Treating Generalized Pustular Psoriasis (GPP): Timing and Rationale for Biologic Treatment Switching—A Japanese e-Delphi Survey

Abstract

Introduction

Generalized pustular psoriasis (GPP) is a chronic, inflammatory disease characterized by the sudden and recurrent development of widespread sterile pustules on the skin. The treatment of GPP includes non-biologic and biologic therapies. In Japan, biologic agents are being increasingly used as first-line treatment, with more biologics approved in Japan than in other countries. A previous secondary data-based study utilizing data in the Medical Data Vision database and the Japan Medical Data Center in Japan demonstrated heterogeneity in real-world biologic treatment patterns, with at least one switch during the follow-up period (mean n switches 3.8; mean length of follow-up 3.3 years) for approximately one third of patients with GPP treated with a biologic drug. The aim of this study was to evaluate where consensus lies among experts regarding switching biologic treatments for patients with GPP in Japan.

Methods

A Delphi exercise that consists of three survey rounds was performed with ten Japanese dermatologists. Participants were asked to respond to questions related to experts’ experience with specific biologics, experience with switching, timing of switches and importance of specific criteria (drivers) when making the decision to switch. The consensus threshold was 70%.

Results

Based on the results of the Delphi exercise, most experts rarely (60%) or never (20%) switch a biologic agent and only 20% switch often during acute symptoms/GPP flare driven by the short time of the flare; this result may be different during the maintenance phase. Lack of efficacy, loss of efficacy due to long-term use, side effects, contraindications, new products with better efficacy and safety evidence, risk of infection, and lack of adherence play an important role in making the decision to switch.

Conclusion

Switches may occur for patients on biologics when flares occur (loss of effectiveness) or when there is insufficient response (lack of effectiveness). The decision to switch a biologic is impacted by several other criteria, including safety and the availability of more efficacious and better tolerated therapies. Overall, there is still an unmet need for robust evidence to inform GPP treatment choice.

Supplementary Information

The online version contains supplementary material available at 10.1007/s13555-025-01377-3.

Key Summary Points

Why carry out this study?

Generalized pustular psoriasis (GPP), while rare, represents a serious and potentially life-threatening condition that places a considerable burden on patients.

Treatment of GPP includes both non-biologic and biologic therapies, and newer biologics have developed to target the main pathologic pathway in GPP (interleukin 36).

Biologic agents are being increasingly used for GPP treatment, including in Japan where more biologics are approved than in the rest of the world (ROW). Despite this, patients often experience treatment switches. There is a need to better understand the timing and reasons for switching biologics.

What was learned from this study?

A panel of ten dermatologists were asked questions following an e-Delphi process to establish consensus. Biologic drugs are the first choice to treat GPP flares in an acute phase. Experts never or rarely switch drugs during the GPP maintenance phase.

Reasons for switching include lack of effectiveness, loss of effectiveness due to long-term use, side effects, contraindications, new product with better efficacy and safety evidence, risk of infection and lack of adherence.

Introduction

Generalized pustular psoriasis (GPP) is a severe and chronic neutrophilic skin disease that manifests acutely with widespread eruptions of sterile pustules, often accompanied by systemic inflammation, placing a substantial burden on patients [1]. While occurrences in infancy and adolescence have been documented, GPP primarily afflicts adults, with a peak incidence typically observed between the ages of 40 and 59 years, with a higher prevalence among females [2, 3]. The rarity of GPP is notable, and prevalence rates show considerable geographical and ethnic diversity. For example, the reported prevalence figures range from 1.76 cases per million in France to as high as 124 per million in Korea [2, 4, 5]. These disparities underscore the need for a comprehensive understanding of GPP's epidemiology and its impact on affected populations.

The disease's clinical course is characterized by sudden and recurrent flares, often triggered by factors such as emotional distress, seasonal changes, or infections [6]. These flares pose significant systemic risks, including superinfection of lesions and potential organ involvement, such as renal, hepatic, and cardiac complications, along with acute respiratory failure [2, 7, 8]. The gravity of these complications is underscored by mortality rates ranging from 2% to 16% [9, 10].

