Abstract
Introduction
The aim of this observational, multicenter study was to assess the real-world use of brodalumab for the treatment of moderate-to-severe plaque psoriasis in patients in the Czech Republic, using data from the BIOREP registry.
Methods
The study included 273 patients aged ≥ 18 years with moderate-to-severe psoriasis who received brodalumab. Endpoints were drug survival (time from treatment initiation to discontinuation), effectiveness [Psoriasis Area and Severity Index (PASI)], and health-related quality-of-life [Dermatology Life Quality Index (DLQI)].
Results
Predicted drug survival probability was 92.4% [95% confidence interval (CI): 89.1, 95.7%] at 6 months and 84.2% (95% CI 79.5, 89.1%) at 12 months; this was maintained at 24 months [80.4% (95% CI 74.5, 86.8%)]. Younger age, higher body mass index, and no previous biologic treatment were significantly associated with longer drug survival. Absolute PASI ≤ 3 after 3 months was achieved by 89.8% of patients; 92.4%, 77.8%, and 59.1% reached PASI 75, PASI 90, and PASI 100, respectively. After 12 months, 96.5% of 141 patients had an absolute PASI ≤ 3. The proportion of patients achieving DLQI 0/1 was 87.3% at 12 months.
Conclusion
This study demonstrated high and sustained drug survival with high rates of skin clearance and improved quality of life in patients with relatively severe disease treated with brodalumab. Improvements were observed as early as 3 months post-treatment initiation and were sustained for up to 24 months in a real-life setting.
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In several Phase III trials, brodalumab was more effective than placebo and ustekinumab in reducing the area and severity of moderate-to-severe plaque psoriasis. It also demonstrated efficacy in difficult-to-treat nail and scalp psoriasis. |
Several recent network meta-analyses comparing biological agents suggest that brodalumab may be like ixekizumab and superior to several anti-tumor necrosis factor biologics in Psoriasis Area and Severity Index (PASI) 50,75, 90, and 100 responses. |
Given patient selection bias in clinical trials, it is necessary to confirm that these data can be extrapolated to routine clinical practice in the Czech Republic in a real-world setting, with a broad range of patients; patient-reported outcomes give substantial insights into treatment with modern biologics outside of a clinical trial setting. |
Using real-world data from the BIOREP registry, we have shown that brodalumab treatment has led to sustained drug survival, high rates of skin clearance, and improved quality of life as early as 3 months from treatment initiation in a broad range of patients. |
These data confirm differences in responses between real-life and clinical trials, in particular higher response rates (PASI 100) in real-world settings in short-term observation, and the proportion of patients achieving better PASI scores in a long-term evaluation, confirming brodalumab as an effective treatment in a broad range of patients with moderate-to-severe psoriasis. |
Introduction
Psoriasis is a common chronic inflammatory disease with a substantial negative impact on health-related quality of life, affecting physical and psychological well-being and interfering with daily activities [1,2,3]. The advent of biological treatments for moderate-to-severe plaque psoriasis resulted in significantly improved outcomes, and complete skin clearance is now an attainable goal for many patients [2, 4]. The first biological therapies for plaque psoriasis were the tumor necrosis factor-α inhibitors, infliximab, adalimumab, and etanercept, followed by the interleukin (IL)-12/23 inhibitor, ustekinumab [5]. More recently approved biological therapies include the IL-23 inhibitors, guselkumab, tildrakizumab, and risankizumab [4], the IL-17 inhibitors, secukinumab and ixekizumab, which bind only to the IL-17A ligand, and brodalumab, which targets the IL-17-receptor subunit A (IL-17RA) [3, 6].
The fully human anti-IL-17RA brodalumab is approved for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy [7]. The efficacy and safety of brodalumab in patients with moderate-to-severe psoriasis has been established in three large, phase 3 trials in which brodalumab was compared with placebo and ustekinumab (AMAGINE-1, AMAGINE-2, and AMAGINE-3) [8,9,10], as well as in a phase 4 trial versus oral administrations of fumaric acid esters [11].
