Martínez-Domenech Alvaro (Orcid ID: 0000-0002-1252-1001) Ruiz-Villaverde Ricardo (Orcid ID: 0000-0002-0381-6174) Llamas-Velasco Mar (Orcid ID: 0000-0002-1187-1341) Rivera Raquel (Orcid ID: 0000-0002-4604-0724) Carrascosa Jose Manuel (Orcid ID: 0000-0003-4266-0771) del Alcázar Viladomiu Elena (Orcid ID: 0000-0002-5935-356X) Effectiveness and safety of guselkumab for the treatment of psoriasis in real-world settings at 24 weeks: A retrospective, observational, multicentre study by the Spanish Psoriasis Group Authors: Elena del Alcázar (1), Anna López-Ferrer (2), Álvaro Martínez-Doménech (3), Ricardo Ruiz-Villaverde (4), Mª del Mar Llamas-Velasco (5), Vicenç Rocamora (6), Marc Julià (7), Jaime Notario (8), Lourdes Rodríguez Fernández-Freire (9), Antonio Sahuquillo-Torralba (10), David Vidal (11), Raquel Rivera (12), Gregorio Carretero (13), Almudena Mateu (14), Pablo de la Cueva (15), y José Manuel Carrascosa (1). Affiliations: 1. Department of Dermatology. Hospital Universitari Germans Trias i Pujol. Universitat Autònoma de Barcelona (UAB). Badalona, Spain 2. Department of Dermatology Hospital de la Santa Creu i Sant Pau, Barcelona,Spain 3. Department of Dermatology.Hospital General Universitario de Valencia, Spain 4. Department of Dermatology. Hospital Clínico Universitario San Cecilio, Granada, Spain 5. Department of Dermatology. Hospital Universitario de la Princesa, Madrid, Spain 6. Department of Dermatology. Hospital de Manacor (Illes Balears), Spain 7. Department of Dermatology. Hospital Universitario de Basurto, Bilbao (Vizcaya), Spain 8. Department of Dermatology. Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat (Barcelona), Spain This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/dth.15231 This article is protected by copyright. All rights reserved. 9. Department of Dermatology. Hospital Universitario Virgen del Rocío, Sevilla, Spain 10. Department of Dermatology. Hospital Universitario y Politécnico La Fe, Valencia. Instituto de Investigación Sanitaria La Fe. Valencia, Spain. 11. Department of Dermatology. Complex Hospitalari Moisès Broggi, Sant Joan Despí (Barcelona), Spain 12. Department of Dermatology. Hospital Universitario 12 de Octubre, Madrid, Spain 13. Department of Dermatology. Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria (Las Palmas), Spain 14. Department of Dermatology. Hospital Universitario Dr. Peset, Valencia, Spain 15. Department of Dermatology. Hospital Infanta Leonor, Madrid, Spain Collaborators Spanish Psoriasis Group of the Spanish Academy of Dermatology and Venereology: Antonio Martorell, Marta Ferran, Diana Patricia Ruiz, Laura García, Elena Remedios Martínez, Esther de Eusebio, Amalia Pérez, Gloria Aparicio, Josep A. Pujol, Laura Salgado, Mariano Ara, Carlos Muñoz, Isabel Belinchón, Jesús Rodero, Alberto Romero, Noemí Eirís, Anna Isabel Lázaro. Corresponding author: Elena del Alcázar, MD. E-mail: elenadelalcázarviadomiu@gmail.com Conflicts of interest: Elena del Alcázar has served as a consultant or paid speaker for or participated in clinical trials sponsored by companies, including Abbvie, Amgen, Leo Pharma, Almirall, Janssen-Cilag, Lilly, Novartis, Sanofi and UCB Anna López- Ferrer has perceived consultancy/educational support/speakers honoraria and/or participated in clinical trials sponsored by AbbVie, Almirall, Amgen, Boehringer Ingelheim, Celgene, Janssen, Leo Pharma, Lilly, MSD, Novartis, Pfizer and UCB Álvaro Martínez-Doménech has participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Almirall and Janssen-Cilag. Ricardo Ruiz-Villaverde has received grants, and research support, served as a consultant or received honoraria from Pfizer, Novartis, Lilly, Celgene, Almirall and Abbvie M. Llamas-Velasco has potential conflict of interests (advisory board member, consultant, research support, participation in clinical trials and honorary for speaking) with the following pharmaceutical companies: Abbvie, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Lilly and Celgene. Vinveç Rocamora has received grants, and research support, served as a consultant or received honoraria from Novartis, Janssen-Cilag, Abbvie, Celgene, UCB i MSD Marc Julià has served as a consultant or paid speaker for or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Janssen-Cilag, LEO Pharma, Lilly, Novartis, and Pfizer. Jaime Notario has served as a consultant or