PLoS ONE plos plosone PLOS ONE 1932-6203 Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0244620 PONE-D-20-24855 Research Article Medicine and health sciencesClinical medicineClinical immunologyAutoimmune diseasesPsoriasis Biology and life sciencesImmunologyClinical immunologyAutoimmune diseasesPsoriasis Medicine and health sciencesImmunologyClinical immunologyAutoimmune diseasesPsoriasis Medicine and health sciencesOncologyCancer treatment People and placesGeographical locationsAsiaTaiwan Medicine and health sciencesPharmaceuticsDrug therapyCardiovascular therapy Research and analysis methodsResearch designClinical research designAdverse events Social sciencesEconomicsHealth economicsHealth insurance Medicine and health sciencesHealth careHealth economicsHealth insurance Medicine and health sciencesPharmaceuticsDrug therapy Medicine and health sciencesMedical conditionsCardiovascular diseases Medicine and health sciencesCardiologyCardiovascular medicineCardiovascular diseases Real-world efficacy of biological agents in moderate-to-severe plaque psoriasis: An analysis of 75 patients in Taiwan Real-world efficacy of biological agents in moderate-to-severe plaque psoriasis https://orcid.org/0000-0002-9467-0325 Chen Yu-Chen Investigation Writing – review & editing 1 ‡ Huang Yi-Ting Writing – original draft Writing – review & editing 1 ‡ Yang Chao-Chun Formal analysis Investigation Methodology Supervision Writing – review & editing 1 2 Lai Edward Chia-Cheng Formal analysis 3 Liu Cheng-Han Investigation 1 Hsu Chao-Kai Investigation 1 2 Wong Tak-Wah Investigation 1 4 5 Chao Sheau-Chiou Investigation 1 Sheu Hamm-Ming Investigation 1 https://orcid.org/0000-0002-0848-0657 Lee Chaw-Ning Investigation Methodology Writing – original draft Writing – review & editing 1 3 * Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan Center of Applied Nanomedicine, National Cheng Kung University, Tainan, Taiwan Rai Vineet Kumar Editor ISF College of Pharmacy, Moga, Punjab, India, INDIA

The authors have declared that no competing interests exist.

‡ These authors co-first authors on this work.

 * E-mail: joyce060324@gmail.com 29 12 2020 2020 15 12 e0244620 9 8 2020 12 12 2020 2020 Chen et al This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background

Real-world clinical data on psoriasis patients receiving different biological agents is needed, especially in Asian populations.

 Objectives

Our aim is to compare and analyze the efficacy and safety profile of four biological agents (etanercept, adalimumab, ustekinumab and secukinumab) in a real-world setting in Taiwan.

 Methods

We retrospectively analyzed the clinical data of all patients with moderate-to-severe plaque psoriasis (Psoriasis Area and Severity Index (PASI) ≥ 10) who received etanercept, adalimumab, ustekinumab or secukinumab between January 2011 and December 2018 in a tertiary hospital in Taiwan.

 Results

A total of 119 treatment episodes in 75 patients were included in this study. Ustekinumab was used in 49 treatment episodes, followed by secukinumab in 46 treatment episodes, adalimumab in 14 treatment episodes and etanercept in 10 treatment episodes. The proportion of the biologic-naïve was highest in etanercept (100%) and lowest in secukinumab (23.9%). The PASI-75, -90 and -100 were the highest in secukinumab (91.3%, 82.6%, 41.3%, respectively), followed by ustekinumab (79.6%, 44.9%, 16.3%), adalimumab (64.3%, 28.6%, 7.1%) and etanercept (50.0%, 30.0%, 0%). The rate of adverse events that required treatment was highest for secukinumab (15.2%), followed by adalimumab (14.3%), ustekinumab (8.2%), and etanercept (0%), including 4 cases of infections, 2 cases of cardiovascular diseases and 4 cases of cancers.