The GPP therapeutic landscape is evolving, with treatment options broadly categorized into biological and non-biological agents. Historically, non-biologic therapies, such as retinoids, cyclosporine, and methotrexate, have been employed, albeit with limited supporting evidence [11]. Due to a unique approach in Japan to allow patients more treatment options, a range of biologics developed for plaque psoriasis has been approved for GPP based on the results of small open-label studies [12–15]. In addition, recent advancements in our understanding of the pathogenesis of GPP have paved the way for targeted biologic therapies aimed at modulating key cytokine pathways implicated in the disease process [7]. Notably, genetic studies have identified mutations in the IL36RN gene, which encodes interleukin (IL)-36 receptor antagonist (IL-36Ra), as pivotal in GPP pathogenesis [16, 17]. These discoveries have spurred the development of biologic therapies, including IL-36R inhibitor-like spesolimab, which have shown promising efficacy in clinical trials [18, 19], with spesolimab receiving approval for GPP treatment [20, 21]. More recent research has shown that variants in the SERPINA3 gene [22], as well and in the CARD4 and AP1S3 genes, are potentially involved in GPP pathophysiology. However, not all patients with GPP carry these mutations, suggesting that other genes might be involved and partially explaining the observed variability in treatment effectiveness among patients.

In Japan in particular, where GPP prevalence is relatively high, the utilization of biologic therapies has increased in recent years, with approximately two-thirds of patients with GPP receiving treatment with biologics [23]. While spesolimab (IL-36R inhibitor) is the first biologic treatment approved for GPP in the USA [21] and European Union [20], following the Effisayil randomized trials that had a relatively large cohort compared to other trials [18], many other biologics are currently approved for use and covered in Japan, including adalimumab, infliximab, certolizumab pegol (tumor necrosis factor alpha [TNFα]-blocking agents) [1, 24], secukinumab, brodalumab, ixekizumab and bimekizumab (IL-17/IL-17R inhibitors) [1, 25], risankizumab and guselkumab (IL-23 inhibitors) [26–28], and spesolimab [29].

Japanese guidelines for the management and treatment of GPP published in 2018 include a special section for biologic treatments [1], highlighting that the drugs infliximab, adalimumab, secukinumab, ixekizumab, and brodalumab are covered by the healthcare system and that any of these can be used for the management of GPP due to the mechanism of action of the drugs, despite the lack of evidence from randomized clinical trials in this patient population [1]. These guidelines underscore the importance of understanding real-world treatment patterns, including rates of biologic utilization and switching behaviors, to optimize patient care and inform clinical decision-making.

Rationale and Study Aim

As part of planned parallel research activities, analyses were conducted to investigate real-world treatment patterns for GPP in Japan utilizing secondary data (claims) in two large Japanese databases, the Japan Medical Data Center (JMDC) and the Medical Data Vision (MDV) hospital claims database [30, 31]. The results of the secondary data analyses demonstrated heterogeneity in real-world biologic treatment patterns for patients with GPP, with multiple combinations of biologics and non-biologics monotherapy or combination therapy with topical steroids.

Considering these findings and given the lack of consensus regarding optimal real-world management of GPP with biologic therapies in Japan, further research was deemed warranted in order to understand the timing and reasons for biologic treatment switching. Indeed, the unpredictable nature of GPP in terms of clinical presentation, such as the acute symptoms/GPP flares, as well as the variable duration of intervals between acute symptoms/GPP flares, makes treatment decision-making and treatment switching challenging.

An expert’s rationale for switching from one biologic treatment to another, including reasons for early and/or recurrent switching, greatly impacts real-world practice and treatment patterns. This information could supplement existing evidence on clinical decision-making as well as support the development of evidence-based positioning of novel therapies in the guidelines. Therefore, we used a structured and systematic approach to evaluate where consensus lies among experts for the timing of and reasons for switching biologic treatments for patients with GPP in Japan and designed and conducted a Delphi study.

Methods

Study Design

An observational direct-to-participant study design using online Delphi survey methods was conducted in Japan [32]. The e-Delphi method is widely recognized and applied in healthcare research [33] as it allows for the aggregation of experts’ insights and the anonymized sharing of these in subsequent survey rounds. This design enables experts to safely review the aggregated anonymized responses and to have the opportunity to revise their judgments, fostering the genuine expression of personal opinions [34–38]. Published guidelines for reporting studies using consensus methodologies were followed [33–35]. This type of study does not require any patient information, hence no ethical review or approval was necessary. The study utilized data from anonymized experts’ answers, and all experts involved in the e-Delphi were included as authors.