paid speaker for and/or participated in clinical trials sponsored by AbbVie, Almirall, Celgene, Gebro, Janssen, Leo Pharma, Lilly, MSD, Novartis and Pfizer Lourdes Rodríguez Fernández-Freire has served as a consultant and speaker for AbbVie Laboratories, Janssen Pharmaceuticals Inc, MSD, Pfizer-Wyeth, Novartis, Celgene, Almirall SA, Lilly and Leo-Pharma Antonio Sahuquillo-Torralba has served as a consultant or paid speaker for or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis, and Pfizer. Raquel Rivera-Diaz acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Abbvie/Abbott, Almirall, Amgen, Celgene, Janssen-Cilag, Leo Pharma, Lilly, MSD-Schering-Plough, Novartis, Pfizer and UCB . https://orcid.org/0000-0002-4604-0724 David Vidal has participated in clinical trials and/or received honoraria as a consultant, investigator, speaker from AbbVie, Celgene, Janssen, Lilly, LeoPharma and Novartis. Gregorio Carretero has participated as PI/SI,and/or member of steering committee, and/or advisor and/or invited speaker for Celgene, Amgen, Abbvie, Almirall, Novartis, Leo-Pharma, Lilly, Sandoz, Mylan, Janssen Almudena Mateu has potential conflict of interests (advisory board member, consultant, research support, participation in clinical trials and honorary for speaking) with the following pharmaceutical companies Abbvie , Almirall SA, Celgene, Jansen-Cilag, Leo- Pharma, Lilly, Novartis y Pfizer Pablo de la Cueva has served as a consultant or paid speaker for or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Almirall, Astellas, Biogen, Boehringer, Celgene, Janssen., LEO Pharma, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, UCB . José Manuel Carrascosa has participated as PI/SI, and/or member of steering committees and/or advisor and/or invited speaker for Celgene, Amgen, Abbvie, Almirall, Novartis, Leo-Pharma, Lilly, Sandoz, Mylan, and Janssen. PI/SI clinical trials Dermatology IGTP. None of the aforementioned has any relation to the present work. Author contribution: All authors contributed to the design and implementation of the research. Elena del Alcázar contributed to collect data from the different centres, the analysis of the results and to the writing of the manuscript. José Manuel Carrascosa contributed to the supervision of the final manuscript. Funding Sources: None Keywords: psoriasis, guselkumab, real-world Running head: Guselkumab in plaque psoriasis in routine clinical care ABSTRACT Background: Data on the effectiveness and safety of a drug in real-world clinical practice complement the evidence from clinical trials, which are carried out in a different setting. Little has been published on the effectiveness and safety of guselkumab in the treatment of psoriasis in clinical practice. Objectives: To assess the effectiveness and safety of guselkumab at 24 weeks in patients with moderate to severe plaque psoriasis in routine clinical practice. Methods: Retrospective, multicentre study of adult patients with moderate to severe plaque psoriasis treated with guselkumab for at least 24 weeks in Spain. Results: We studied 343 patients, 249 of whom were followed for 24 weeks. By week 24, the mean (SD) Psoriasis Area and Severity Index (PASI) had decreased from 11.1 (7.3) to 1.7 (2.8) (-9.3; [-10.2;-8.4]), 85.9% of the patients had achieved PASI score of 4 or less and 77.9% a PASI score of 2 or less. In terms of relative PASI response, 59.4% of the patients achieved a PASI-90 response and 49.0% a PASI-100 response. On multivariate analysis, 2 factors reduced the probability of a PASI of 2 or less at 24 weeks: a BMI ≥30 (OR, 0.44; 95% CI, 0.22-0.88) and a greater previous exposure to biologic therapy (OR, 0.69; 95% CI, 0.56-0.84]). Adverse events were rare (9.9%) and led to withdrawal from treatment in only 9 patients (2.6%) by the end of the follow-up period. Conclusion: The results of this study confirm the high efficacy and safety of guselkumab indicated by the clinical trial data. In clinical practice, the absolute PASI score appears to be a better marker of response to treatment than the relative value. INTRODUCTION Guselkumab is a fully human immunoglobulin G1 lambda monoclonal antibody to the interleukin (IL)-23 protein, which it inhibits by binding selectively to the p19 subunit with high specificity and affinity (1). The immune response of the IL-23/T17 axis is currently thought