 Conclusions

This real world data showed differential efficacy and safety of the four biological agents.

 http://dx.doi.org/10.13039/100007225 Ministry of Science and Technology 109-2628-B-006 -035 Yang Chao-Chun The work was funded by a grant (MOST 109-2628-B-006 -035) from the Ministry of Science and Technology, Taiwan to CCY. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data Availability All relevant data are within the manuscript. Introduction

Psoriasis is a common, chronic and inflammatory skin disease, affecting approximately 2–3% of the world population [1]. Plaque psoriasis, or psoriasis vulgaris, is the most frequent clinical variant (approximately 85 to 90%) of this disease [2], which manifest as raised, well-demarcated, erythematous and oval plaques with adherent silvery white scales [1]. Moderate-to-severe psoriasis usually requires systemic treatment such as phototherapy, retinoids, methotrexate, cyclosporine, or biological agents [3]. Over the past decades, the introduction of biological agents has remarkably changed the treatment of moderate-to-severe psoriasis and psoriatic arthritis [4]. Today, for patients with inadequate response, contraindication or intolerable adverse effects to traditional systemic medication, biological agents represent an important and effective therapeutic tool [4]. Along with the progress in understanding of the molecular and immunologic basis of psoriasis, highly targeted biological agents have since developed with the perspective not only to improve but to clear psoriasis [5]. In recent years, many randomized clinical trials and real-life study have already shown the good efficacy and safety of biological agents [6–13]. However, more real-world data are needed to reflect the clinical situations without undergoing strict patient selection and monitoring [14]. Besides, real-world therapeutic data of biological agents of non-Caucasian populations is currently limited [15]. In this study, the objective is to compare the efficacy and safety profiles of four different biological agents, etanercept (TNF-α inhibitor), adalimumab (TNF-α inhibitor), ustekinumab (IL-12/IL-23 inhibitor) and secukinumab (IL-17 inhibitor), in a real-world setting in Taiwan.

 Methods Patients and data collection

The study protocol was approved by the Institutional Review Board of National Cheng Kung University Hospital (No. A-ER-108-163). No consent was obtained, because the data were analyzed anonymously. The researchers anonymized the data after obtaining the data. All data was collected from the electronic medical record system and the electronic imaging database of the Department of Dermatology.

For the cohort selection, we included all patients with moderate-to-severe psoriasis vulgaris (defined as Psoriasis Area and Severity Index (PASI) [16] ≥ 10) who received etanercept, adalimumab, ustekinumab or secukinumab between January 2011 and December 2018 at the Department of Dermatology, National Cheng Kung University Hospital, Tainan, Taiwan, and the databases was accessed on July 25, 2019. All the biological treatments were approved and fully reimbursed by National Health Insurance in Taiwan. The prescription of all biological agents complied with the recommended dose and schedule. For etanercept, the starting dose was 50 mg twice weekly for 3 months and the maintenance dose was 25 mg twice weekly. For adalimumab, the initial dose was 80 mg, followed by 40 mg since week 1. For ustekinumab, 45 mg was administered initially at week 0, followed by 45 mg every 12 weeks since week 4, in patients with body weight less than 100 kg. The dose of ustekinumab for patients with body weight greater than 100 kg was doubled. For secukinumab, 300 mg SC was the initial dose at weeks 0, 1, 2, 3, and 4, followed by monthly 300mg beginning at week 8. Other systemic treatments for psoriasis and phototherapy had to be discontinued within two months after the initiation of the biological agents according to the regulation of National Health Insurance in Taiwan. Patients with incomplete serial PASI score data, ie. more than one PASI score missed, were excluded. There were some cases who paid the expenses of biological treatment by themselves, but these cases were also excluded due to the irregular dosing regimen. One patient could have more than one treatment episodes if he or she received more than one biological agent.

 Data analysis

The demographic and clinical data (age, sex, body mass index (BMI), presence/absence of arthralgia, age of diagnosis, duration of disease, comorbidities and previous biological agents use) of the patients were collected and analyzed. The severity of psoriasis vulgaris was evaluated using PASI score before the biological treatment (as baseline PASI score) and at each clinic visit according to the different administration protocols of the 4 biological agents. For the treatment efficacy, it was analyzed by the best improvement (%) of PASI score, PASI-75, PASI-90, and PASI-100. Drug survival was defined as the total treatment duration of a certain biological agent until discontinuation or switch to another agent. The drug survival, time to achieve best PASI score and percentage of discontinuation were also analyzed and compared among treatment groups. Adverse events (AEs) that required medical treatment or follow-up during biological agent use were recorded at each visit. The case number (n) throughout the article indicates the numbers of treatment episodes, rather than numbers of patients, unless specified otherwise.