Delphi Panel Composition

The selection criteria for the e-Delphi panel experts were rigorously established to ensure representation from diverse backgrounds relevant to the treatment of GPP in Japan. Specifically, experts were eligible if they met one or more of the following criteria: (1) being a Japan-based clinician and/or a Japan-based academic specialized in dermatology; (2) having initiated therapy with biologic drugs in patients with GPP; or (3) having treated at least one patient with GPP in the past 5 years (for clinicians) or having published at least one article in this area (for academics). Ten eligible experts were recruited via e-mail for participation. Documents were provided to all invited experts, providing the results of the MDV and JMDC analyses as well as delineating the e-Delphi survey study objectives and iterative stepwise process.

Definition of Consensus

The consensus threshold, i.e., the percentage agreement to achieve consensus was set at 70% for all questions in the survey. This termination criterion was defined a priori for each given question.

Number of e-Delphi Survey Rounds

Since the Delphi method is a multi-round survey technique, this e-Delphi survey adhered to a maximum of three rounds. The termination criterion of three rounds was set a priori for the survey.

Survey Instrument (Questionnaire) Development

The first step in questionnaire development was to perform a targeted literature review (TLR) to identify and select published evidence (between 2007 and 2022) on drivers of GPP and reasons that may explain or justify switches among biological treatments in GPP [39–45]. This review exercise, combined with the MDV and JMDC claims data analyses, provided a suitable springboard for robust questionnaire development. Given the time frame of this study, not all biologic treatments, such as IL-36 inhibitors like spesolimab, were included in the survey.

e-Delphi Survey Process

Following the first round of the e-Delphi survey, all responses were aggregated and anonymized for all questions and shared in subsequent survey rounds 2 and 3. Questions that did not reach consensus were re-presented in the subsequent round for reconsideration. Figure 1 illustrates the stages of this e-Delphi study process, including a preparatory phase, the actual ‘Delphi rounds,’ data processing and analysis, and concluding steps.

Fig. 1.

Flowchart of e-Delphi survey. JMDC Japan Medical Data Center, MDV Medical Data Vision database

Consensus Meeting

Following completion of the three-round e-Delphi survey exercise, experts were invited to a meeting to discuss the main study findings as well as the questions that did not reach consensus (shown in Fig. 1) to support contextualization of the results.

Data Analysis

All data analyses were descriptive. Quantitative results were presented as the percentage of participants who agreed with the same answer. The level of agreement on each question/item was summarized to show the frequencies and percentages (n, %). Responses were analyzed to identify trends, common themes, or emerging patterns within the responses to facilitate understanding of the collective opinions and viewpoints. All questions and the measurement scale they utilized, e.g., 9-point Likert scale, is provided in the electronic supplementary materials (ESM). The data analysis was performed using Microsoft Excel (Microsoft Corp., Redmond, WA, USA).

Results

In round 1, consensus was reached for Question 1 (see ESM for the full list of questions per round). Question 1, which referred to the JMD and MDV databases analyses showing agreement (90%) on whether the results presented are somewhat representative of real-world clinical practice., with the answers given using a 4-point Likert scale, ranging from very much to not at all.

The characteristics of the e-Delphi panel (n = 10) are shown in Table 1.

Table 1.

Characteristics of the e-Delphi panel

Characteristics of the e-Delphi panel	Respondents, n (%)
Professional role/function (in addition to being a specialist dermatologist)	n = 10 (100%)
Professor	5 (50%)
Associate professor	1 (10%)
Lecturer	1 (10%)
Director of clinic/division	3 (30%)
Experience in years	n = 10 (100%)
15–25 years	4 (40%)
25–30 years	4 (40%)
> 30 years	2 (20%)
Type/setting of practice	n = 10 (100%)
Hospital-based only	6 (60%)
Office-based only	1 (10%)
Mixed practice	3 (30%)
GPP-related publications	n = 10 (100%)
At least 3	9 (90%)
Less than 3	1 (10%)
Number of patients with GPP during the last 2 years	n = 10 (100%)
1–10	6 (60%)
11–20	2 (20%)
≥ 21	2 (20%)

GPP Generalized pustular psoriasis

Biologic Treatment

Biologics have been approved for GPP in Japan since 2010 [1]. In the e-Delphi survey, all experts (n = 10, 100%) reported having prescribed at least one of the biologic drugs presented in a list to treat the acute symptoms/GPP flare in the past 2 years (round 1).

