Abstract
Introduction
The German national psoriasis registry PsoBest collects long-term data on the effectiveness, safety, and tolerability of systemic treatments for psoriatic disease. Here, we describe patient characteristics and the safety and effectiveness of apremilast for the treatment of psoriatic disease in Germany based on data from PsoBest.
Methods
This was a descriptive analysis of observational data collected from PsoBest using cross-sectional (baseline characteristics) and longitudinal (outcomes, safety) designs. PsoBest recruits patients with moderate to severe plaque psoriasis or psoriatic arthritis who initiate a new systemic psoriasis treatment. Adverse events (AEs) and sociodemographic descriptors were reported for patients exposed to apremilast during the study period (safety cohort). Clinical and patient-reported outcomes were collected 3, 6, and 12 months after the initiation of apremilast monotherapy (outcomes cohort).
Results
From January 15, 2015 to June 30, 2020, 595 registry patients were exposed to apremilast; 417 were treated with apremilast monotherapy. Patients taking apremilast had a higher mean age and higher proportions of comorbidities such as cardiovascular or metabolic disease compared with those taking other nonbiologic systemic or biologic drugs. The most common nonserious AEs were drug ineffectiveness (14.1%), diarrhea (9.4%), nausea (7.1%), and headache (6.1%). The highest incidence rates of nonserious and serious AEs of special interest were for infections and infestations per system organ class (8.03/100 patient-years) and malignant or unspecified tumors (2.50/100 patient-years), respectively. Improvements in Dermatology Life Quality Index, patient-defined treatment benefits (Patient Benefit Index), body surface area, and Psoriasis Area and Severity Index were observed after 3, 6, and 12 months of apremilast treatment.
Conclusions
Patients in routine care treated with apremilast in the German PsoBest registry experienced treatment benefits and improved skin, psoriasis severity, and quality of life. Safety was consistent with the established safety profile. Apremilast is safe and effective for treating moderate to severe psoriatic disease.
Graphical Abstract
Supplementary Information
The online version contains supplementary material available at 10.1007/s13555-025-01631-8.
Keywords: Apremilast, Dermatology, Psoriasis, Real World, Therapeutics
Key Summary Points
| Why carry out this study? |
| This was a post-authorization safety study (PASS) mandated by the European Medicines Agency at the time of apremilast marketing authorization. |
| On the basis of data from the PsoBest registry of German patients with psoriatic disease, we explored patient characteristics, safety, and effectiveness in patients receiving apremilast. |
| What was learned from the study? |
| This real-world analysis showed differences in the patient profiles of German patients treated with apremilast vs other psoriatic therapies and demonstrated that apremilast had a safety profile comparable to previous reports and led to improvements in physician- and patient-reported outcomes. |
| Real-world German patients treated with apremilast experienced improvements in psoriasis severity, quality of life, and patient-relevant treatment benefits. |
| No new safety signals were identified, and the safety profile was aligned with previous reports, indicating that apremilast is safe and effective for treating moderate to severe psoriatic disease. |
Digital Features
A graphical abstract is available for this article at 10.6084/m9.figshare.30847844.
Introduction
Prevalence of psoriasis, a chronic inflammatory skin disease, in Germany is about 2.5% [1]. Psoriatic disease is highly burdensome to patients; skin lesions can be bothersome and painful, and patients’ quality of life (QoL) is often impacted [2, 3]. Furthermore, psoriasis is associated with an increased likelihood of comorbid conditions, such as hypertension, obesity, diabetes, or depression [4–7].
Patients with moderate to severe psoriasis in Germany often begin systemic treatment with nonbiologic therapies, including fumaric acid esters (FAEs), methotrexate, cyclosporine, or phototherapy [8]. However, many require regular laboratory monitoring, and long-term use of these therapies may lead to the increased risk of toxicities such as nephrotoxicity or renal toxicity [9]. Apremilast is an oral immunomodulating phosphodiesterase 4 inhibitor approved in Europe for the treatment of moderate to severe chronic plaque psoriasis in adults who have failed, are intolerant to, or have a contraindication to other systemic therapy, as well as for active psoriatic arthritis in adults who have failed or are intolerant to disease-modifying antirheumatic drugs [10]. Apremilast has been shown to be effective at improving clinical symptoms and QoL in patients with psoriasis, including in real-world dermatology practices in Germany, where patients treated with apremilast had sustained improvements in several disease measures, including the Psoriasis Area and Severity Index (PASI), Skin Pain Visual Analog Scales, and Dermatology Life Quality Index (DLQI) [11]. In other real-world studies, patients treated with apremilast had a higher mean age and lower mean PASI at baseline compared with patients in clinical trials, and safety profiles were similar to those reported in clinical trials [11–18].
The German national psoriasis registry PsoBest collects long-term data on the effectiveness, safety, and tolerability of systemic treatments for psoriatic disease [19]. This study was a post-authorization safety study (PASS) mandated by the European Medicines Agency at the time of apremilast authorization. This analysis explored apremilast use in Germany based on data from the PsoBest registry. Objectives included understanding the patient characteristics, safety signals in clinical practice, burdens and treatment needs associated with psoriasis, and changes in clinical and patient-reported outcomes after apremilast treatment.