 Statistical analysis

All analysis was performed with Prism 8 and SAS, Version 9.3. Data were presented as mean for continuous variables and number and percentage for categorical variables. One-way analysis of variance (ANOVA) and Chi-squared test were applied to compare baseline differences in the four treatment groups for continuous variables. The effects between biologics was compared by multivariate generalized estimating equations (GEE) models with repeated measures of patients for each outcome indicators, including the best PASI score, PASI-75, -90 and -100. PASI was treated as a continuous variable while analyzing the best PASI score. The outcomes of PASI-75, -90 or -100 were regarded as binary categories with PASI-75, -90 or -100 as the cut-off value, respectively. The age, sex, baseline PASI, BMI and bio-naïve/experienced were included in the models. Student’s t-test was used to compare between the bio-naïve subgroup and the bio-experienced subgroup.

 Results Patient characteristics

A total of 119 treatment episodes, which were administered in 75 patients, were included in this study. Detailed demographic data was presented in Table 1. Among all the study population, the mean age was 44.0 years. The number of treatment episodes in male patients outnumbered female patients (101 vs.18 treatment episodes). The mean age of diagnosis of psoriasis was 28.3 years and mean disease duration was 15.8 years. The mean BMI was 27.6 kg/m2, which fell into the category of obesity for Taiwanese population. The mean PASI score at baseline was 23.1, which indicated that the severity of psoriasis of the patients included in this study was high. There were no significant differences in terms of age, disease duration, age of diagnosis, BMI, and baseline PASI score between the four treatment groups (Table 1).

10.1371/journal.pone.0244620.t001 Demographic data and disease characteristics of the study population.
Etanercept (n = 10) Adalimumab (n = 14) Ustekinumab (n = 49) Secukinumab (n = 46) Total (n = 119)
Sex
Men, n (%) 9 (90.0) 12 (85.7) 41 (83.7) 39 (84.8) 101 (84.9)
Women, n (%) 1 (10.0) 2 (14.3) 8 (16.3) 7 (15.2) 18 (15.1)
Age, mean (range), years 38.7 (13–49) 40.5 (22–66) 43.3 (14–67) 46.8 (25–41) 44.0 (13–67)
Age of diagnosis, mean, years 23.9 26.9 28.0 29.8 28.3
BMI at baseline, mean, kg/m2 28.6 27.7 27.6 27.3 27.6
Patient with arthralgia, n (%) 7 (70.0) 10 (71.4) 23 (46.9) 24 (52.2) 63 (53.3)
Disease duration, mean, years 14.8 13.6 15.3 17.0 15.8
Baseline PASI, mean (range) 24.0 (15.2–32.8) 24.2 (10.0–39.6) 25.4 (10.4–126.6) 20.2 (10.5–43.1) 23.1 (10.0–126.6)

BMI, body mass index; PASI, Psoriasis Area Severity Index.

The comparison between the 4 groups was performed by ANOVA or Chi-square test.

Among all the treatment episodes, there was 52.5% biologic-naïve. In the etanercept group, all the treatment episodes were biologic-naïve since it was the first biological agent approved for psoriasis treatment by National Health Insurance in Taiwan. The most recently approved biological agent, secukinumab, had the lowest percentage of biologic-naïve series (23.9%) (Table 2).

10.1371/journal.pone.0244620.t002 The numbers of treatment series receiving first-line therapy to forth-line therapy in the four treatment groups.
Etanercept (n = 10) Adalimumab (n = 14) Ustekinumab (n = 49) Secukinumab (n = 46) Total (n = 119)
First-line, n (%) 10 (100.0) 10 (71.4) 31 (63.3) 11 (23.9) 62 (52.5)
Second-line, n (%) 0 (0.0) 3 (21.4) 16 (32.7) 20 (43.5) 38 (32.2)
Third-line, n (%) 0 (0.0) 1 (7.1) 2 (4.1) 11 (23.9) 14 (11.9)
Forth-line, n (%) 0 (0.0) 0 (0.0) 0 (0.0) 4 (8.7) 4 (3.4)
Efficacy of etanercept, adalimumab, ustekinumab and secukinumab

The treatment efficacy of the four biological agents was summarized in Table 3. In general, the data showed that secukinumab had the lowest “best PASI score”, shortest “time to achieve best PASI”, best rate of PASI-75, PASI-90 and PASI-100 (Table 3). On the other hand, etanercept had highest “best PASI score”, lowest rate of PASI-75, -90 and -100, while adalimumab had the longest “time to achieve best PASI”.