There was no consensus on which non-biologic drug to use as first-choice drug. There was also no consensus on which biologic or non-biologic drug to use as second-choice drug if the first choice fails, or on the third-choice drug if the second-chose drug fails.

For the period after the acute phase of a flare, i.e., the maintenance period, experts reported that they “often” (60%) or “always” (40%) treat GPP with biologic drugs (round 1). Of the experts, 80% agreed that biologic treatments are prescribed in combination with another therapy during maintenance phase (round 1).

The number of patients treated with biologics per expert during the last 2 years ranged from two to 20 (Fig. 2). Switches in biologic treatment is rare, the number of patients having experienced a switch from their biologic treatment in the last 2 years ranged from zero to ten depending on the expert (Fig. 2).

Fig. 2.

Number of patients treated with biologic drugs and number of switches from biologic drugs per expert. GPP Generalized pustular psoriasis

Switching Timing

Regarding the timing of biologic treatment switching in Japanese patients with GPP, this e-Delphi exercise showed that 80% of experts never (20%) or rarely (60%) switch during acute symptoms/GPP flare (round 1). Physicians reported usually waiting 1 week to switch from one biologic drug to another during acute symptoms/GPP flare (round 2; 70% consensus). If a switch occurs, 70% agreed that they would not prescribe a non-biologic drug before a switch to another biologic drug (round 2). All experts (100%) agreed that they never (20%) or rarely (80%) switch drugs during the maintenance phase (round 1).

Switching Drivers

The results showed that drivers for switching tend to be specific for some biologic drugs irrespective of phase (acute symptoms/GPP flare or maintenance phase) (Table 2).

Table 2.

Five top ranked drivers for switching biologic drug on which consensus was achieved, according to the biologic drug and disease phase (acute symptoms/generalized pustular psoriasis flare and maintenance phase)

Biologic drug	Five top ranked drivers (1–5) for switching biologic drug
	1	2	3	4	5
Acute symptoms/flare
Infliximab (TNFα-blocking agent)	Lack of effectiveness (100% round 1)	Loss of effectiveness (100% round 2)	NC	NC	Risk of infection (100% round 3)
Secukinumab (IL-17/17R inhibitors)	Lack of effectiveness (71% round 1)	Loss of effectiveness (71% round 2)	NC	NC	NC
Adalimumab (TNFα-blocking agent)	Lack of effectiveness (100% round 1)	Loss of effectiveness (75% round 2)	NC	NC	NC
Ixekizumab (IL-17/IL-17R inhibitors)	Lack of effectiveness (86% round 1)	NC	NC	NC	NC
Brodalumab (IL-17/IL-17R inhibitors)	NC	NC	NC	NC	NC
Certolizumab pegol (TNFα blocking agent)	NC	NC	NC	NC	NC
Maintenance phase
Infliximab (TNFα blocking agent)	NC	NC	Side effects (83% round 3)	NC	NC
Secukinumab (IL-17/IL-17R inhibitors)	NC	NC	Side effects (71% round 3)	NC	NC
Adalimumab (TNFα-blocking agent)	Lack of effectiveness (80% round 1)	Loss of effectiveness (80% round 2)	NC	NC	NC
Ixekizumab (IL-17/IL-17R inhibitors)	NC	NC	NC	NC	NC
Brodalumab (IL-17/IL-17R inhibitors)	Lack of effectiveness (100% round 1)	Loss of effectiveness (75% round 2)	NC	Risk of infection (75% round 3)	NC

For a criterion to reach consensus as the top 1 reason for switching, at least 70% of the experts must select the criterion as the first driver in order of priority in the list of criteria. The same approach would apply to the top 1 to top 5 reasons for switching

IL Interleukin, NC no consensus, TNFα tumor necrosis factor alpha

Switching Drivers During Acute Symptoms/GPP Flare

Among the drivers of switching a biologic drug during the acute symptoms/GPP flare, on a Likert scale of 9 points, experts agreed with the following reasons as the top five drivers for switching:

1. Lack of efficacy,

2. Loss of efficacy due to long-term use,

3. Side-effects,

4. Risk of infection” and “patient’s decision to end the treatment,

5. Mode and frequency of administration.

Note that two reasons, namely “risk of infection” and “patient’s decision to end the treatment,” had the same number of votes and both remained in the fourth position (round 3: 70% consensus)

Switching Drivers During Maintenance Phase

Top ranked drivers for switching during the maintenance phase, regardless of the biologic drug used, were “lack of effectiveness,” “side-effects,” “patient’s decision to end the treatment,” “loss of effectiveness due to long-term use,” and “risk of infections”.

Criteria for Selecting a New Treatment

The criteria considered to be critical (on a Likert scale from 7 to 9) when selecting a new biologic drug for both acute symptoms/GPP flares and the maintenance phase are presented in Table 3. There was no consensus on which biologic or non-biologic drug to use as the second-choice drug if the first-choice drug fails or as the third-choice drug if the second-choice drug fails.

Table 3.

Critical criteria for selecting a new biologic drug that reached consensus according to phase (acute symptoms/generalized pustular psoriasis flare and maintenance phase)

Critical criteria	Acute symptoms/flare	Maintenance phase
Highly effective product in terms of resolution of flare and skin clearance	Critical (80% round 1)	Critical (90% round 1)
Highly effective product in terms of reducing inflammatory biomarkers and systemic symptoms	Critical (100% round 1)
Sustained effectiveness, avoiding recurrence of flares	Critical (90% round 1)	Critical (100% round 1)
Mode of action	Critical (80% round 1)	Critical (80% round 2)
Favorable safety profile	Critical (90% round 2)	Critical (100% round 1)
Good tolerability profile	Critical (90% round 2)	Critical (100% round 1)
Avoiding emergency room visits	Not applicable /not mentioned as critical	Critical (80% round 1)
Possibility of long-term usage	Critical (80% round 2)	Not applicable, not mentioned as critical

Discussion

This study aimed to evaluate where consensus lies among experts on the reasons for and the timing of biologic treatment switching in patients with GPP in Japan. Case studies have provided some evidence for biologic drugs providing long-term effectiveness and safety. This evidence is supported by the results of this Delphi panel as biologic drugs were not switched frequently, and switching, when it occurred, was only under specific conditions or circumstances [46].

In this Delphi panel, experts were asked the following questions on the timing of a switch: (1) “From your experience, how often do you decide to switch the biologic during the acute symptoms/GPP flare?” and (2) “from your experience, how often do you decide to switch the biologic during the maintenance phase?”. The participating experts answered that they would never (20%) or rarely (60%) switch, and only 20% answered that they would often switch during acute symptoms/GPP flare. Upon discussion during the consensus meeting, experts clarified that the acute symptoms/GPP flare phase is typically short, and that switching from a biologic treatment to another would be considered in certain specific cases. A switch during an acute symptoms/GPP flare phase may happen should the patient already be on treatment with a biologic drug, yet still experience a flare exacerbation (loss of efficacy). A switch during an acute symptoms/GPP flare may also happen in patients for whom biologic treatment was started during the acute symptoms/GPP flare but who is not responding to the drug, or the drug seems to have insufficient effect (lack of effectiveness). Regarding the response to switching occurring “rarely to never” during the maintenance phase, experts further justified this result in the meeting citing that this phase is characterized largely by controlled GPP symptoms.

Published research in the wider therapeutic domain (commonly from patient cohorts with psoriasis and psoriatic arthritis) postulates that reasons for a biologic drug switch may primarily be a lack of effectiveness and loss of effectiveness [39, 40]. Although these reasons are consistent with the results of the Delphi panel in the present study, these similarities should be interpreted with caution as the GPP population is very small and more severely impacted compared to the target population covered in these review articles [39, 40]. While GPP has historically been considered to be a variant of psoriasis, there is a medical consensus that GPP is distinct from plaque psoriasis in terms of phenotype, genetics, immunology, and histopathology [47] and that there is a need for consistent treatment algorithms with the right and most apt agents, such as the newly approved IL-36 inhibitors, which directly inhibit a pathway, unlike IL-17/23 inhibitors that have a partial inhibition mechanism [29, 48]. Genetic variations and lifestyle factors, such as smoking, can influence GPP activity and treatment response, which in turn may influence treatment effectiveness from one patient to another, and may consequently prompt treatment switch for better response. As mentioned in the Introduction, mutations in the SERPINA3 and IL36RN genes have been found to have the potential to be involved in disease severity and responsiveness to treatment [22], a finding which might necessitate switching due to a lack of effectiveness in certain patients based on whichever mutation they have. Another example is the GPR15 gene, which regulates epidermal T cells; this gene is upregulated in smokers and linked to increased psoriasis activity, highlighting the role of genetic markers in disease progression and outcomes [49].