Methods
Study Design
This observational analysis was based on data from the German psoriasis registry PsoBest and was designed as a cross-sectional (demographics and clinical characteristics) and longitudinal (patient-reported and safety outcomes) study. PsoBest is designed to collect long-term data on the effectiveness, safety, and tolerability of systemic treatments for psoriatic disease. PsoBest recruits patients who initiate a new systemic treatment during routine care (i.e., patients who are naïve to enrollment treatment but may have received prior systemic treatments). While registry recruitment began in December 2007 and data began accruing for patients on nonbiologic or biologic systemic therapies, apremilast data collection began on January 15, 2015, after the European Medicines Agency approved apremilast for the treatment of psoriatic diseases. Adult patients aged 18 years or older with a dermatologist-confirmed diagnosis of moderate to severe plaque psoriasis or psoriatic arthritis who were treated at one of more than 1000 dermatology practices or outpatient hospitals in Germany and had initiated treatment with apremilast during the study window (January 15, 2015 to June 30, 2020) were included. Informed consent was provided, and German language proficiency was confirmed. While the registry is still recruiting, a data cutoff of June 30, 2020 was chosen for this analysis to ensure that at least 5 years of apremilast observation data were completely digitalized and fully quality assured.
Data Collection and Outcomes
Data for this analysis were collected by the registry using standardized questionnaires from dermatologists and patients. Sociodemographic and baseline clinical characteristics were collected at enrollment. Therapy-specific data (e.g., dosage and switches) were collected during routine visits. Clinical and patient-reported outcomes (e.g., body surface area [BSA], PASI, DLQI, and Patient Benefit Index [PBI]) were assessed at baseline and 3, 6, and 12 months. Details on reported outcomes are provided in Supplementary Appendix. Nonserious adverse events (AEs) were reported with routine visit documentation from dermatologists; serious adverse events (SAEs) were reported to the registry immediately. Safety events were coded using Medical Dictionary for Regulatory Activities (MedDRA) version 23.0 for analysis; select standardized MedDRA query (SMQ) and system organ classes (SOCs) were evaluated. SAEs were any AEs that were life-threatening or resulted in death, indicated a newly diagnosed malignancy, required inpatient hospitalization or prolongation of existing hospitalization, resulted in a persistent or significant disability or incapacity, resulted in a congenital anomaly or birth defect, or were important medical events.
Statistical Analysis
Patient and clinical characteristics and safety analyses were based on patients treated with apremilast during the study window, regardless of any comedication (safety cohort). To contextualize the characteristics of patients who were being prescribed apremilast, descriptives were provided for patients treated with nonbiologic systemic therapies excluding apremilast (e.g., retinoids, FAEs, methotrexate, cyclosporine) or biologic therapies (e.g., tumor necrosis factor alpha inhibitors, interleukin-17 inhibitor [IL-17i], IL-12/23i) for comparison. Nonserious AEs and SAEs were described with patient-level incidence rates (IRs) and crude standardized IRs per 100 patient-years (PY) of exposure by select SMQ, preferred term, and MedDRA SOC. The 95% confidence intervals (CIs) were computed with a method based on the link between Poisson and chi-square distributions. Events were considered treatment-emergent if the onset of the event was between the beginning and end of treatment (+ 90-day risk window). Death and malignancies were considered treatment-emergent if the beginning of treatment was before the onset of the event (ever-exposed).
Patient-reported outcomes were evaluated descriptively among patients on apremilast monotherapy (outcomes cohort). Frequencies were calculated for nominal and ordinal scaled data (e.g., treatment response rates). Medians, means, standard deviations (SDs), and CIs were calculated for metric data (e.g., change in patient- or physician-reported outcomes). Clinical, patient-reported, and safety outcome comparisons between treatment cohorts were out of scope for this analysis as a result of protocol design and differences in populations. No imputation was performed for missing values. All analyses were performed using SPSS 24 and R 3.5.1.
Ethics
The PsoBest registry was planned and performed under strict rules of patient protection as suggested by German and European laws, the Declaration of Helsinki, and Good Clinical Practice as described in the International Council for Harmonisation Guideline E6. Consent from the ethics committee of the physician’s chamber of the Federal State of Hamburg was obtained (Ethikkommission der Ärztekammer Hamburg, Weidestr. 122b, 22,083 Hamburg, Bearbeitungs-Nr. 2805). Signed informed consent was required before study participation.
Results
Patient Characteristics
As of June 30, 2020, 11,378 patients with psoriasis or psoriatic arthritis were enrolled in the PsoBest registry, and 10,301 of these patients had validated follow-up information. From January 15, 2015 to June 30, 2020, 595 patients were exposed to apremilast and included in the sociodemographic and safety analysis (safety cohort); data on 417 patients who started apremilast monotherapy at registry initiation were analyzed for clinical and patient-reported outcomes (outcomes cohort) (Fig. 1). Duration of apremilast treatment is summarized in Table 1. Table S1 provides a summary of prior systemic treatments for patients in the apremilast outcomes cohort and shows that most patients had previously been treated with nonbiologic systemic therapy.
Fig. 1.
Patient disposition in apremilast cohort. aPatients could have more than one reason for treatment discontinuation. AE adverse event
Table 1.
