller Austrian study [5,10]. Loss of efficacy
ease were significantly less likely to discontinue apremilast.                                 was the main reason for apremilast cessation in a Japanese
Limitations of our study are its retrospective nature, lack of                                 study (46.4%) [9]. Apremilast survival was significantly re-
a control group and absence of subgroup analysis of patients                                   duced in patients with scalp psoriasis (P = 0.001) in a small
having received concurrent topical treatment.                                                  Spanish study [12]. The results of this study are comparable
                                   According to real-world evidence, median apremilast sur-    to other real-life apremilast survival data. Median apremi-
vival ranges from 12.5 to 65 weeks, while 52-week survival                                     last survival at 52 weeks was found less than that of other
probability ranges from 40.7% to 53.4% [7–11]. Two-year                                        systemic treatments for psoriasis, as presented in various re-
survival probability was 37.4% in a Japanese study [7]. Me-                                    al-life reports.
dian time to drug discontinuation was 23 weeks for primary
drug failure, 63 weeks for secondary failure and 8 weeks
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Original Article | Dermatol Pract Concept. 2022;12(2):e2022076                                                                                   5