10.1371/journal.pone.0244620.t003 The summary of mean PASI score changes, time to achieve best PASI and proportion of PASI-75, PASI-90 and PASI-100.
Etanercept (n = 10) Adalimumab (n = 14) Ustekinumab (n = 49) Secukinumab (n = 46) Total (n = 119)
Baseline PASI, mean 24.0 24.2 25.4 20.2 23.1
Best PASI ever achieved, mean 10.6 6.9 3.9 1.6 3.9
Time to achieve best PASI, mean, weeks 48.6 70.4 39.1 20.0 36.2
PASI-75, n (%) 5 (50.0) 9 (64.3) 39 (79.6) 42 (91.3) 95 (79.8)
PASI-90, n (%) 3 (30.0) 4 (28.6) 22 (44.9) 38 (82.6) 67 (56.3)
PASI-100, n (%) 0 (0.0) 1 (7.1) 8 (16.3) 19 (41.3) 28 (23.5)

PASI, Psoriasis Area Severity Index.

Using GEE models, the chance of achieving PASI-75 was higher in secukinumab patients, compared to ustekinumab (OR = 4.9, P = 0.004), adalimumab (OR = 13.8, P = 0.0002) and etanercept (OR = 28.6, P = 0.0001) (Table 4). For PASI-90, secukinumab patients were associated with greater chance of achieving it, compared to ustekinumab (OR = 20.2, P<0.0001), adalimumab (OR = 89.2, P<0.0001) and etanercept (OR, 58.6, P = 0.0007). For PASI-100, secukinumab patients were associated with greater chance of achieving it, compared to ustekinumab (OR = 5.5, P = 0.003). The result of GEE models was listed in detail in Table 4.

10.1371/journal.pone.0244620.t004 The comparison of the rate of PASI-75, PASI-90 and PASI-100 in four biological agents by GEE models.
SEC vs. UST SEC vs. ADA SEC vs. ETA UST vs. ADA UST vs. ETA ADA vs. ETA
PASI-75, OR 4.9 (P = 0.004) 13.8 (p = 0.0002) 28.6 (p = 0.0001) 2.8 (p = 0.16) 5.8 (p = 0.06) 2.1 (p = 0.43)
PASI-90, OR 20.2 (p<0.0001) 89.2 (p<0.0001) 58.6 (p = 0.0007) 4.4 (p = 0.04) 2.9 (p = 0.31) 0.6 (p = 0.7)
PASI-100, OR 5.5 (p = 0.003) N/A† N/A† N/A† N/A† N/A†

ADA, adalimumab; ETA, etanercept; SEC, secukinumab; UST, ustekinumab.

N/A, not available; OR, odds ratio; PASI, Psoriasis Area Severity Index.

†Data not available due to the small case numbers in PASI-100 patients of the adalimumab and etanercept groups which could not be applied in GEE models.

We further analyzed and compared the efficacy on treatment episodes with and without exposure to previous biological agents (bio-naïve and bio-experienced) (Table 5). In general, the biologic-naïve group had better treatment response than the biologic-experienced group in terms of best PASI score, PASI-75, PASI-90 and PASI 100 in all biological agents.