Patients included in clinical studies may not be fully representative of those seen in clinical practice, due to trial eligibility criteria which exclude many patients [12]. Real-world evidence provides valuable insights into the effectiveness and safety of treatments in everyday clinical practice in a broad range of patients, including groups typically excluded from clinical trials [13]. To date, real-world evidence on the use of brodalumab is limited [14,15,16,17]. The aim of this observational, multicenter study was to assess drug survival, skin clearance, and health-related quality of life with the real-world use of brodalumab for moderate-to-severe plaque psoriasis in adult patients in the Czech Republic, using data from the BIOREP registry.
Methods
Study Design and Patient Population
BIOREP is a nationwide registry, established in May 2005 (updated in 2011 and 2018) and supervised by the Czech Dermatovenereology Society, with the primary purpose of monitoring the safety of biologics in patients with psoriasis in the Czech Republic. The BIOREP database records drug safety and effectiveness, demographic data, Psoriasis Area and Severity Index (PASI) scores, Dermatology Life Quality Index (DLQI) scores, and comorbidities.
In the Czech Republic, biological therapy is administered at 31 specialized centers, 29 of which are included in the BIOREP registry. Biological therapy is initiated in patients with moderate-to-severe psoriasis at these centers when two of four conventional systemic treatments (acitretin, methotrexate, cyclosporine, and narrowband UVB phototherapy) cannot be used, due to intolerance, lack of efficacy, or the presence of contra-indications. Eligible patients in this analysis were adults aged ≥ 18 years who initiated brodalumab therapy at enrollment in BIOREP before February 2021 and had at least one follow-up visit at 3, 6, 12, 18, and/or 24 months. The decision to use brodalumab was at the discretion of the treating dermatologist. The study was conducted in accordance with the Helsinki Declaration of 1964 and all subsequent amendments, and all patients provided written informed consent for their data to be included in the BIOREP registry. Patient-level data used for this analysis were de-identified, and Institutional Review Board approval was not required for this study. Permission to access/use data from the BIOREP registry was obtained.
Patient Baseline Characteristics
Baseline data were collected for the following patient characteristics: age, sex, body mass index (BMI), PASI, and DLQI, previous treatment regimen and line of therapy, reason for switching to brodalumab, and number and type of comorbidities. Data for all variables were summarized descriptively.
Study Endpoints and Analysis
Study endpoints were drug survival, effectiveness (PASI), and health-related quality of life (DLQI). Drug survival was defined as time from initiation to failure of brodalumab (brodalumab treatment discontinuation, defined as termination, re-induction, or switching to a different biological therapy) in the full analysis set. Patients were censored if they were lost to follow-up or if data were not available for follow-up visits. Reasons for discontinuing brodalumab treatment were recorded. A sensitivity analysis of the primary endpoint of drug survival was also performed, which assessed time from initiation to failure of brodalumab or brodalumab dose adjustment or add-on of psoriasis therapy in the full analysis set.
Drug survival was also analyzed by previous biologic therapy (naïve, i.e., never previously treated with biologic, or experienced, i.e., had received biologic treatment prior to initiating brodalumab), age group (18–35, 36–50, 51–65, or > 65 years), sex, smoking status (current smoker, ex-smoker, or never-smoker), presence of psoriatic arthritis at baseline (yes or no), and BMI category [< 18.5 (underweight), 18.5–24.9 (normal), 25.0–29.9 (overweight), or ≥ 30.0 kg/m2 (obese)]. Drug survival analysis was conducted by Kaplan–Meier estimation for all patients and by subgroups.
A Cox proportional hazards model was developed to investigate the association between time to discontinuation of brodalumab and potential predictor variables at the time of brodalumab initiation [i.e., age, BMI, previously naïve to biological therapy (yes or no), and presence of psoriatic arthritis at baseline (yes or no)].
Effectiveness and quality-of-life endpoints included the proportions of patients achieving an absolute PASI score of ≤ 3, PASI 75, PASI 90, and PASI 100, and DLQI 0/1 at 3 months [patients with ≥ 3 months of follow-up (short-term analysis set)] and 12 months [patients with ≥ 12 months of follow-up (long-term analysis set)]; mean changes in PASI and DLQI at 3 months (short-term analysis set); and time to response as absolute PASI ≤ 3, PASI 75, and PASI 90 (long-term analysis set). Windowing analyses were conducted for absolute PASI, PASI and DLQI for baseline (week 0), 3 months (weeks 10–18), 6 months (weeks 18–39), 12 months (weeks 39–65), 18 months (weeks 65–91), and 24 months (weeks 91–117) after treatment initiation. All analyses were conducted as observed. In cases of multiple values within a time window, the value recorded closest to the defined timepoint (i.e., 3, 6, 12, 18, or 24 months) was selected.