to be the main pathogenic pathway in psoriasis, which would explain why agents targeting this pathway achieve the best clinical response and are currently the drugs most often used to treat these patients (2,3). The Phase III clinical trials (VOYAGE 1 and 2) demonstrated the superiority of guselkumab over adalimumab in the treatment of moderate to severe plaque psoriasis (4,5). In VOYAGE 1 and 2, respectively, 80.2% and 75.2% of patients treated with guselkumab achieved a PASI-90 response at week 24 as compared to 53.0% and 54.8% of those treated with adalimumab (P < 0.001). The results of the Phase III trials also showed that guselkumab has a good safety profile, similar to that of adalimumab (4,5) and ustekinumab (6), with upper respiratory tract infections being the most commonly reported adverse event. Guselkumab also showed superior efficacy over secukinumab in the ECLIPSE study. In that study, a PASI 90 response at week 48 was achieved by 84% of the patients treated with guselkumab compared to 70% of those treated with secukinumab (P < 0.0001) (7). In November 2017, guselkumab became the first IL-23 inhibitor to be approved by the EMA. Since February 2019, it has been available in Spain for the treatment of moderate to severe plaque psoriasis in patients who have had an inadequate response or a contraindication or intolerance to conventional systemic treatments and PUVA (1). In accordance with the criteria of the treatment appraisal report issued by the Spanish Ministry of Health, guselkumab is only prescribed to patients who have previously received a biologic TNF inhibitor. Clinical trial data are obtained under conditions distinct from those found in routine clinical practice. Authors studying the real-world use of various drugs have observed that the patient population in clinical practice has different characteristics to that of clinical trials (8,9) and, in some cases, the outcomes observed in registry data are different from those reported in clinical trials (10). For this reason, data on the use of a drug in a real-world setting help clinicians to predict how it will work in the patients they attend in their practice. The objective of this study was to assess the effectiveness and safety of guselkumab at 24 weeks in patients with moderate to severe plaque psoriasis. MATERIAL AND METHODS Study Design, Patients and Data Collected The Spanish Psoriasis Group of the Spanish Academy of Dermatology and Venereology carried out a retrospective, observational, multicentre study with the participation of 35 Spanish hospitals. The patients included were adults (≥ 18 years) with a diagnosis of moderate to severe plaque psoriasis who had been treated with guselkumab between 1 February 2019 and 30 June 2020. Patients who completed at least 16 weeks of follow-up were deemed not to have withdrawn from treatment. The following patient data were extracted from anonymized electronic medical records: age, sex, weight, height, body mass index (BMI; categorised as normal or overweight < 30 or obesity ≥ 30), comorbidities, personal history of cancer, and previous treatment for psoriasis, including systemic and biologic therapies. Patients received guselkumab 100 mg at weeks 0 and 4 followed by a maintenance dose every 8 weeks as indicated in the Summary of Product Characteristics, except in the case of 10.2% of the patients (35/343), who did not receive an induction dose. The present study was conducted in accordance with the Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects and was approved by the local clinical research ethics committee at Hospital Universitari Germans Trias i Pujol (reference number: EDA-GUS-2019-01). Response Assessment The 35 dermatologists who took part in the study are all members of the Spanish Psoriasis Group. Data on the following variables were obtained from the patients’ medical records: PASI, body surface area (BSA), physician global assessment (PGA) and Dermatology Life Quality Index (DLQI) at baseline and at weeks 16 and 24. The PGA was assessed on a 6-point scale (0 = clear, 1 = almost clear, 2 = mild, 3 = moderate, 4 = severe, and 5 = very severe). The primary endpoints were improvement in mean PASI score and the percentage of patients who had achieved a PASI score of 2 or less (PASI ≤2) or of 4 or less (PASI ≤4) at week 24. The secondary endpoints were the percentage