10.1371/journal.pone.0244620.t005 The comparison of efficacy between the bio-naïve and the bio-experienced.
Etanercept (n = 10) Adalimumab (n = 14) Ustekinumab (n = 49) Secukinumab (n = 46)
Case number, n (%) Bio-naïve 10 (100.0) 10 (71.4) 31 (63.3) 11 (23.9)
Bio-experienced 0 (0) 4 (28.6) 18 (36.7) 35 (76.1)
Baseline PASI, mean Bio-naïve 24.0 23.9 25.9 19.9
Bio-experienced N/A 24.9 24.6 20.2
Best PASI ever achieved, mean Bio-naïve 10.6 5.1 3.1 1.2
Bio-experienced N/A 11.1 5.5 1.7
PASI-75, n (%) Bio-naïve 5 (50.0) 8 (80.0) 27 (81.8) 11 (100.0)
Bio-experienced N/A 1 (25.0) 12 (66.7) 31 (88.6)
PASI-90, n (%) Bio-naïve 3 (30.0) 4 (40.0) 18 (58.1*) 11 (100.0)
Bio-experienced N/A 0 (0.0) 4 (22.2*) 27 (77.1)
PASI-100, n (%) Bio-naïve 0 (0.0) 1 (10.0) 7 (22.6) 6 (54.5)
Bio-experienced N/A 0 (0.0) 1 (5.6) 13 (37.1)

N/A, not available, PASI, Psoriasis Area Severity Index.

*p<0.05, bio-naïve vs. bio-experienced, t-test.

 Adverse events of etanercept, adalimumab, ustekinumab and secukinumab

The AEs that required medical treatment or follow-up during biological agents use were analyzed (Table 6). AEs were further categorized into four groups: infection, cardiovascular diseases, neoplasm and others. There was no severe infection that led to long-term discontinuation of biological therapy or death. There were two patients with herpes zoster infection; one in ustekinumab group and one in secukinumab group. Besides, there was one patient having hepatitis B reactivation during ustekinumab treatment. One patient had folliculitis on scalp with lymphadenopathy during secukinumab treatment. There was no case of candida infection or tuberculosis reactivation. There were two major cardiovascular adverse events during treatment of secukinumab. There were three malignancies which led to long-term suspension of biological agents; one patient diagnosed with esophageal cancer during ustekinumab treatment, one patient diagnosed with rectal cancer and one diagnosed with hepatocellular carcinoma during secukinumab treatment.

10.1371/journal.pone.0244620.t006 Adverse events (AEs) during the use of biological agents.
Etanercept (n = 10) Adalimumab (n = 14) Ustekinumab (n = 49) Secukinumab (n = 46)
All AE that requires treatment or follow-up, n (%) 0 (0.0) 2 (14.3) 4 (8.2) 7 (15.2)
    • Infection, n (%) 0 (0.0) 1 (7.1) 2 (4.1) 3 (6.5)
    • Cardiovascular diseases, n (%) 0 (0.0) 0 (0.0) 0 (0.0) 2 (4.3)
    • Neoplasm, n (%) 0 (0.0) 1 (7.1) 1 (2.0) 2 (4.3)
    • Others†, n (%) 0 (0.0) 0 (0.0) 1 (0.0) 0 (0.0)

AE, adverse event.

†The AE was liver function impairment.

 Discussions

This single-center retrospective study presents real-world data on drug efficacy, and AEs in patients with moderate-to-severe psoriasis using etanercept, adalimumab, ustekinumab and secukinumab in Taiwan. To date, there are limitedreal-world studies comparingdrug efficacy and safety profile of etanercept, adalimumab, ustekinumab and secukinumab together [17, 18]. Our result is comparable with the head-to-head trials and real-life studies [6–13]. Secukinumab had the highest rate of PASI-75, PASI-90 and PASI-100, followed by ustekinumab, adalimumab and etanercept. It is remarkable that secukinumab showed the best efficacy in reaching PASI-75, PASI-90 and PASI-100, despite that this group had highest proportion of the biologic-experienced (76.0%). However, because of shorter follow-up for patients receiving secukinumab compared to other three drugs, and most of the treatments are still ongoing (52.2%), we should interpret our result with great caution. Longer follow-up for recurrence or adverse events should be done in the future.

In line with other studies [19, 20], biologic-naïve subgroup had better treatment response in our study. However, the reasons why previous biological agents use is a predictor of worse efficacy remains uncertain and further investigation is warranted [19].