Duration of apremilast treatment Please switch the order of the columns in this table so that "Safety cohort" is left and "Outcomes cohort" is right.
| Duration of apremilast treatment, years | Safety cohort | Outcomes cohort |
|---|---|---|
| n = 595 | n = 417 | |
| Mean (SD) | 0.9 (0.8) | 0.9 (0.8) |
| Median (range) | 0.7 (0.1–4.5) | 0.6 (0.0–3.9) |
SD standard deviation
Patient demographics and baseline clinical characteristics of the safety cohort are shown in Table 2. Patients from the PsoBest registry who were treated with other nonbiologic systemic therapies (n = 6002) or biologic therapies (n = 4460) are included in Table 2 to contextualize apremilast results. The apremilast cohort had a higher mean age (52.5 years) compared with the other cohorts (47.3 and 47.6 years in the nonbiologic and biologic cohorts, respectively); ages in the apremilast cohort ranged from 18 to 89 years. Additionally, the mean duration of disease was similar for both the apremilast and biologic cohorts (20.3 and 19.8 years, respectively), both of which were higher than that for the nonbiologic cohort (15.7 years). The most common comorbidities in the apremilast cohort were hypertension (40.2%), psoriatic arthritis (23.2%), smoking (21.3%), type 2 diabetes mellitus (11.4%), and depression (11.3%); the prevalence of cardiovascular and metabolic diseases was higher in the apremilast cohort than in the nonbiologic systemic or biologic therapy cohorts (cardiovascular, 43.2% vs 28.9% [nonbiologic] and 33.0% [biologic]; metabolic, 22.4% vs 16.7% [nonbiologic] and 20.5% [biologic]).
Table 2.
Patient demographics and clinical characteristics of apremilast (safety), nonbiologic systemic, and biologic cohorts
| Apremilast safety cohort | Nonbiologic systemic therapy | Biologic therapy | |
|---|---|---|---|
| n = 595 | n = 6002 | n = 4460 | |
| Age, mean (SD), years | 52.5 (15.4) | 47.3 (14.7) | 47.6 (13.9) |
| Female, n (%) | 279 (46.9) | 2572 (42.9) | 1748 (39.2) |
| BMI, mean (SD), kg/m2 | 29.1 (6.2) | 28.5 (5.9) | 29.0 (6.0) |
| Weight, mean (SD), kg | 86.5 (20.0) | 85.7 (19.7) | 88.3 (20.2) |
| Duration of disease, mean (SD), years | 20.3 (15.8) | 15.7 (14.3) | 19.8 (14.2) |
| Comorbidities (present), n (%) | |||
| Cardiovascular disease | 257 (43.2) | 1732 (28.9) | 1474 (33.0) |
| Hypertension | 239 (40.2) | 1546 (25.8) | 1292 (29.0) |
| Coronary heart disease | 36 (6.1) | 209 (3.5) | 196 (4.4) |
| Psychiatric and addiction disease | 189 (31.8) | 2002 (33.4) | 1503 (33.7) |
| Smoking | 127 (21.3) | 1595 (26.6) | 1122 (25.2) |
| Depression | 67 (11.3) | 482 (8.0) | 414 (9.3) |
| Rheumatic and immunological disease | 152 (25.5) | 910 (15.2) | 1373 (30.8) |
| Psoriatic arthritis | 138 (23.2) | 842 (14.0) | 1307 (29.3) |
| Metabolic disease | 133 (22.4) | 1002 (16.7) | 913 (20.5) |
| Type 2 diabetes mellitus | 68 (11.4) | 471 (7.8) | 437 (9.8) |
| Dyslipidemia | 58 (9.7) | 410 (6.8) | 363 (8.1) |
| Pulmonary disease | 50 (8.4) | 399 (6.6) | 313 (7.0) |
| Dermatologic/allergological disease | 43 (7.2) | 551 (9.2) | 445 (10.0) |
| Allergic rhinitis | 30 (5.0) | 391 (6.5) | 271 (6.1) |
| Cancer | 41 (6.9) | 119 (2.0) | 75 (1.7) |
| Liver disease | 38 (6.4) | 169 (2.8) | 259 (5.8) |
| Gastrointestinal disease | 36 (6.1) | 226 (3.8) | 228 (5.1) |
| Renal disease | 33 (5.5) | 72 (1.2) | 125 (2.8) |
| Other | 73 (12.3) | 483 (8.0) | 412 (9.2) |
BMI body mass index, SD standard deviation
Safety Outcomes
Nonserious AEs reported in ≥ 5% of patients in the safety cohort (n = 595; cutoff chosen to align with clinical trial reports [20]) were similar to the known safety profile of apremilast, with the highest incidence reported for drug ineffectiveness, diarrhea, nausea, and headache (Table 3). The most common SAE was condition aggravated. Nonserious AEs and SAEs by SOC are reported in Table S2. No new safety signals were identified.
Table 3.
Common AEs among patients treated with apremilast
| Most common AEs | Nonserious AEs (≥ 5%) | Serious AEs (≥ 2%) | ||
|---|---|---|---|---|
| Patients with event(s), n (%) | Patients with event(s)/100 PY (95% CI) | Patients with event(s), n (%) | Patients with event(s)/100 PY (95% CI) |
|
| n = 595 | PY = 560.55 | n = 595 | PY = 560.55 | |
| Condition aggravated | 27 (4.54) | 4.82 (3.17, 7.01) | 12 (2.02) | 2.14 (1.11, 3.74) |
| Diarrhea | 56 (9.41) | 9.99 (7.55, 12.97) | 1 (0.17) | 0.18 (0.00, 0.99) |
| Drug ineffective | 84 (14.12) | 14.99 (11.95, 18.55) | 1 (0.17) | 0.18 (0.00, 0.99) |
| Headache | 36 (6.05) | 6.42 (4.50, 8.89) | 0 | 0.00 (0.00, 0.66) |
| Nausea | 42 (7.06) | 7.49 (5.40, 10.13) | 0 | 0.00 (0.00, 0.66) |
AE adverse event, CI confidence interval, PY patient-years
A total of 44 patients discontinued apremilast because of an AE (38 [86.4%] due to nonserious AEs; 6 [13.6%] due to SAEs). Of the 11 deaths that occurred after exposure to apremilast, eight were considered not related to treatment, one was considered improbable, and two were considered possibly related (suicide [n = 1] and unknown cause of death [n = 1]).