of patients who achieved a PASI ≤2 or PASI ≤4 at week 16 and a PASI-90, or PASI-100 at weeks 16 and 24. Other effectiveness variables analysed were the mean reduction in BSA, PGA and DLQI scores at weeks 16 and 24. Other objectives included describing the clinical characteristics of the patients, identifying variables that might condition the clinical response, and evaluating the clinical response according to prior treatments received. Safety Data were collected on the frequency of adverse events and the percentage of patients who discontinued treatment due to such events. Reasons for discontinuation were also recorded and classified as follows: lack or loss of efficacy, serious adverse events, and others (lack of compliance, patient's decision, etc.). Statistical Analysis Qualitative variables were expressed in absolute (n) and relative (percentages) values and quantitative variables as mean and standard deviation (SD). Pearson's chi- square test was used to compare qualitative variables. For quantitative variables Student's t-test was used once the normality hypothesis had been tested. To compare the same variable over time at different time points, we used statistical tests for pairwise comparison and expressed the results as the difference in the mean and 95% confidence interval (difference; 95% CI). The clinical characteristics associated with the achievement of PASI-90 and PASI ≤2 were analysed using simple and multiple logistic regression models and the forward method. The results were expressed as odds ratios (OR) and 95% CI. The statistical analysis was performed using the SPSS software package (version 22.0 for Windows). A P value of less than 0.05 was considered significant. The as observed method was used in the case of missing data as this is the most common method used in this type of study. We also performed a modified non- responder imputation (NRI) analysis of the data. A non-responder was defined as any patient in whom treatment was discontinued, whether due to treatment-related factors (lack of efficacy, adverse events) or other reasons (i.e. patient decision). RESULTS Demographic and Clinical Characteristics The study included 343 patients with plaque psoriasis who received guselkumab in the 35 participating hospitals. The clinical and demographic characteristics of the study population are shown in Table 1. The mean (SD) values for the physical characteristics of the population (198 men and 145 women) were as follows: age, 48.3 (14.1) years; weight, 85.5 (20.7) kg; and BMI, 29.7 (6.5). At baseline, mean PASI was 11.1 (7.3), mean BSA was 13.7 (13.8), and mean DLQI was 11.9 (7.3). In total, 90.1% (309) of the patients had received conventional systemic therapy (ciclosporin, methotrexate or acitretin), 55.7% (191) had undergone phototherapy, and 8.2% (28) had received apremilast. In all, 91.8% (315) had received biologic therapy and the mean number of biologic agents received was 2.4 (1.7). Of the patients included, 16% (55) had psoriatic arthritis, 5.2% (18) had a history of cancer, 4.4% (15) a history of hepatitis (4 with hepatitis C, 3 of whom had been treated and cured prior to the administration of guselkumab, and 11 with hepatitis B), and 2.2% (7) a history of inflammatory bowel disease. Patient Distribution Over Time (Figure 1) Of the 343 patients included in the study, 249 completed 24-weeks follow-up. At week 16, 8 patients had discontinued treatment (4 due to adverse events and 4 for other reasons) and by week 24 a further 10 patients had discontinued (5 due to adverse events, 3 due to lack of efficacy, and 2 for 2 lack of efficacy for joint symptoms). In addition, no data on effectiveness were collected at 24 weeks for 36 patients who were still receiving treatment but could not be assessed due to the COVID-19 pandemic, nor for 40 others, who were between weeks 16 and 24 of treatment. Effectiveness Mean PASI, which was 11.1 (7.3) at baseline, decreased to 2.4 (3.2) (-8.8; [9.6; -8.0]) by week 16 and to 1.7 (2.8) (-9.3; [-10.2; -8.4]) at week 24, with statistically significant differences observed at both points (Figure 2). This represents a decline in mean PASI of 78.4% at week 16 and 84.7% at week 24. After 6 months of treatment, 85.9% (214/249) of the patients still receiving treatment had achieved PASI ≤4 and 77.9% (194/249) PASI ≤2 (Figure 3a). In terms of relative