Ethics
The study was conducted in accordance with good pharmacoepidemiology practices by research groups belonging to the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP), in accordance with the ENCePP Code of Conduct and, if possible, under the ENCePP Study Seal. Patient-level data used for this analysis were de-identified, and Institutional Review Board approval was not required for this study. Permission to access/use data from BIOREP registry was obtained.
Results
Baseline Characteristics
Demographics and baseline characteristics of the study population, overall and stratified by prior exposure to biological therapy for psoriasis, is shown in Table 1. The study included 273 patients with moderate-to-severe psoriasis who had received brodalumab. Patients were predominantly males (66.3%). Mean age at psoriasis diagnosis was 25.5 ± 13.6 years, and mean time from diagnosis to initiation of brodalumab therapy was 21.5 ± 12.8 years. Mean BMI was 29.8 ± 6.2 kg/m2 and 44.9% of patients had obesity, with a BMI of ≥ 30 kg/m2. Almost half of patients had a family history of psoriasis (48.4%). At baseline, mean PASI score was 17.2 ± 7.1, mean DLQI was 14.4 ± 6.7, and mean body surface area (BSA) was 24.7 ± 16.5.
Baseline comorbidities were reported in 68.5% of patients, 37.7% of whom had more than one comorbidity. The most frequently reported comorbidities were hypertension (35.2%), dyslipidemia (25.6%), psoriatic arthritis (16.5%), and diabetes (11.7%).
Over half of all patients were biologic naïve (n = 156) before initiating brodalumab therapy. Of the biologic-experienced patients (n = 117), most initiated brodalumab as second-line therapy (46.2%, n = 54); 28.2% (n = 33), 14.5% (n = 17), and 11.1% (n = 13) initiated brodalumab as third line, fourth line, or after more than four lines of therapy, respectively. Antitumor necrosis factor-α was the most common previous biological therapy (54.7%; adalimumab 34.2%, etanercept 16.2%, certolizumab pegol 3.4%, infliximab 0.9%), followed by anti-IL-17As (28.2%; secukinumab 17.1%, ixekizumab 11.1%), anti-IL-23/12 (ustekinumab 15.4%), and anti-IL-23s (1.7%; guselkumab 0.9%, risankizumab 0.9%).
Drug Survival
At the time of analysis, 41 patients (15.0%) had stopped brodalumab treatment (Table 1). Six patients (2.2%) discontinued due to adverse events (five of these patients switched to another biologic; one patient with latent tuberculosis continued brodalumab treatment after 3 months). Other reasons for discontinuation were loss of effectiveness (31 patients; 11.3%); pregnancy (one patient; 0.4%), patient non-cooperation (one patient; 0.4%), and other (two patients, 0.7%).
Predicted drug survival probability was 92.4% [95% confidence interval (CI) 89.1, 95.7%] at 6 months and 84.2% (95% CI 79.5, 89.1%) at 12 months; this was maintained at 24 months [0.4% (95% CI 74.5, 86.8%)] (Fig. 1). For the sensitivity analysis (time from initiation to failure of brodalumab, brodalumab dose adjustment during the study period or add-on of psoriasis therapy after initiation of brodalumab), no dose adjustments were made and seven patients had add-on systemic therapy (methotrexate, n = 5; prednisone, n = 2); predicted drug survival probability was 90.7% (95% CI 87.2, 94.4%) at 6 months and 82.0% (95% CI 77.1, 87.2%) at 12 months.