Among the safety cohort (n = 595), the total PY for apremilast exposure was 560.55 (used to calculate crude rates of treatment-emergent AEs); ever-exposed PYs (i.e., time since the first exposure to apremilast regardless of discontinuation) was 744.02 (used to calculate rates of malignancy and death). Malignancies were reported in 14 patients (crude IR [95% CI], 1.88/100 PY [1.03, 3.15]); of these, four had squamous cell carcinoma of the skin and two had basal cell carcinoma. For all other malignancies, one event each was observed (listed in Supplementary Appendix). The crude IRs of nonserious AEs and SAEs of special interest are shown in Table 4. The highest rates of nonserious AEs were for SOC infections and infestations (8.03/100 PY) and depression or suicide/self-injury (3.03/100 PY). Malignant or unspecified tumors (2.50/100 PY) were the class of SAEs of special interest with the highest incidence. The crude IR (95% CI) for death (all cause) of patients exposed to apremilast was 1.48/100 PY (0.74, 2.64).
Table 4.
Crude incidence rates of nonserious and serious AEs of special interest among patients treated with apremilast
| AEs of special interest | Nonserious AEs | Serious AEs | ||
|---|---|---|---|---|
| Patients with event(s), n (%) | Patients with event(s)/100 PY (95% CI) | Patients with event(s), n (%) | Patients with event(s)/100 PY (95% CI) | |
| n = 595 | PY = 560.55 | n = 595 | PY = 560.55 | |
| Hypersensitivitya | 7 (1.18) | 1.25 (0.50, 2.57) | 1 (0.17) | 0.18 (0.00, 0.99) |
| Depression and suicide/self-injurya | 17 (2.86) | 3.03 (1.77, 4.86) | 1 (0.17) | 0.18 (0.00, 0.99) |
| Suicide/self-injurya | 1 (0.17) | 0.18 (0.00, 0.99) | 1 (0.17) | 0.18 (0.00, 0.99) |
| Depressiona | 16 (2.69) | 2.85 (1.63, 4.64) | 0 | 0.00 (0.00, 0.66) |
| Anxiety and nervousnessb | 1 (0.17) | 0.18 (0.00, 0.99) | NR | NR |
| Vasculitisa | NR | NR | 0 | 0.00 (0.00, 0.66) |
| Malignant or unspecified tumorsa,c | 0 | 0.00 (0.00, 0.66) | 14 (2.35) | 2.50 (1.37, 4.19) |
| Hematological malignant tumorsa | NR | NR | 1 (0.17) | 0.18 (0.00, 0.99) |
| Nonhematological malignant tumorsa | 0 | 0.00 (0.00, 0.66) | 13 (2.18) | 2.32 (1.23, 3.97) |
| Nonhematological tumors of unspecified malignancya | 0 | 0.00 (0.00, 0.66) | 0 | 0.00 (0.00, 0.66) |
| Malignant lymphomasa | NR | NR | 0 | 0.00 (0.00, 0.66) |
| Infections and infestationsd | 45 (7.56) | 8.03 (5.86, 10.74) | 11 (1.85) | 1.96 (0.98, 3.51) |
| MACEa | 3 (0.50) | 0.54 (0.11, 1.56) | 9 (1.51) | 1.61 (0.73, 3.05) |
| Myocardial infarctiona | NR | NR | 2 (0.34) | 0.36 (0.04,1.29) |
| Other ischemic heart diseasea | 1 (0.17) | 0.18 (0.00, 0.99) | 2 (0.34) | 0.36 (0.04,1.29) |
|
Conditions associated with CNS hemorrhages and CVAsa |
NR | NR | 0 | 0.00 (0.00, 0.66) |
| Hemorrhagic CNS vascular conditionsa | 0 | 0.00 (0.00, 0.66) | 0 | 0.00 (0.00, 0.66) |
| Ischemic CNS vascular conditionsa | 0 | 0.00 (0.00, 0.66) | 3 (0.50) | 0.54 (0.11, 1.56) |
| Arterial embolic and thrombotic eventsa | 0 | 0.00 (0.00, 0.66) | 7 (1.18) | 1.25 (0.50, 2.57) |
| Venous embolic and thrombotic eventsa | 1 (0.17) | 0.18 (0.00, 0.99) | 0 | 0.00 (0.00, 0.66) |
| Embolic and thrombotic events, vessel type unspecified and mixed arterial and venousa | 1 (0.17) | 0.18 (0.00, 0.99) | 3 (0.50) | 0.54 (0.11, 1.56) |
| Tachyarrhythmiasa | 1 (0.17) | 0.18 (0.00, 0.99) | 2 (0.34) | 0.36 (0.04, 1.29) |
| Supraventricular tachyarrhythmiasa | 1 (0.17) | 0.18 (0.00, 0.99) | 2 (0.34) | 0.36 (0.04, 1.29) |
| Tachyarrhythmia, nonspecifica | NR | NR | 0 | 0.00 (0.00, 0.66) |
| Ventricular tachyarrhythmiasa | 0 | 0.00 (0.00, 0.66) | 0 | 0.00 (0.00, 0.66) |
AE adverse event, CI confidence interval, CNS central nervous system, CVA cerebrovascular accident, MACE major adverse cardiac events, MedDRA Medical Dictionary for Regulatory Activities, NR not reported, PY patient-years
aStandardized MedDRA Query
bPreferred terms
cBased on ever-exposed PY: 744.02
dSystem organ class
Clinical Effectiveness Outcomes
The outcomes cohort was treated with apremilast for a mean (SD) of 0.9 (0.8) years. At baseline, 3 months, 6 months, and 12 months, 417, 262, 204, and 138 patients, respectively, were eligible for the analysis of clinical efficacy.
