Clinical Characteristics and Disease Burden of Patients with Moderate-to-Severe Generalized Pustular Psoriasis Flares in Taiwan

Abstract

Introduction

Generalized pustular psoriasis (GPP) is a rare and severe psoriasis subtype characterized by the rapid onset of coalescing sterile pustules over broad body areas and systemic inflammation. Data on its clinical course and outcomes in Taiwan are limited. We evaluated the clinical profile and outcomes of patients with GPP flares in Taiwan.

Methods

This retrospective analysis included adult patients with moderate-to-severe GPP flares occurring in January 2008–December 2021. Data were extracted from medical charts and electronic health records in the Chang Gung Research Database. Statistical analyses were performed using SAS for Windows (version 9.4). Multivariate Poisson regression models were built to investigate different predictors of GPP flare rate.

Results

Thirty-four patients with 81 moderate-to-severe GPP flares were identified. Of the 14 patients undergoing genetic analysis, 10 (71.4%) had an IL36RN mutation. Patients’ mean age at the index GPP flare was 47.1 ± 16.5 years; 58.0% of the flares were severe, while 42.0% were moderate. Overall, 96.3% of GPP flares were treated with at least one systemic therapy, acitretin being the most prescribed (85.2%), followed by cyclosporine (45.7%) and methotrexate (18.5%). After treatment, the proportion of flares responding positively increased from 0% on day 2 to 6.2% by week 12. Patients were newly diagnosed with psoriasis (23.5%), hypertension (20.6%), diabetes mellitus (14.7%), psoriatic arthritis (2.9%), malignant tumor (8.8%), and depression/anxiety (2.9%) after enrollment. Complications occurring within 12 weeks of GPP flares included arthritis (25.9% of the flares), skin infection (8.6%), and other infections (2.5%). No fatalities were reported. In the multivariate model, former smokers, patients with hepatic disease, and patients with psoriatic arthritis had an increased GPP rate ratio (RR) of 13.33 (95% confidence interval, CI, 2.87–61.78), 14.08 (95% CI 3.04–65.29), and 34.84 (95% CI 4.77- 254.42), respectively. Contrarily, obese and rheumatoid arthritis patients had a lower GPP rate ratio of 0.21 (95% CI 0.08–0.54) and 0.07 (95% CI 0.006–0.78), respectively.

Conclusions

Our findings highlight the complexity of GPP flare presentations and the need for individualized, patient-centered management approaches and continued research to improve affected individuals’ care and outcomes.

Supplementary Information

The online version contains supplementary material available at 10.1007/s13555-024-01228-7.

Key Summary Points

Despite the alarming increase in the generalized pustular psoriasis (GPP) burden in Taiwan, data on its clinical course and outcomes are scarce.

We characterized the clinical profile of patients with GPP flares, assessed their disease burden through the clinical course of the disease, and evaluated the clinical outcomes of various current treatment regimens using multicenter data.

This study’s data on the GPP comorbidity profiles, treatment regimens, and associated outcomes provide a valuable reference for clinicians in various settings.

We aimed to emphasize the need to closely monitor patients with GPP for the appearance of comorbidities and administer tailored treatment strategies based on individual patient characteristics.

Introduction

Generalized pustular psoriasis (GPP) is a rare and severe subtype of psoriasis characterized by the rapid onset of coalescing sterile pustules over broad areas of the body and systemic inflammation. It represents an extreme inflammatory response distinctly different from the more common chronic plaque-type psoriasis [1]. There is consensus on the definition of GPP, with broad agreement that the condition involves primary sterile pustules within non-acral skin and in the vicinity of psoriasis plaques [2]. Although the pathophysiology of GPP remains incompletely understood, it is often attributed to genetic factors, immune system dysregulation, and external triggers [3]. Several genes have been linked to GPP, including interleukin (IL)-36 receptor antagonist (IL36RN), caspase recruitment domain family member 14 (CARD14), and adaptor-related protein complex 1 subunit sigma 3 (AP1S3) [4]. Environmental triggers, including infections, medications (e.g., lithium and beta-blockers), sudden systemic corticosteroid withdrawal, and stress, can precipitate or exacerbate GPP [5–7].

The presentation and clinical course of GPP can be highly variable. Patients with GPP usually present with signs of systemic inflammation, including fever, fatigue, and leukocytosis, due to the eruption of sterile pustules [8, 9]. It is also characterized by a dynamic clinical course and often presents with a relapsing course with acute flares interspersed with periods of remission [10]. However, some patients show a chronic course in which pustulation persists without clear remission periods [10]. Patients with GPP are prone to a variety of extracutaneous manifestations, including hypocalcemia, arthritis, uveitis, and neutrophilic cholangitis [3]. Moreover, GPP flares can be life-threatening and may lead to sepsis, acute respiratory distress syndrome, congestive heart failure, liver and renal failure, and, ultimately, death [7]. The economic burden due to GPP is substantial and associated with a significant increase in healthcare resource use [3].

Convectional systemic agents available for plaque psoriasis have been often used for the treatment of GPP. This includes acitretin, methotrexate, and cyclosporin [11]. Nevertheless, the adverse events, contraindications, and sometimes limited efficacy of those medications limit its use in GPP. In the recent few years, several biologics have been developed for the treatment of psoriasis with promising therapeutic effects. This includes a list of 13 biologics [12]. Of them, spesolimab, a humanized, anti-IL-36 receptor (IL-36R) monoclonal antibody, is the only FDA approved biologic for the treatment of GPP [12].

Contemporary literature indicates that the global prevalence of GPP varies, with estimates ranging from one to seven cases per million individuals [8, 13]. Notably, Germany has reported a markedly higher incidence, with up to 140 cases per million individuals [14]. Comparable high incidence rates have been observed in the US, where figures reach up to 90 cases per million individuals [14]. In Asia, the incidence rates reported are also significant; for instance, Korea has documented between 88 and 124 cases per million [15], while Japan has reported a prevalence of 7.5 cases per million individuals [16].