In this Delphi exercise, experts responded to two questions regarding which criteria are important to them when deciding when or whether to switch, with one question focusing on the acute symptoms/GPP flare and the other question focusing on the maintenance period. Experts reached consensus on several drivers as a critical consideration during the decision-making process to switch—when such a decision was being considered—which included: “lack of effectiveness,” “contraindication,” “loss of effectiveness due to long-term use,” “new product with higher efficacy and safety data,” “side effects,” “risk of infection,” and “lack of adherence to the treatment.” The results further showed that two drivers, “patient’s decision to end the treatment” did not reach consensus as one of the drivers for switch during the acute symptoms/GPP flare, and “cost of the drug” did not reach consensus as one of the drivers for switch during the maintenance phase. The effectiveness of the biologic drug was considered the most critical criterion for acute symptoms/GPP flare. Likewise, the patient’s decision to change treatment in the acute symptoms/GPP flare was considered as important. However, since the patient’s condition is typically quite severe and uncontrolled, the patient usually has no choice but to continue treatment and trust that the desired clinical response will be achieved. Nevertheless, if the patient’s condition is reasonably stable and there is good response then “patient’s decision to end the treatment” will be considered in shared decision-making. Regarding “cost of the drug” as a driver, experts clarified that GPP is designated as an intractable disease in Japan, and the cost is covered by the healthcare system via public financial aid. Therefore, the patient’s contribution to the cost of the treatment is very low.

With respect to this Delphi panel and the results regarding the five (1–5) top drivers for specific drugs, among the ten physicians prescribing each one of the biologic drugs during the last 2 years, seven mentioned that they have prescribed secukinumab and ixekizumab, four mentioned that they have prescribed infliximab and adalimumab, and three mentioned that they have prescribed brodalumab and certolizumab pegol. At the time of this study, IL-36 inhibitors, such as spesolimab, were not yet available and thus this class of drugs was not included in the study for assessment. Spesolimab has not only shown success in randomized clinical trials [19], it has also shown real-world success, as showcased in multiple case reports describing its use in patients with persistent GPP flares that failed to respond to conventional therapy; in contrast, spesolimab was effective in rapidly and significantly ameliorating the flares within 1–4 weeks with a tolerable profile even in pregnant patients, accompanied by an improvement in quality of life [50, 51]. The availability of spesolimab and its demonstrated profile may push clinicians to choose it as drug of choice over older agents when the former is deemed the most fitting therapy in patients. “Lack of effectiveness” and “loss of effectiveness” were the drivers that reached consensus for being ranked as the top 1 and 2 criteria for switching from secukinumab, infliximab, adalimumab, and ixekizumab. In expanded discussions on each specific drug, panelists explained that secukinumab was the first effective IL-17 inhibitor in the Japanese market for which physicians had high expectations for the treatment of GPP. Experts further clarified that a loss of effectiveness is observed with secukinumab over time. Infliximab was described as the historical “go to” drug for patients with GPP because it was the only available biologic drug in the market at the time. Experts clarified that infliximab is not the most efficacious drug and that it can show effectiveness in some patients but not all. Additionally, the intravenous route of administration of infliximab is a disadvantage as it must be administered in a hospital setting, which patients may find disruptive and inconvenient. Further, infliximab use is associated with a high risk of infection. Panelists also cited other side effects observed with the use of infliximab, such as allergy and anaphylaxis (infusion reaction). In this Delphi exercise, “risk of infection” reached consensus as one of the five top reasons for switching infliximab therapy. Regarding adalimumab, experts elucidated that “lack of effectiveness” is a main driver for switching adalimumab as it is usually less potent than IL inhibitors. Furthermore, there is lack of evidence to support the “double dose” regimen that can be prescribed by clinicians in Japan when the indicated dose of 40 mg is not effective. IL-17 inhibitors are widely used based on clinical experts’ experience. However, it would be immediately obvious if it were not effective, therefore “lack of effectiveness” is a top driver for switch. None of the reasons reached consensus as a top ranked criterion for brodalumab and certolizumab pegol. Experts elucidated that these two drugs are not routinely nor frequently prescribed for patients with GPP; therefore, there is lack of experience with these drugs. Experts emphasized that the availability of robust evidence would also be a key driver to consider for choice of treatment for evidence-based switching.