Kaplan–Meier analysis estimated that biologic-naïve patients had a 67.4% lower risk of discontinuation compared to biologic-experienced patients; 12-month drug survival of biologic-naïve patients was 91.2% (95% CI 86.3, 96.4%) compared to 76.7% (95% CI 69.0, 85.2%) for biologic-experienced patients (Fig. 2A). Estimated drug survival at 12 months appeared to be better in patients aged > 65 years, compared with younger age groups (Fig. 2B); however, patient numbers were low in this oldest age group (aged > 65 years), with only 18 patients at 12-month follow-up. When stratifying by BMI category, estimated drug survival at 12 months appeared to be better in patients who were overweight, and worse in those who were obese, compared with patients of normal weight (Fig. 2C). No statistically significant differences were observed in estimated drug survival at 12 months between female and male patients [81.1% (95% CI 72.6, 90.7) vs. 85.6% (95% CI 80.2, 91.4); p = 0.53], patients with or without psoriatic arthritis [79.5% (95% CI 67.7, 93.4%) vs. 85.1% (95% CI 80.1, 90.4%); p = 0.73], and patients who were current, ex- or non-smokers [81.0% (95% CI 72.6, 90.3), 88.5% (95% CI 80.1, 97.7), and 84.3% (95% CI 77.2, 92.0); p = 0.76] (Fig. 2D–F).
In a Cox proportional hazards regression model, lower age [hazard ratio (HR) 0.968, (95% CI 0.944, 0.992), p = 0.009], higher BMI [HR 1.081, (95% CI 1.037, 1.126), p < 0.001], and being biologic naïve [HR 0.326, (95% CI 0.165, 0.644), p < 0.001] were significantly associated with time to discontinuation and seemed to be predictors of better drug survival. The risk of discontinuation of brodalumab treatment was 3.2 times lower for every 1-year age increase since initiation of brodalumab treatment and 1.1 times higher for every increase in BMI of one unit (kg/m2).
Effectiveness
Of the 273 patients who initiated brodalumab therapy, 224 (82.1%) had a 3-month follow-up visit in the registry (short-term analysis set) and 141 had a 12-month follow-up (long-term analysis set). In the short-term analysis set, an absolute PASI ≤ 3 after 3 months was achieved by 89.8% of patients. Numerically more biologic-naïve than biologic-experienced patients achieved absolute PASI ≤ 3 (95.9% vs. 82.7%, respectively) (Fig. 3; Table 2). Mean PASI at baseline was 17.0 and decreased to 1.1 (mean change: − 16.0) after 3 months. A total of 92.4% of patients reached PASI 75, 77.8% reached PASI 90, and 59.1% reached PASI 100 after 3 months (Fig. 3; Table 2).
After 12 months, 96.5% of 141 patients with 12 months’ follow-up had an absolute PASI ≤ 3, with a similar proportion of responders in patients who were biologic naïve (97.4%) and biologic experienced (95.5%) (Fig. 3; Table 2). A total of 95.1%, 87.3%, and 69.7% of patients achieved PASI 75, PASI 90, and PASI 100, respectively (Fig. 3; Table 2).
A decrease in DLQI was observed at 3 months from 14.2 to 1.3 (− 12.9), and 73.8% of patients achieved DLQI 0/1 (Fig. 3; Table 2). The proportion of patients achieving DLQI 0/1 increased to 87.3% at month 12 (Fig. 3; Table 2). These high proportions for PASI and DLQI remained through to 18 and 24 months.
Discussion
Real-world evidence can provide valuable insights into treatment effectiveness in more diverse clinical settings and in a broader range of patients than provided by clinical trials, which often have strict eligibility criteria [18, 19], with many patients, including the elderly and those with comorbidities, typically excluded [20]. This can result in selection bias and uncertainty about external validity when applied to the real-world setting. Patients in the real-world setting may also be more likely to have failed previous biological therapy, especially when newer agents are being investigated [20]. Previous analyses of the BIOREP registry showed that half the patients had cardiovascular risk factors, approximately 70% patients were either overweight or obese, and over a third (41.0%) reported a history of psoriatic arthritis [21], while 62% of patients initiating risankizumab had failed previous biological therapy [20]. Similarly, this study showed that close to 7 in 10 patients initiated on brodalumab therapy had comorbidities, most frequently those associated with metabolic syndrome, in particular hypertension, dyslipidemia, and type 2 diabetes, while 43% were biologic experienced.
Drug survival is often used as a surrogate measure to evaluate the effectiveness, safety, and real-world utility of biologics in psoriasis [22]. Biological drug survival reflects long-term treatment success and is an important measure in guiding clinical decision-making [22]. This analysis of real-world data demonstrated high and sustained drug survival for patients with moderate-to-severe plaque psoriasis treated with brodalumab for up to 24 months in a real-life setting. Moreover, data were analyzed at a 24-month cut-off, and it should be noted that drug survival may continue beyond this point.