response, 59.4% (148/249) achieved a PASI-90 and 49.0% (122/249) a PASI-100 (Figure 4a). The analysis carried out using the modified NRI method produced slightly lower results: 80.1% (214/267) of the patients achieved PASI ≤ 4, 72.7% (194/267) achieved PASI ≤ 2, 55.4% (140/267) a PASI 90 response and 45.7% (122/267) a PASI 100 response (Figures 3b and 4b). Reductions at weeks 16 and 24 were also observed for the other variables studied (BSA, PGA and DLQI) and significant differences were observed. The mean baseline BSA of 13.7 (13.8) decreased to 3.8 (7.0) (-9.8; [-11.1;-8.4]) by week 16 and to 2.3 (4.7) (-11.3; [-12.9;-9.7]) by week 24. The baseline PGA of 3.2 (0.8) fell to 1.1 (0.9) (-2.1; [-2.2;- 1.9]) by the end of the fourth month and to 0.9 (0.9) (-2.2; [-2.5;-2.1]) by the end of the study. With respect to quality of life, the baseline mean DLQI of 11.9 (7.3) decreased to 2.7 (4.1) (-9.3; [-10.2;-8.4]) at week 16 and to 2.4 (4.3) (-9.9; [-11.1;-8.9]) by the end of the study. To identify variables that might interfere with the PASI-90 and PASI ≤2 responses, we performed a bivariant analysis to observe the direct effect between variables complemented by a multivariate analysis to adjust for confounding variables (Table 2). On multivariate analysis the following factors decreased the probability of a PASI ≤2 at 24 weeks: BMI ≥30 (OR, 0.44; 95% CI, 0.22-0.88) and greater exposure to prior biologic therapy (OR, 0.69; 95% CI, 0.56-0.84). No significant differences were observed in the other variables analysed: age, sex, psoriatic arthritis, initial severity of psoriasis (PASI >10 and PASI <10), and duration of disease. Analysis of the clinical response according to the drug patients had received before guselkumab (Table 3) showed that PASI ≤2 at 24 weeks was achieved by 92.4% (61/66) of the patients treated with guselkumab after treatment with a TNF inhibitor, 84.9% (62/73) of those who switched from ustekinumab, and 60.8% (45/74) of those previously treated with an IL-17 inhibitor, with significant differences (P < 0.001). Safety Adverse events were reported by 9.9% (34/343) of patients, with infections being the most common (Table 4). Only 9 patients (2.6%) discontinued treatment owing to adverse events: 2 headache, 2 joint pain, 2 COVID-19 pneumonia, 1 flu-like symptoms, 1 respiratory infection, and 1 acute myocardial infarction. Other reasons for stopping treatment were as follows: patient decision (2), poor adherence (2), primary treatment failure (3), and lack of efficacy on joint disease (2). DISCUSSION We present a series of 343 patients with plaque psoriasis treated with guselkumab in clinical practice, the largest series reported in the literature to date. Our clinical practice data reflect the effectiveness of guselkumab in a context different from that of clinical trials. It is well known that the profile of patients treated in a clinical practice is more complex than that of patients included in trials, with real- world patients having more comorbid conditions and greater exposure to previous biologic therapy (11). In our study, over 90% of patients had received prior biologic therapy as compared to 20% to 22% of the patients included in VOYAGE 1 and 2 (4,5). Furthermore, patients treated in real-world practice usually have a lower PASI score when they start treatment than participants in pivotal trials, mainly due to the absence of a washout period. In our study, the mean baseline PASI was 11, half that of the VOYAGE trials in which baseline PASI was around 22 (4,5). For this reason, the absolute PASI value is a better measure of the success of treatment than the relative values expressed as a 75% (PASI-75) or 90% (PASI-90) reduction over the baseline score. The advantage of using absolute PASI scores is that they are not dependent on baseline values, which are not thought to be clinically relevant 6 months after the start of treatment (12). The British BADBIR group recently reported that an absolute PASI ≤2 corresponds to a PASI-90 response and that PASI ≤4 corresponds to a PASI- 75 response (13). These were the 2 absolute values used as primary endpoints in our study. At week 24, nearly 80% of our patients had a PASI ≤2, a percentage similar to that achieved for PASI-90 in VOYAGE 1 (80.2%) and VOYAGE 2 (75.2%). In addition, our results for complete clearing (PASI-100) at week 24 were