A systematic review on patients with inflammatory diseases other than GPP (e.g., psoriatic arthritis) showed that information on patient-reported experiences of switching biologic treatments is scarce and that patients’ perspectives on switching are poorly understood [38]. A further limitation in the methods of this review included studies showed that when patients did report on switching, ranking categories were mainly used. In the current study involving experts’ perspectives, various scales (from top 5 reasons, Likert scale, and frequency information) were utilized.

Limitations

There are a number of limitations to the present study. The sample size was small (10 respondents). Some questions, such as those focused on drivers per specific drug, were answered by even a smaller sample size which made consensus difficult to reach. It was not possible to reach a consensus for all questions. Indeed, this was expected and is not the aim of a Delphi exercise.

Conclusion

This Delphi exercise showed that despite the currently available treatment options in Japan, physicians may need to switch from a biologic drug when treating patients with GPP, and that “lack of effectiveness” and “loss of effectiveness” were the most important and top ranked drivers for switching from a biologic drug. A newly published consensus guideline proposed different diagnosis and treatment algorithms to assist physicians in their patient management. The treatment algorithm took into consideration disease state (acute flare vs. maintenance phase), preference for either conventional therapies or biologics, and age of patient [52]. A recently published Delphi panel study [47] reported consensus among dermatologists on various clinical aspects of GPP disease, mainly multidisciplinary management of patients and clinically meaningful goals for GPP treatment. Consistent with the findings of that recent Delphi panel, the present study showed that efficacy, resolution of flares and skin clearance, sustained effects, avoidance of recurrence of acute symptoms/GPP flares, and a good safety and tolerability profile were critical criteria to consider when selecting a new drug. Recently, biologics targeting the IL-36 pathway, such as spesolimab, have shown promising efficacy and a favorable safety profile for acute flare and continuous treatment. The results of this e-Delphi panel highlight the need to develop new therapies targeting GPP that can achieve these treatment goals.

Supplementary Information

Below is the link to the electronic supplementary material.

Authors Contributions

All authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). Yayoi Tada, Shinichi Imafuku, Kazumitsu Sugiura, Hideki Fujita, Noriko Tsuruta, Teruyuki Mitsuma, Ayumi Yoshizaki, Masatoshi Abe, Yukie Yamaguchi, and Akimichi Morita contributed to the study design, were involved in the data interpretation, revised the manuscript, and provided their final approval of submission for publication.

Funding

The study was supported and funded by Boehringer Ingelheim. Boehringer Ingelheim will also be funding the journal’s Rapid Service Fee.

Data Availability

All data generated or analyzed during this study are included in this article and its electronic supplementary material files. Further enquiries can be directed to the corresponding author.