At baseline, patients treated with apremilast (n = 403) had a mean (SD) DLQI of 11.1 (7.1), indicating that psoriasis had a very large effect on their QoL, on average [21]. DLQI improved following apremilast treatment: mean (SD) score was 6.1 (5.6), 4.7 (5.0), and 5.3 (5.9) at 3, 6, and 12 months, respectively. The proportions of patients achieving a DLQI of 0 or 1 (no effect on QoL) and/or a DLQI < 5 (no effect or small effect on QoL) generally increased over time, and 61.6% and 60.9% of patients had a score of < 5 at 6 and 12 months, respectively (Fig. 2) [21]. From the Patient Needs Questionnaire, the most identified patient needs at baseline (identified as “very important” by ≥ 75% of patients) were to regain control of the disease, get better skin quickly, have confidence in therapy, be healed of all skin defects, and find a clear diagnosis and therapy. At 3 months, more than half of the patients felt that apremilast helped them “very much” or “quite a lot” in four of the five identified treatment goals (Fig. 3). Patient benefit after apremilast treatment was demonstrated by mean (SD) PBI scores of 2.1 (1.0), 2.3 (1.1), and 2.3 (1.1) at 3, 6, and 12 months, respectively. At 12 months, 85.6% of patients taking apremilast had achieved a PBI ≥ 1 (minimal clinically relevant treatment benefit). The proportion of patients with PBI scores between 3 and 4 (i.e., high perceived benefit) increased from 19.1% to 35.6% between 3 and 12 months (Fig. 4).
Fig. 2.
Achievement of DLQI 0/1 and <5 at 3, 6, and 12 months of apremilast treatment. A DLQI score of 0/1 indicates no effect on quality of life; a DLQI score of <5 indicates no or small effect on quality of life. DLQI Dermatology Life Quality Index
Fig. 3.
PBQ results after 3 months of apremilast treatment for the five patient needs that > 75% of patients identified as very important. The PBQ asks how much the current treatment has helped to achieve specified goals. Goals are shown in order based on proportion of patients that chose “very important” in the PNQ; the goal with the greatest proportion is shown on the bottom. PBQ Patient Benefit Questionnaire, PNQ Patient Needs Questionnaire
Fig. 4.
PBI score ranges at 3, 6, and 12 months of apremilast treatment. PBI Patient Benefit Index
Patients treated with apremilast also experienced improvements in BSA after 3, 6, and 12 months of treatment (Fig. 5a). Mean BSA decreased from 22.1% at baseline to 8.1% after 12 months, corresponding to a reduction of 63.3% from baseline. Similarly, PASI decreased from baseline following apremilast treatment (Fig. 5a). Nearly half of the patients on apremilast achieved a ≥ 75% PASI reduction (PASI-75) from baseline to 12 months (Fig. 5b). Censoring was involved at each stage, leading to a reduced sample size at each follow-up period.
Fig. 5.
a Change from baseline in BSA and PASI after 3, 6, and 12 months of apremilast treatment. b Achievement of PASI-50, PASI-75, and PASI-90 at 3, 6, and 12 months of apremilast treatment. Missing values are minimized by definition as mandatory in data collection and by query mechanisms of the data management procedures. No imputation was done. BSA body surface area, n number of patients, PASI Psoriasis Area and Severity Index, PASI-50 ≥ 50% reduction from baseline in PASI, PASI-75 ≥ 75% reduction from baseline in PASI, PASI-90 ≥ 90% reduction from baseline in PASI, SD standard deviation
Discussion
This observational analysis, based on results from the PsoBest registry, found that patients in Germany treated with apremilast after failure of or contraindication to conventional systemic therapies had a safety profile consistent with previous reports and package labeling, including common AEs (e.g., diarrhea, nausea, and headache) and SAEs with relatively low incidence [10, 20]. While differences in safety reporting and analyses must be considered, crude IRs for depression and serious infections in this real-world setting were the same magnitude as those from a pooled analysis of 15 clinical trials of apremilast (2.85 vs 1.78 [depression] and 1.96 vs 1.10 [serious infections] per 100 PY) [20]. Additionally, crude IRs remained low for major adverse cardiac events and thrombotic events, consistent with clinical data [20]. Findings from this analysis also aligned with those of prior real-world studies evaluating apremilast use: diarrhea, nausea, and headache were consistently reported among the most common treatment-emergent AEs and rates of SAEs were minimal [11, 14–18]. The most commonly observed AEs mostly occurred within the first few weeks of treatment; the management of other AEs is described in the prescribing information [10, 22]. While the molecular mechanism of apremilast on common AEs is not known, diarrhea is thought to be secretory and related to increases in intracellular cyclic adenosine monophosphate in response to apremilast treatment [23]. These long-term real-world results in combination with clinical data suggest that the safety profile of apremilast remains consistent since approval and that apremilast is well tolerated for long-term use.