The predicted drug survival probability was 84.2% and 80.4% at 12 and 24 months, respectively, with these results largely consistent with those from other real-world studies of biologics, although direct comparisons are not possible due to differences in their designs, patient populations, and definitions of drug survival. Previous analysis of BIOREP data estimated a 76% survival rate for adalimumab at month 20, falling to 58.1% in the 80th month of treatment [23], while analysis of five PSONET registries including BIOREP reported survival rates after 1 year of 43–92% with etanercept, 28–83% with adalimumab, 65–87% with infliximab, and 53–77% with ustekinumab, all when combined with methotrexate [24]. In a meta-analysis of 29 cohort studies in psoriasis, estimated pooled drug survival rates at 2 years were 53.2% for adalimumab, 48.9% for infliximab, and 47.6% for etanercept [22], while a retrospective, multicenter cohort study of 3145 patients from 16 centers across Europe and North America reported cumulative probabilities of drug survival at 18 months of 96.4% for risankizumab, 91.1% for guselkumab, 86.3% for brodalumab, 86.1% for ustekinumab, 82.0% for ixekizumab, and 79.9% for secukinumab [25].
Previous reports have indicated negative predictors of drug survival as female gender, obesity, and previous failed biological therapies [23, 26,27,28,29]. Consistent with this, in our analysis, biologic-naïve patients had a 76.5% lower risk of discontinuation after 12 months compared to biologic-experienced patients. However, no difference in drug survival rates were observed between males and females, while, rather surprisingly, patients who were overweight had better drug survival than normal weight patients, although drug survival was lower in patients with obesity. This may be due to the relatively small patient numbers in each of the different body weight groups, so these data should be interpreted with caution. Drug survival also appeared to be higher in patients aged over 65 years treated with brodalumab, although, again, the number of patients included in the analysis was small (n = 26) and this failed to reach statistical significance. However, age was found to be significantly associated with time to discontinuation (p = 0.009), and appeared to predict drug survival. There was also no statistically significant difference in drug survival between patients with and without psoriatic arthritis, although patients with psoriatic arthritis had a 1.28 times higher risk of discontinuation of treatment.
Loss of effectiveness and adverse events were the most common reasons for discontinuation of brodalumab (11% of patients), which is consistent with other studies of biologics for the treatment of psoriasis in real-world settings [30].
This real-world study also demonstrated the effectiveness of brodalumab when assessed by PASI, with improvements in PASI 75, 90, and 100 observed as early as 3 months (rates of 92.4%, 77.8%, and 59.1%, respectively), and being sustained at 1-year (95.1%, 87.3%, and 69.7%, respectively) and for up to 2 years. In two phase 3 trials of brodalumab in patients with moderate-to-severe psoriasis (AMAGINE-2 and -3), PASI 75 rates were 85% and 86% at week 12 and 80% and 80% at week 52, while PASI 100 rates were 44% and 37% at week 12 and 56% and 53% at week 52 [8]. Also, in a smaller real-world Italian study in 78 adult patients, a higher proportion achieving PASI 100 (51.3%) was observed in the short-term evaluation after 12 weeks [31]. Similarly, a real-world study of risankizumab in moderate-to-severe psoriasis recorded PASI 90 and PASI 100 rates of 63.8% and 44.7% after 16 weeks, increasing to 82.4% and 67.6%, respectively, at week 52 [20]. These data confirm differences in responses between real-life and clinical trials, in particular higher response rates (PASI 100) in short-term observation, and the proportion of patients achieving better PASI scores in a long-term evaluation. Improvements in quality of life were also reported for patients with psoriasis on brodalumab therapy with 74% of patients reporting DLQI 0/1 at week 12, increasing to 87% at 1 year. In AMAGINE-2 and -3, 60% of patients with a DLQI score > 1 at baseline treated with brodalumab achieved a DLQI score of 0/1 at 12 weeks and 55% at 1 year [2].