Declarations

Conflict of Interest

Yayoi Tada has received grants, consultancy/speaker's honoraria, and honoraria as an advisory board member from Boehringer Ingelheim. Shinichi Imafuku has received grants from AbbVie, Eisai, Kyowa Kirin, Taiho Pharmaceutical, Mitsubishi Tanabe, Tsumura, Torii Pharmaceutical, Maruho, LEO Pharma, Sun Pharmaceutical Industries, Kaken, Nippon Zoki Pharmaceutical, Sato Pharmaceutical, Eli Lilly, and Sanofi; received consulting activities fees from Meiji Seika Pharma, Bristol Myers Squibb, JT, LEO Pharma, Boehringer Ingelheim, Pfizer, Maruho, and UCB; received speaker’s honoraria from Astellas Pharma, AbbVie, Eli Lilly, Otsuka Pharmaceutical, Kaken, Kyowa Kirin, Sato Pharmaceutical, Sanofi, Sun Pharmaceutical Industries, GSK, Amgen, Daiichi Sankyo, Takeda Pharmaceutical, Taiho Pharmaceutical, Mitsubishi Tanabe, Tsumura, Torii Pharmaceutical, Nippon Zoki Pharmaceutical, Novartis, Pfizer, Bristol Myers Squibb, Maruho, LEO Pharma, Janssen, and UCB; and received honoraria as an advisory board member from Kyowa Kirin, Pfizer, LEO Pharma, AbbVie, Bristol Myers Squibb, and Boehringer Ingelheim. Kazumitsu Sugiura has received grants from AbbVie, Eli Lilly, Maruho, Taiho Pharmaceutical, Eisai, Kyowa Kirin, and Boehringer Ingelheim; received consulting fees from AbbVie, Janssen, Boehringer Ingelheim, Eli Lilly, and LEO Pharma; received speaker’s honoraria from AbbVie, Eisai, Janssen, LEO Pharma, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Kyowa Kirin, Maruho, Novartis, Taiho Pharmaceutical, Torii Pharmaceutical, and UCB; and received support for attending meetings and/or travel from AbbVie, Janssen, Boehringer Ingelheim, Eli Lilly, Kyowa Kirin, Novartis, Taiho Pharmaceutical, and UCB. Hideki Fujita has received grants from Maruho, Taiho, Torii Pharmaceutical, Kaken, Eisai, Kyowa Kirin, and Sun Pharmaceutical Industries; received consultancy/speaker's honoraria from Boehringer Ingelheim, AbbVie, LEO Pharma, Taiho Pharmaceutical, Amgen, Eisai, Eli Lilly, Janssen, JMEC, Kyowa Kirin, Maruho, Mitsubishi Tanabe, Novartis, Sun Pharmaceutical Industries, Taiho Pharmaceutical, Torii Pharmaceutical, UCB, Ushio, and Bristol Myers Squibb; and received honoraria as an advisory board member from Boehringer Ingelheim, AbbVie, LEO Pharma, Sun Pharmaceutical Industries, UCB. Noriko Tsuruta has received consulting fees from Boehringer Ingelheim. Teruyuki Mitsuma has nothing to disclose. Ayumi Yoshizaki has received speaker’s honoraria and payment for expert testimony from Boehringer Ingelheim. Masatoshi Abe has received speaker’s honoraria from Taiho Pharmaceutical, Sanofi, Maruho, Eli Lilly, Amgen, AbbVie, Torii Pharmaceutical, Kyowa Kirin, and Novartis. Yukie Yamaguchi has received grants from Maruho, Taiho Pharmaceutical, Sun Pharmaceutical Industries, Kyowa Kirin, Eli Lilly, Mitsubishi Tanabe, and Torii Pharmaceutical; received consulting honoraria from UCB, LEO Pharma, Taiho Pharmaceutical, and Boehringer Ingelheim; and received speaker’s honoraria from UCB, Eli Lilly, Janssen, Amgen, LEO Pharma, Mitsubishi Tanabe, Bristol Myers Squibb, Taiho Pharmaceutical, AbbVie, Kyowa Kirin, Novartis, and Sun Pharmaceutical Industries. Akimichi Morita has received grants from AbbVie, Kyowa Kirin, LEO Pharma, Maruho, Torii Pharmaceutical, Taiho Pharmaceutical, Mitsubishi Tanabe, Sun Pharmaceutical Industries, and Eisai; received consulting honoraria from Boehringer Ingelheim, Novartis, AbbVie, Nichi-Iko, and Nippon Kayaku; received speaker’s honoraria from AbbVie, Eli Lilly, Eisai, Janssen, Kyowa Kirin, Maruho, Mitsubishi Tanabe, Pfizer, Sun Pharmaceutical Industries, Torii Pharmaceutical, UCB, Taiho Pharmaceutical, and Novartis; and received honoraria as an advisory board member from Bristol Myers Squibb, GSK, Eli Lilly, Kyowa Kirin, Pfizer, and UCB.

Ethical Approval

This type of study does not require any patient information, hence no ethical review or approval was necessary. The study utilized data from anonymized experts’ answers, and all experts involved in the e-Delphi were included as authors.