In this study, apremilast was prescribed to a patient population with a mean age of 52.5 years, an older population than that seen in clinical trials (mean age of 2676 pooled patients 47.3 years) [20] and overall PsoBest registry (mean age of 10,131 enrolled patients 47.7 years). The older population may indicate a delay in switching to apremilast and an extended duration of use of nonbiologic systemic therapies. Furthermore, the apremilast cohort notably had higher proportions of patients with comorbid cardiovascular disease and metabolic disease than the nonbiologic systemic or biologic therapy cohorts. Patients with moderate to severe psoriasis are known to have a higher risk of comorbidities than the general population [4, 24, 25], which may increase susceptibility to AEs. However, a case series and systematic review of 841 patients with psoriasis found that patients with serious comorbidities at baseline who were treated with apremilast were not at an increased risk of AEs or worsening of their comorbid condition(s); additionally, treatment efficacy was not impacted by serious comorbidities [26]. Similarly, an observational study of 28 patients with psoriatic arthritis and comorbidities showed improved clinical outcomes and no worsening of comorbid condition(s) with apremilast [27]. Despite high rates of comorbidities in this study, especially cardiovascular and metabolic diseases, the safety profile among patients in the apremilast cohort remained consistent with that known for apremilast [20].
First-line systemic treatments for German patients are often nonbiologic and targeted synthetic options (e.g., methotrexate, FAEs) [28]. After failing first-line, patients are often switched to another nonbiologic systemic therapy for second-line treatment. An observational study in France found that apremilast was preferred by physicians to methotrexate among older patients and those with chronic hepatopathy or a history of cancer [29]. As demonstrated in this analysis and previously in the observational LAPIS-PSO study [11], apremilast is a favorable alternative option for systemic therapy as a result of its tolerable safety coupled with its positive effect on QoL and psoriasis symptoms and severity.
In this real-world setting, improvements in psoriasis symptoms and QoL were similar to those seen in previous clinical reports and observational studies [11–18]. DLQI at baseline indicated a patient population with a largely impacted QoL [21]. Mean values of DLQI at 3, 6, and 12 months of apremilast treatment met the minimum clinically important difference of 4 for DLQI, with scores indicating improvement to a small or moderately affected QoL [21, 30]. The Italian DARWIN study yielded similar results for DLQI: mean scores at baseline and 6 months for this analysis vs DARWIN were 11.1 vs 13.5 and 4.7 vs 5.9, respectively [17]. In this study, the most important patient needs identified at baseline were to regain control of their disease, get better skin quickly, and have confidence in their therapy. PBI scores at 3, 6, and 12 months demonstrated patient benefit with apremilast. The proportion of patients achieving a PBI score of ≥ 1 at defined endpoints was slightly higher than that in French and Belgian real-world studies (REALIZE and OTELO), but was consistently > 80% across all three studies [16, 18]. Affected skin and psoriasis severity (BSA and PASI) improved with apremilast. In a subanalysis of the APPRECIATE study, 36.7% of Spanish patients achieved PASI-75 at 6 months, similar to the 33.3% in this study [15]. After 1 year of treatment, nearly half of the patients in this study achieved PASI-75.
This observational study has some inherent limitations. Medical history and outcomes documentation may have been incomplete. A series of plausibility checks was performed, and requests for clarification were sent to the study sites when data were found to be incomplete or contradictory during data entry and review. There may also be selection bias of patients willing or unwilling to participate. While baseline data might have been impacted by recall bias, the follow-up data were collected prospectively to reflect disease conditions and patient perspectives at the time of collection. Patient dropout and discontinuation rates in this real-world setting resulted in smaller analysis populations over time. Thus, internal validity was limited. However, this was balanced by a marked external validity since the data were derived from a robust sample of patients in routine care being observed across a large sample of nonspecialized German centers, reflecting real-world care. In addition, given that apremilast was newly approved by the European Medicines Agency at the start of this analysis, safety reporting may have been more frequent. This study was not designed to compare outcomes between the apremilast cohort and the other treatment cohorts.
Conclusion
In Germany, apremilast is approved for the treatment of moderate to severe chronic plaque psoriasis and psoriatic arthritis in adults who have failed, are intolerant to, or have a contraindication to other systemic therapy [10]. On the basis of our observational analysis using data from the PsoBest registry, patients treated with apremilast in Germany experienced treatment benefit and improvements in affected skin, psoriasis severity, and QoL. Despite being prescribed to an older population with high rates of comorbidities, safety was consistent with the established safety profile of apremilast. These findings support the use of apremilast as a nonbiologic systemic therapy for patients with moderate to severe psoriatic disease in Germany.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
The authors thank the patients who participated in the PsoBest registry.