The drug survival time, a commonly used indicator for the efficacy of the biological agents, may not be a good indicator for Taiwanese population, because the treatment period was greatly influenced by the insurance policy which terminates the reimbursement of biological agents after 2 years.The National Health Insurance system in Taiwan covers the full expenses of biological treatment for moderate to severe psoriasis patients (PASI ≥10) and the prerequisite criteria are lack of efficacy of two conventional medications and phototherapy [21, 22]. Biological agents are provided up to 2 years as long as PASI-50 is reached. After a 2-year treatment, if the PASI score is below 10, biological agents will not be reimbursed until there is a relapse with PASI ≥10. Drug survival was also influenced by the timing when the individual biological agent was available. Therefore, we should interpret our data with caution and also consider the differences in the frequency of dosing, market entry times, duration of follow-up and reimbursement regulations.

There was no severe infection leading to long-term drug discontinuation. There were three malignancies occurring during ustekinumab or secukinumab treatment and all resulted in long-term withdrawal of biologicaltreatment. This result showed that safety was still a concern in around 10% of the patients under the treatment of biological agents in a real-life setting.

The strengths of our study included complete recording of serial PASI scores of each patient and standard dosage and fixed injection schedule of biological treatment in order to meet the criteria of reimbursement of National Health Insurance. It provided real-world therapeutic data of non-Caucasian ethnic populations. The main limitations of this study were its retrospective nature and non-comparative study design. The patients were not randomized or blinded during treatment course. Besides, the sample size of this study is small, with 119 treatment episodes. The follow-up period was too short for the latest available biological agent, secukinumab.

In conclusion, our study provides real-life clinical experience on biological treatment for psoriasis in Taiwan. The results showed differential efficacy of the four biological agents. Special attention still needs to be paid on AEs which occur during the use of biological agents, including infection, cardiovascular diseases and cancers.

We would like to thank the participants for their willingness to contribute data that make analyses such as these possible, and also appreciate the staff and administrators for their work.

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12 Oct 2020

PONE-D-20-24855

Real-world efficacy of biological agents in moderate-to-severe plaque psoriasis: an analysis of 75 patients in Taiwan

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We look forward to receiving your revised manuscript.

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Vineet Kumar Rai, PhD

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: No

Reviewer #2: Partly

Reviewer #3: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: Yes

Reviewer #3: No

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This is a very small sample size with a short follow-up time, so it's difficult to make any conclusions. I think this paper would be a better fit for a psoriasis journal.

----------------------------

Reviewer #2: The Manuscript “Real-world efficacy of biological agents in moderate-to-severe plaque psoriasis: an analysis of 75 patients in Taiwan” is written in presentable manner. However, the number of patients is very less. Manuscript can be accepted after minor revision, if authors agreed to satisfy following comments.

Q1. Please clarify annotations “*” and “†” used in table 4 and 3 to avoid confusion. Same sign is also used for author’s equal contribution.

Reviewer #3: 1. Though the article is well written and presented, the sample size could have been large enough.

2. Line no. 88 and 89, authors have written that “the prescription of all biological agents complied with the recommended dose and schedule”.

3. The dose and schedule of the dosing should have been specified in the manuscript along with the details of the injections and make.

4. Data to support the adverse events cases is inadequate with a short follow-up time.

5. However, the discussion part needs to be extensively re-written because there are some major problems with the information presented.

6. It would be more transparent if the authors provide information on how the authors search and correlate the discussion part.

7. I understand that this manuscript is based on clinical studies, however, authors should cite more scientific evidence with proper updated citation.

8. Since the authors mentioned that the effect of the selected drugs for the treatment of mild-to-moderate psoriasis patients the information there should therefore specific about psoriasis as a combined regimen.

9. The first half of the conclusion seems irrelevant at some level and main content.

10. The author must apply some more statistical tools for the confirmation of evidence in the experiment part.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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 10.1371/journal.pone.0244620.r002 Author response to Decision Letter 0 Submission Version 1

20 Nov 2020

Answers to Review Comments to the Author

Reviewer 1#

This is a very small sample size with a short follow-up time, so it's difficult to make any conclusions. I think this paper would be a better fit for a psoriasis journal.

Reply from authors: We agree that the sample size of this study was relatively small. However, there were several strengths of this work, as stated in the Discussion section. The major strength which made us advantageous to other real world study was that the efficacy of the four biological agents under the standard regimens could be compared in a real-work setting due the reimbursement policy of the National Health Insurance in Taiwan.