slightly higher than those reported in the pivotal trials: 49% versus 44%. Little evidence is available on the effectiveness of guselkumab in real-world clinical practice, with only 9 series published in the literature (14–22) (Table 5). Analysis of the baseline values in all of those series reveals that—in line with our findings—a higher proportion of the patients in clinical practice had received prior biologic therapy (59%-75.3%) than in the VOYAGE trials and that the mean baseline PASI was lower (12.7-15.1) in clinical practice than in the pivotal trials, with the exception of the series by Galluzzo et al (19) with a mean baseline PASI of 20. In most of those series, effectiveness was expressed in relative PASI values and the response rates achieved for PASI-90 and PASI-100 in the two largest series are similar to those found in our study (14,15). The only earlier study that assessed treatment response in terms of absolute PASI reported that 74.4% of the patients achieved a PASI ≤3 at week 20 (19). It appears, therefore, that guselkumab achieves high efficacy rates in patients who have previously been treated with other biologic drugs. It is known that certain variables or factors can negatively influence the efficacy of a drug: duration of the disease, obesity, a history of psoriatic arthritis, and prior treatment with multiple biologic agents (23,24). In our series, the probability of achieving PASI ≤2 at 24 weeks decreased in the presence of obesity (BMI ≥30) and greater prior exposure to biologic therapy. Obesity has, in general, been associated with lower efficacy in biologic therapy, particularly in the case of drugs for which the dose is not weight adjusted (25). There are a number of possible explanations for this effect, including the fact that body mass modifies the pharmacokinetics and clearance of biologic drugs, and that visceral fat triggers proinflammatory effects mediated by the release of adipokines. Although the dose of guselkumab is not adjusted to body weight, fat may interfere with pharmacokinetics (apparent clearance and volume of distribution) (26). Subgroup analyses of pooled data from the head-to-head Phase III trials that compared guselkumab, adalimumab and placebo showed that guselkumab provided superior sustained efficacy compared to adalimumab and placebo across all bodyweight classes (27). The impact of prior biologic therapy has also been studied in other clinical practice series (15,19). Galluzzo et al. (19) reported that lower prior exposure to biologic therapy was associated with a higher probability of achieving PASI-90, a finding similar to that of our study. Benhadou et al., by contrast, found no statistically significant differences in PASI-75, PASI-90 or PASI-100 response between biologic- naive patients and biologic-experienced patients, although those authors do not specify what the differences were (15). Our study reviewed the effectiveness of guselkumab as a function of prior biologic treatment. It is particularly interesting to evaluate the efficacy of guselkumab in patients who have failed to respond to treatment with ustekinumab because of the similar mechanism of action in the pathogenicity of psoriasis. In patients who have received IL-17 inhibitors, it is interesting because of the role of IL-23 in the positive regulation of IL-17 in the IL-23/IL-17 axis. In our study, almost 60% of the patients who switched from ustekinumab to guselkumab achieved PASI-90 at week 24, a result similar to that reported in the NAVIGATE trial (6), reflecting that guselkumab may be an effective option for patients who do not achieve an optimal response with ustekinumab in clinical practice. In the group of patients who switched to guselkumab following failure with an IL-17 inhibitor, 43.2% achieved a PASI- 90 response by week 24. It should, however, be noted that the mean number of prior biologic treatments was higher in the IL-17 inhibitor group (3.2 [1.7]) than in the groups that received ustekinumab (2.4 [1.4]) or tumour necrosis factor inhibitors (2.0 [1.5]), and that this difference probably influenced the lower therapeutic response obtained. With respect to safety, there were no serious adverse events during the follow-up period. Almost 10% (34/343) of the patients experienced some adverse effects, with infections being the most common. However, only 2.7% (9/343) discontinued treatment for this reason, a percentage similar to that observed in the VOYAGE 1 and 2 trials (4,5) and the series reported by Fougerousse et.al.