Strengths and Limitations of the Study
Key strengths of the study were the large patient population and representation of most specialist centers in the Czech Republic within the BIOREP registry, ensuring high internal validity. However, the study had several weaknesses inherent in its design. Firstly, real-world data are subject to various sources of potential bias and confounding factors [18]. Secondly, effectiveness endpoints were based on observed data as collected in routine clinical practice, and may therefore be incomplete or missing; in particular, missing data for later study visits due to premature discontinuations may reduce the accuracy of long-term estimations of treatment effectiveness. However, assumptions about data being missing at random, as carried out in a clinical trial setting, may not be valid in a real-world situation, with multiple imputation and non-responder imputation leading to a larger bias than simply analyzing data as observed. Finally, the study was conducted in a single country, which could limit the generalizability of the results, particularly as prescribing patterns for psoriasis may differ between countries.
Conclusions
This multicenter, observational study demonstrated high and sustained drug survival as well as high rates of skin clearance and improvement in quality of life for patients with moderate-to-severe plaque psoriasis treated with brodalumab for up to 24 months in a real-life setting.
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Acknowledgements
The authors wish to thank all of participants who took part in this study, the dermatologists and collaborators who participated in the creation of BIOREP for their efforts and dedication to the project. BIOREP Group Members: Zdenek Antal, Petr Arenberger, Jirina Bartonova, Alzbeta Bezvodova, Linda Blahova, Petra Brodska, Hana Buckova, Martin Cetkovsky, Dominika Diamantova, Hana Duchkova, Olga Filipovska, Petra Gkalpakioti, Martina Grycova, Jiri Horazdovsky, Eva Horka, Katerina Hrazdirova, Eduard Hrncir, Jaromira Janku, Renata Kopova, Dora Kovandova, Iva Lomicova, Romana Machackova, Hana Malikova, Martina Matzenauer, Miroslav Necas, Helena Nemcova, Radka Neumannová, Jitka Osmerova, Veronika Pallova, Blanka Pinkova, Zuzana Plzakova, Marie Policarova, Tomas Pospisil, Miloslav Salavec, Veronika Slonkova, Ivana Strouhalova, David Stuchlik, Alena Stumpfova, Jaroslav Sevcik, Jan Sternbersky, Jirí Stork, Katerina Svarcova, Katerina Tepla, Martin Tichy, Hana Tomkova, Yvetta Vantuchova, Vladimir Vasku, Ivana Vejrova, Iva Zampachova.
Medical Writing/Editorial Assistance
Medical writing and editorial assistance were provided by Andy Bond of Rhea, OPEN Health Communications, funded by Leo Pharma A/S, in accordance with Good Publication Practice (GPP) guidelines (www.ismpp.org/GPP-2022).
Author Contribution
Martina Kojanova, Spyridon Gkalpakiotis, Petra Cetkovska, Jorga Fialova, and Alena Machovcova contributed to data collection, analysis and interpretation, and manuscript development. Barbora Turkova, Tomas Dolezal and Eydna Didriksen Apol contributed to data analysis and interpretation, and manuscript development.
Funding
This work, including funding of the journal’s Rapid service and Open Access fees, were supported by Leo Pharma A/S.
Data Availability
The datasets generated and analyzed during this study are available from the corresponding author on reasonable request.
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Open access publishing supported by the National Technical Library in Prague.
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Conflict of Interest
Martina Kojanova, Spyridon Gkalpakiotis, Petra Cetkovska, Jorga Fialova, Alena Machovcova, and Tomas Dolezal have served as consultants, speakers, or investigators for AbbVie, Amgen, Eli Lilly, Janssen, LEO Pharma, Novartis, Pfizer, and UCB. Barbora Turkova declares that she has nothing to disclose. Eydna Didriksen Apol is an employee of Leo Pharma A/S.
Ethical Approval
The study was conducted in accordance with good pharmacoepidemiology practices by research groups belonging to the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP), in accordance with the ENCePP Code of Conduct and, if possible, under the ENCePP Study Seal. Patient-level data used for this analysis were de-identified, and Institutional Review Board approval was not required for this study. Permission to access/use data from BIOREP registry was obtained.
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Kojanova, M., Turkova, B., Gkalpakiotis, S. et al. Real-World Data on Brodalumab Treatment in Patients with Moderate-to-Severe Plaque Psoriasis: An Observational Study from the Czech Republic BIOREP Registry. Adv Ther 41, 3951–3971 (2024). https://doi.org/10.1007/s12325-024-02952-4
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DOI: https://doi.org/10.1007/s12325-024-02952-4