Medical Writing, Editorial, and Other Assistance
Writing support was funded by Amgen Inc. and provided by Christina Mulvihill, PharmD, of Peloton Advantage, LLC, an OPEN Health company.
Author Contributions
Matthias Augustin, Stephan J. Rustenbach, Ralph von Kiedrowski, Hamid Amouzadeh, Kathy Tran, Myriam Cordey, and Ulrich Mrowietz were involved in the conception and design of the study and interpretation of data; Matthias Augustin, Stephan J. Rustenbach, Ralph von Kiedrowski, and Ulrich Mrowietz were involved in the acquisition of data; Matthias Augustin, Stephan J. Rustenbach, Ralph von Kiedrowski, Hamid Amouzadeh, Kathy Tran, Myriam Cordey, and Ulrich Mrowietz drafted the article and revised it critically for important intellectual content and provided final approval of the version to be submitted.
Funding
Celgene (formerly Summit, USA) and Amgen Inc. (Thousand Oaks, USA) sponsored this study, and Amgen Inc. funded the journal’s Rapid Service Fee.
Data Availability
Due to European and German data protection regulations, the transfer of patient-level data is not permitted.
Declarations
Conflicts of Interest
Matthias Augustin: Consultant for, paid speaker for, and/or recipient of institutional research grants from AbbVie, Almirall, Amgen, Bayer Healthcare, Beiersdorf, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Centocor, Lilly, Fresenius, Galderma, GlaxoSmithKline, Hexal, Janssen, Klinge, LEO Pharma, MC2, Medac, Merck, MSD, Novartis, Pfizer, Sandoz, Sun Pharma, UCB, and Viatris. Stephan J. Rustenbach: No conflicts of interest to declare. Ralph von Kiedrowski: Consultant and/or paid speaker for AbbVie, Almirall, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion HC, Fresenius Kabi, Galderma, Hexal, Lilly, Janssen, LEO Pharma, MoonLake, Novartis, Pfizer, Sanofi-Aventis, and UCB. Hamid Amouzadeh: Employment and stock ownership in Amgen. Kathy Tran: Employment and stock ownership in Amgen. Myriam Cordey: Employment and stock ownership in Amgen. Ulrich Mrowietz: Advisor for, received speakers’ honoraria and grants from, and participated in clinical trials for AbbVie, Aditxt, Almirall, Amgen, Aristea, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Dr. Reddy’s, Lilly, Foamix, Formycon, Immunic, Janssen, LEO Pharma, Medac, MetrioPharm, Novartis, Phi-Stone, Pierre Fabre, Sanofi-Aventis, and UCB.
Ethical Approval
The PsoBest registry was planned and performed under strict rules of patient protection as suggested by German and European laws, the Declaration of Helsinki, and Good Clinical Practice as described in the International Council for Harmonisation Guideline E6. Consent from the ethics committee of the physician’s chamber of the Federal State of Hamburg was obtained (Ethikkommission der Ärztekammer Hamburg, Weidestr. 122b, 22083 Hamburg, Bearbeitungs-Nr. 2805). Signed informed consent was required before study participation.
Footnotes
Publisher's Note
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References
- 1.Hagenström K, Müller K, Garbe C, Augustin M. Prevalence of psoriasis and psoriatic arthritis in Germany—analysis of claims data. J Dtsch Dermatol Ges. 2024;22:45–54. [DOI] [PubMed] [Google Scholar]
- 2.Augustin M, Krüger K, Radtke MA, Schwippl I, Reich K. Disease severity, quality of life and health care in plaque-type psoriasis: a multicenter cross-sectional study in Germany. Dermatology. 2008;216:366–72. [DOI] [PubMed] [Google Scholar]
- 3.Lebwohl M, Langley RG, Paul C, et al. Evolution of patient perceptions of psoriatic disease: results from the Understanding Psoriatic Disease Leveraging Insights for Treatment (UPLIFT) survey. Dermatol Ther (Heidelb). 2022;12:61–78. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Augustin M, Reich K, Glaeske G, Schaefer I, Radtke M. Co-morbidity and age-related prevalence of psoriasis: analysis of health insurance data in Germany. Acta Derm Venereol. 2010;90:147–51. [DOI] [PubMed] [Google Scholar]
- 5.Augustin J, Wolf S, Stephan B, Augustin M, Andrees V. Psoriasis comorbidities in Germany: a population-based study on spatiotemporal variations. PLoS ONE. 2022;17:e0265741. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Mrowietz U, Sümbül M, Gerdes S. Depression, a major comorbidity of psoriatic disease, is caused by metabolic inflammation. J Eur Acad Dermatol Venereol. 2023;37:1731–8. [DOI] [PubMed] [Google Scholar]
- 7.Mrowietz U, Lauffer F, Sondermann W, Gerdes S, Sewerin P. Psoriasis as a systemic disease. Dtsch Arztebl Int. 2024;121:467–72. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Nast A, Altenburg A, Augustin M, et al. German S3-Guideline on the treatment of Psoriasis vulgaris, adapted from EuroGuiDerm - Part 1: treatment goals and treatment recommendations. JDDG J Dtsch Dermatol Ges. 2021;19:934–150. [DOI] [PubMed] [Google Scholar]
- 9.Menter A, Gelfand JM, Connor C, et al. Joint American Academy of Dermatology-National Psoriasis Foundation guidelines of care for the management of psoriasis with systemic nonbiologic therapies. J Am Acad Dermatol. 2020;82:1445–86. [DOI] [PubMed] [Google Scholar]
- 10.Otezla [summary of product characteristics]. Breda, Netherlands: Amgen Europe B.V., 2022.