(14) Our study has some limitations. Due to its retrospective design, some of the data or variables were missing or incomplete and the as observed assessment may have overestimated the effectiveness findings. However, the experience of the Spanish Psoriasis Group in collaborative studies and the use of systematic data collection methods favours more homogeneous data collection in clinical practice than generally found in multicentre studies. Another limitation is that the COVID-19 pandemic may have led to a higher percentage of patients for whom data was missing at 24 weeks. Nonetheless, one of the strengths of the study is the large sample size (343 patients included and 249 with data collected up to 24 weeks) for a study of routine clinical practice. CONCLUSION We present the largest series to date of patients treated with guselkumab in a clinical practice setting with data on effectiveness and safety at 24 weeks. Guselkumab achieved high response rates measured in terms of absolute PASI ≤2 and PASI ≤4 in a population with a more complex profile than that of the patients included in clinical trials. The drug also has a good safety profile and a very low withdrawal rate due to adverse effects. This is the first study in which response to treatment was evaluated using the absolute PASI score, which, in the authors’ opinion, may be a more useful measure in clinical practice than relative response (PASI-75 or PASI-90). We therefore highlight the usefulness of using absolute PASI scores to assess response to treatment in real-world clinical practice. ACKNOWLEDGMENTS: We would like to thank all the members of the Spanish Psoriasis Group who contributed patients to this series of patients treated in real-world clinical practice. 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Baseline characteristics of study patients† Characteristic n = 343 Male 198 (57.7) Age, mean (SD) years 48.3 (14.1) Weight, mean (SD) kg 85.5 (20.7) Height, mean (SD) cm 169.5 (10.1) Body Mass Index, mean (SD) kg/m2 (n = 331) 29.7 (6.5) <30 192 (58.0) ≥30 139 (42.0) Duration of psoriasis, mean (SD) years (n = 338) 22.4 (12.0) Baseline PASI, mean (SD) (n = 343) 11.1 (7.3) Baseline BSA, mean (SD) (n = 316) 13.7(13.8) Baseline PGA, mean (SD) (n = 202) 3.2 (0.8) Baseline DLQI, mean (SD) (n = 226) 11.9 (7.3) Previous conventional systemic therapy Methotrexate 261(76.1) Ciclosporin 187 (54.5) Acitretin 129 (37.6) Mean (SD) number prior to guselkumab 1.7 (0.9) Phototherapy 191 (55.7) Apremilast 28(8.2) Number of prior biologic therapies 0 28 (8.2) 1 105 (30.6) 2 80 (23.3) 3 54 (15.7) ≥4 76 (22.2) Mean (SD) number prior to guselkumab 2.4 (1.7) Previous biologic therapies Adalimumab 184 (53.6) Etanercept 134 (39.1) Infliximab 63 (18.4) Certolizumab 6 (1.7) Ustekinumab 186 (54.2) Secukinumab 128 (37.3) Ixekizumab 75 (21.9) Brodalumab 6 (1.7) Efalizumab 16 (4.7) Comorbidities Psoriatic arthritis 55 (16) Hypertension 105 (30.6) Dyslipidaemia 126 (36.7) Diabetes mellitus 51 (14.9) Cardiovascular events 22 (6.4) NAFLD 70 (20.4) Bowel disease 7 (2.2) Hepatitis 15 (4.4) HIV 2 (0.6) Cancer in personal history 18 (5.2) Mental disorders 51 (16.6%) SD, standard deviation; PASI, Psoriasis Area Severity Index; BSA, Body Surface Area; PGA, Physician Global Assessment; DLQI, Dermatology Life Quality Index: NAFLD, non-alcoholic fatty liver disease; HIV, human immunodeficiency virus. †Data expressed as number (%) of patients unless otherwise specified Table 2. Factors associated with PASI-90 and PASI ≤ 2 at week 24 (bivariant and multivariant analysis). As observed analysis. Bivariant Analysis Multivariant Analysis WEEK 24 Odds Ratio (95% CI ) Odds Ratio (95% CI) PASI-90 PASI ≤2 PASI-90 PASI ≤2 Age 0.99 (0.97-1.01) 0.99 (0.98-1.02) 0.99 (0.97-1.02) 1.00 (0.97-1.03) Sex Female 1 1 1 1 Male 0.55 (0.33-0.93) 0.49 (0.26-0.92) 0.60 (0.35-1.06) 0.61 (0.30-1.24) Obesity BMI <30 1 1 1 1 BMI ≥30 0.58 (0.34-0.99) 0.34 (0.18-0.64) 0.73 (0.41-1.29) 0.44 (0.22-0.88) Psoriatic arthritis No 1 1 1 1 Yes 0.81(0.41-1.59) 0.60 (0.28-1.29) 1.08 (0.50-2.32) 1.16 (0.46-2.92) Severity psoriasis PASI <10 1 1 1 1 PASI ≥10 1.07 (0.65-1.78) 0.45 (0.25-0.84) 1.16 (0.66-2.02) 0.50 (0.25-1.01) Duration of psoriasis 1.0 (0.99-1.03) 