Reviewer 2#

The Manuscript “Real-world efficacy of biological agents in moderate-to-severe plaque psoriasis: an analysis of 75 patients in Taiwan” is written in presentable manner. However, the number of patients is very less. Manuscript can be accepted after minor revision, if authors agreed to satisfy following comments.

Reply from authors: Thank you for the comments.

Q1. Please clarify annotations “*” and “†” used in table 4 and 3 to avoid confusion. Same sign is also used for author’s equal contribution.

Reply from authors: Thank you for the comments. The annotations were adjusted accordingly.

Reviewer 3#

1. Though the article is well written and presented, the sample size could have been large enough.

Reply from authors: We agree that the sample size of this study was relatively small. However, there were several strengths of this work, as stated in the Discussion section. The major strength which made us advantageous to other real world study was that the efficacy of the four biological agents under the standard regimens could be compared in a real-work setting due the reimbursement policy of the National Health Insurance in Taiwan.

2. Line no. 88 and 89, authors have written that “the prescription of all biological agents complied with the recommended dose and schedule”.

Reply from authors: Thank you for the suggestion. The detail of the dose and schedule is added at line 94-103.

3. The dose and schedule of the dosing should have been specified in the manuscript along with the details of the injections and make.

Reply from authors: Thank you for the suggestion. The detail of the dose and schedule is added at line 94-103.

4. Data to support the adverse events cases is inadequate with a short follow-up time.

Reply from authors: Thank you for the comments. We agree that the follow-up period was relatively short. As stated in the Discussion, a study with longer follow-up period will be conducted to better reflect the occurrence of AE.

5. However, the discussion part needs to be extensively re-written because there are some major problems with the information presented.

Reply from authors: Thank you for the comments. The manuscript has been revised extensively in the text, tables and references.

6. It would be more transparent if the authors provide information on how the authors search and correlate the discussion part.

Reply from authors: The references were searched on PubMed by the name of the four biologicals and “real-world study” or “clinical trials”. The discussion part has been revised and updated references are added.

7. I understand that this manuscript is based on clinical studies, however, authors should cite more scientific evidence with proper updated citation.

Reply from authors: Thank you for the suggestion. The discussion part has been revised and updated references are added.

8. Since the authors mentioned that the effect of the selected drugs for the treatment of mild-to-moderate psoriasis patients the information there should therefore specific about psoriasis as a combined regimen.

Reply from authors: Traditional systemic treatments have to be discontinued within two months after initiation of the biological agents according to the regulation of National Health Insurance in Taiwan. Therefore the effect contributed by concomitant use of traditional biological agents could be neglected. A relevant statement is added into the Method section (Line 101-103).

9. The first half of the conclusion seems irrelevant at some level and main content.

Reply from authors: Thank you for the comments. The Conclusion has been revised to better fit the main content of this study.

10. The author must apply some more statistical tools for the confirmation of evidence in the experiment part.

Reply from authors: Thank you for the suggestion. A new statistic tool, multivariate generalized estimating equations (GEE) models was used for analysis. Relevant description has been added into the Methods and Results sections (Line 129-135, Line 175-182 and Table 4).

Submitted filename: Response to the reviewers 1120.doc

 10.1371/journal.pone.0244620.r003 Decision Letter 1 Rai Vineet Kumar Academic Editor 2020 Vineet Kumar Rai This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 1

14 Dec 2020

Real-world efficacy of biological agents in moderate-to-severe plaque psoriasis: an analysis of 75 patients in Taiwan

PONE-D-20-24855R1

Dear Dr. %Lee%,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Vineet Kumar Rai, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: (No Response)

Reviewer #3: I think the authors have made appropriate responses to my previous comments and concern. Now It is in a good shape for publication.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Reviewer #3: Yes: Dr. Alok Sharma

 10.1371/journal.pone.0244620.r004 Acceptance letter Rai Vineet Kumar Academic Editor 2020 Vineet Kumar Rai This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

16 Dec 2020

PONE-D-20-24855R1

Real-world efficacy of biological agents in moderate-to-severe plaque psoriasis: an analysis of 75 patients in Taiwan

Dear Dr. Lee:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Vineet Kumar Rai

Academic Editor

PLOS ONE