- 11.Reich K, Korge B, Magnolo N, et al. Quality-of-life outcomes, effectiveness and tolerability of apremilast in patients with plaque psoriasis and routine German dermatology care: results from LAPIS-PSO. Dermatol Ther (Heidelb). 2022;12:203–21. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Papp K, Reich K, Leonardi CL, et al. Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM 1]). J Am Acad Dermatol. 2015;73:37–49. [DOI] [PubMed] [Google Scholar]
- 13.Paul C, Cather J, Gooderham M, et al. Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate to severe plaque psoriasis over 52 weeks: a phase III, randomized, controlled trial (ESTEEM 2). Br J Dermatol. 2015;173:1387–99. [DOI] [PubMed] [Google Scholar]
- 14.Augustin M, Kleyn CE, Conrad C, et al. Characteristics and outcomes of patients treated with apremilast in the real world: results from the APPRECIATE study. J Eur Acad Dermatol Venereol. 2021;35:123–34. [DOI] [PubMed] [Google Scholar]
- 15.Herranz P, Trasobares L, Mateu A, et al. Characterization and outcomes in patients treated with apremilast in routine clinical practice in Spain: results from the APPRECIATE study. Actas Dermosifiliogr (Engl Ed). 2021;112:817–27. [DOI] [PubMed] [Google Scholar]
- 16.Ghislain PD, Lambert J, Hoai XL, et al. Real-life effectiveness of apremilast for the treatment of psoriasis in Belgium: results from the observational OTELO study. Adv Ther. 2022;39:1068–80. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Giofrè C, Fabbrocini G, Potenza C, et al. Real-world apremilast use for treatment of plaque psoriasis in Italy: patient perspective, characteristics, and clinical outcomes from the DARWIN study. Adv Ther. 2023;40:3021–37. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Jullien D, Richard MA, Halioua B, Bessette C, Derancourt C, Bouloc A. The needs of patients with psoriasis and benefits of apremilast in French clinical practice: results from the observational REALIZE study. Dermatol Ther (Heidelb). 2023;13:1361–76. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Augustin M, Spehr C, Radtke MA, et al. German psoriasis registry PsoBest: objectives, methodology and baseline data. JDDG J Dtsch Dermatol Ges. 2014;12:48–57. [DOI] [PubMed] [Google Scholar]
- 20.Mease PJ, Hatemi G, Paris M, et al. Apremilast long-term safety up to 5 years from 15 pooled randomized, placebo-controlled studies of psoriasis, psoriatic arthritis, and Behçet’s syndrome. Am J Clin Dermatol. 2023;24:809–20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Basra MK, Fenech R, Gatt RM, Salek MS, Finlay AY. The dermatology life quality index 1994-2007: a comprehensive review of validation data and clinical results. Br J Dermatol. 2008;159:997–1035. [DOI] [PubMed] [Google Scholar]
- 22.OTEZLA [prescribing information]. Thousand Oaks, CA: Amgen Inc., 2021.
- 23.Crowley J, Thaçi D, Joly P, et al. Long-term safety and tolerability of apremilast in patients with psoriasis: pooled safety analysis for ≥156 weeks from 2 phase 3, randomized, controlled trials (ESTEEM 1 and 2). J Am Acad Dermatol. 2017;77:310-7.e1. [DOI] [PubMed] [Google Scholar]
- 24.Reich K, Mrowietz U, Radtke MA, et al. Drug safety of systemic treatments for psoriasis: results from The German Psoriasis Registry PsoBest. Arch Dermatol Res. 2015;307:875–83. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Elmets CA, Leonardi CL, Davis DMR, et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with awareness and attention to comorbidities. J Am Acad Dermatol. 2019;80:1073–113. [DOI] [PubMed] [Google Scholar]
- 26.Tsentemeidou A, Sotiriou E, Sideris N, et al. Apremilast in psoriasis patients with serious comorbidities: a case series and systematic review of literature. Dermatol Pract Concept. 2022;12:e2022179. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Chan A, Rigler K, Herdman L. Real-world experience of apremilast in treating psoriatic arthritis patients with comorbidities. EMJ Rheumatol. 2019;6:134–9. [Google Scholar]
- 28.Heidbrede T, Mevius A, Kessel S, Wilke T, Maywald U, Thiem A. Real-world systemic treatment of patients with psoriasis: a retrospective study based on German claims data. JDDG J Dtsch Dermatol Ges. 2023;21:611–9. [DOI] [PubMed] [Google Scholar]
- 29.Fougerousse AC, Maccari F, Beauchet A, et al. Factors that may influence the choice for initiating apremilast or methotrexate treatment for psoriasis in real-world clinical setting. J Eur Acad Dermatol Venereol. 2019;33:e476–8. [DOI] [PubMed] [Google Scholar]
- 30.Basra MK, Salek MS, Camilleri L, Sturkey R, Finlay AY. Determining the minimal clinically important difference and responsiveness of the Dermatology Life Quality Index (DLQI): further data. Dermatology. 2015;230:27–33. [DOI] [PubMed] [Google Scholar]
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Supplementary Materials
Data Availability Statement
Due to European and German data protection regulations, the transfer of patient-level data is not permitted.