1.01 (0.98-1.03) 1.02 (0.99-1.04) 1.01 (0.98-1.05) Mean no. of prior biologic 0.77 (0.66-0.90) 0.66 (0.55-0.79) 0.78 (0.65-0.92) 0.69 (0.56-0.85) drugs Table 3. Response to guselkumab at week 24 by prior biologic therapies. As observed analysis. WEEK 24 Mean (SD) Nº of Mean (SD) Mean (SD) PASI Prior Biologic Baseline PASI-90 PASI ≤2 Treatments PASI TNF inhibitors 2.0 (1.5) 10.6 (6.3) 0.8 (2.2) 77.3% (51/66) 92.4% (61/66) (n = 92) IL-12/23 inhibitors 2.4 (1.4) 9.0 (5.5)* 1.4 (2.8) 58.9% (43/73) 84.9% (62/73) (n = 105) IL-17 inhibitors 3.2 (1.7) 12.5 (9.1)* 2.7 (3.3) 43.2% (32/74) 60.8% (45/74) (n = 101) P value < 0.001 0.003* < 0.001 < 0.001 < 0.001 *Statistically significant difference Table 4. Adverse events Type of Adverse Event No. Description Mild infections 8 Upper respiratory infection (2), flu-like syndrome (1), sty (1), boils (1), cystitis (1), herpes zoster affecting the first branch of the trigeminal nerve (1) Serious infections 7 COVID-19 pneumonia (3), influenza A (1), acute bronchitis (1), viral pericarditis (1), salmonellosis (1) Injection-site reactions 2 Headache 2 Joint pain 6 Major adverse cardiac 1 Acute myocardial infarction events (MACE) Laboratory test anomalies 2 Hyperuricemia (1) proteinuria (1), leukocytosis with neutrophilia (1) Others 6 Mesenteric paniculitis (1), rosaceiform dermatitis (1), hypertension (1), hip fracture (1), airborne eczema (1), anxiety (1) Table 5. Demographic characteristics of patients, effectiveness and safety outcomes of guselkumab in real-world settings. Our series Fougerousse Benhadou Maliyar et al. Rodriguez Fernandez Galluzzo M et al. Snast et al. Megna et al. (n = 343) et al. (14) et al. (15) (18) Freire et al. (17) (19) (22) (16) (n = 180) (n = 112) (n = 89) (n = 55) (n = 52) (n=33) (n = 23) Age, mean (SD) 48.3 (14.1) 45.2 (14.05) 48.9.(14.1) 54.0 49.8(15.2) 51.3 (14.1) 60 (13) 49.7 (17.9) years Male,n (%) 198 (57.7%) 107 (59%) 63 (56.3%) 43 (48.3%) 37 (67.3%) 30 (57.7) 22 (67) 15 (65.2%) Mean (SD) PASI 11.1 (7.3) 12.7 (8.95) 14.8 (6.5) NA 13.7 (7.7) 20 (13.3) 14 (11) 15.1 (6.1) Previous biologic 91.8% 71.2% 59% 75.3% NA 57.7% 100% 65.2% therapy (%) PASI 90 week 12- 43.9% 50.6% 55.4% NA 69.1% 36% NA 43.5% (week 16 (%) (week 16) (week 16) (week 16) (week 12) (week 12) 12) PASI 90 week 24 59.4% NA NA NA 66.7% 62.8% 62% † 69.6% (week (%) (week 20) (week 24) 28) PASI ≤ 2 or 3 77.9% PASI NA NA NA NA 74.4% PASI ≤3 NA NA week 20-24 (%) ≤2 (week 20) (week 24) Mean (SD) 2.4 (3.2) 2.3 (3.62) 2.03 (2.5) NA 1.5 (1.8) 4.4 (4.7) 3.2 (1.9) reduction in PASI (week 16) (week 16) (week 16) (week 12) (week 12) NA (week12) week 12-16 Mean (SD) 1.7 ( 2.8) NA NA NA 1.7 (3.3) 1.9 2.9 (3.3) 1.1 (0.9) reduction in PASI (week 24) (week 24) (week 28) (week 24) (week 28) week 24-28 Adverse event, n 34 (9.9%) 15 (8.3%) 3 (2.6%) 24 (30.4%) 0 0‡ 0 6 (26%) (%) 4 (17.4%) § Withdrawal due 9 (2.6%) 5 (2.7%) 0 4 (4.5%) 0 0 0 0 to adverse event, n (%) Withdrawal due 3 (0.9%) 0 0 3 (3.4%) 1 (1.8%) 0 2 (6.1%) 0 to lack of efficacy, n (%) NA: not available †Not including 4 patients with palmoplantar psoriasis. ‡No evidence of cumulative or organ toxicity. §Mild blood alterations LEGENDS Figure 1. Distribution of patients over time (Flow-chart) Figure 2. Mean (SD) PASI at weeks 16 and 24 according to as observed analysis Figure 3. Proportion of patients with PASI ≤4 and PASI ≤2 at weeks 16 and 24 according to the as observed analysis (a) and modified non-responder imputation analysis (b) Figure 4. Proportion of patients with PASI-90 and PASI-100 at weeks 16 and 24 according to the as observed analysis (a) and modified non-responder imputation analysis (b) Figure 1. Distribution of patients over time (Flow-chart) Week 0 343 patients 4 due to adverse events: 2 headache, 1 joint pain, 1 COVID-19 pneumonia 8 patients stop 4 for other reasons: 2 due to fear of COVID19 (patient decision), 2 lack of treatment adherence Week 16 335 patients 5 due to adverse events: 1 flu-like syndrome, 1 respiratory infection, 10 patients stop 1 COVID-19 pneumonia, 1 myocardial infarction, 1 joint pain Data not available: 5 for other reasons: Week 24 76 patients* 3 primary treatment failure, 2 lack of efficacy for joint symptoms 249 patients *Reasons for missing data: 36 patients: COVID-19 pandemic 40 patients: between 16 and 24 weeks of treatment DTH_15231_Figure2.jpg DTH_15231_Figure3.jpg DTH_15231_Figure4.jpg