In Taiwan, the GPP prevalence rate reached 4.75 cases per 100,000 population in 2020, which is considerably high compared to the previously mentioned global prevalence of one to seven cases per million population [17]. Despite this alarming increase in the GPP burden in Taiwan, data on its clinical course and outcomes are scarce. This population-based analysis aimed to characterize the clinical profile of patients with GPP flares, assess their disease burden through the clinical course of the disease, and evaluate the clinical outcomes of various current treatment regimens using data from the multicenter electronic medical records in Taiwan.

Methods

The study protocol was approved by an institutional review board. This is an IRB-approved retrospective study, all patient information was deidentified, and patient consent was waived. We prepared this article in accordance with the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) statement [18].

Data Source and Eligibility Criteria

For this retrospective cohort study, we identified adult patients who had a moderate-to-severe GPP flare and visited a hospital network in Taiwan between January 2008 to September 2021. The cohort entry date was the date of the first moderate-to-severe flare in the adult GPP patients during the study period. The diagnosis of GPP flares [19] was confirmed by dermatologists based on history, characteristics of skin lesions, and laboratory test results. Moderate-to-severe GPP flares were characterized by a GPP Physician Global Assessment (GPPGA) total score of ≥ 3 and a GPPGA pustulation sub-score of ≥ 3. A GPPGA total score of 3 and 4 were defined as moderate and severe GPP flares, respectively.

Data were extracted from medical chart reviews and the Chang Gung Research Database (CGRD). The CGRD is a hospital-based database linked to the largest healthcare provider network in Taiwan. This database offers detailed information on patient demographics, clinical diagnosis, laboratory results, procedures, prescriptions, and clinical outcomes. Data spanning the period from January 2008 to December 2021 were extracted. We excluded patients with GPP during pregnancy, a prior psoriasis diagnosis, or any missing sub-score in the GPPGA tool evaluation.

Study Outcomes

The primary outcome was the rate of GPP flare recurrence. From the data, we captured GPP flares, irrespective of severity, occurring for 12 weeks after the cohort entry date, i.e., the date of the first moderate-to-severe GPP flare diagnosis. The window of 12 weeks, the duration of a general flare episode, was set to ensure that we observed a distinct GPP flare. The end of follow-up was either the last visit date or the date the patient developed psoriasis vulgaris. The GPP flare recurrence rate was calculated as the total number of GPP flares divided by the total follow-up time. The secondary outcomes of this study were the clinical characteristics, treatment profile, and outcomes of patients with moderate-to-severe GPP flares. The GPP patients were followed up from the cohort entry date. Only moderate-to-severe GPP flares were eligible for inclusion.

Evaluation of the Treatment Response

For evaluation of patients’ response to treatment, we adopted a similar approach to that used in the Effisayil phase II trial [20]. Complete response was defined as an improvement in GPPGA score reaching 1 (almost clear) or 0 (clear). Partial response was defined as an improvement in GPPGA score by ≥ 1. No response was defined as a stationary GPPGA score.

Statistical Analysis

Statistical analyses were performed using SAS for Windows (version 9.4). The Kolmogorov-Smirnov test was used to check the normality of data distribution. Normally distributed continuous variables are given as means ± standard deviations (SD), while otherwise continuous variables are presented as medians and interquartile ranges (IQR). Categorical variables are given as frequencies and percentages. Mean ± SD and median (IQR) for continuous variables (age, weight, BMI, and GPPGA score) are shown in Supplementary Table S1. The distribution of GPPGA scores are presented in Supplementary Figure S1.

We conducted Poisson regression modeling to evaluate potential predictors of GPP flare rates including age, gender, BMI category, smoking status, alcohol consumption, genetic markers, family history of psoriasis, family history of GPP, and comorbidities such as systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, diabetes mellitus (DM), hypertension, fatty liver/hepatitis, and thyroid disease.

Initially, a univariate Poisson regression was conducted to screen for factors of interest, applying a p value threshold of < 0.25 for inclusion. Variables meeting this criterion were subsequently incorporated into a multivariable Poisson regression model to evaluate their association with GPP flare rates while adjusting for other covariates. For the multivariable Poisson regression model, we applied a backward elimination process for variable selection, and the remaining variables were significant with a p value < 0.05. Furthermore, the rate ratio (RR) associated with each variable was calculated to understand their respective impacts.

Results

We initially identified 180 patients with a diagnosis of GPP at the hospital network. However, only 37 adult patients (accounting for 106 flares) had a GPP diagnosis conforming to our definition; of these patients, 34 were categorized as having at least one moderate-to-severe GPP within our specified identification period. A total of 102 GPP flares, including 81 moderate-to-severe flares, were recorded for these 34 patients during the identification period (Fig. 1). The 102 GPP flares with different severities were used to explore flare recurrence. The 81 moderate-to-severe GPP flares were further studied to ascertain patients’ clinical characteristics and treatment outcomes.

Fig. 1.

Flow diagram of patients and flares in the Chang Gung Research Database

Frequency of Flare Recurrence

The average number of recurrent flares per person-year was 0.6.

Patients’ Clinical Characteristics

The CGRD cohort comprised 34 patients, with a mean age at enrollment of 47.1 ± 16.5 years. The cohort consisted of a smaller percentage of males (41.2%) than females. Their mean body mass index was 26.3 ± 6.3 kg/m². Of the 14 patients who underwent gene analysis, 71.4% had a mutation in the IL36RN gene; however, mutations in CARD14 and AP1S3 were not analyzed (Table 1).

Table 1.

Clinical characteristics of patients with GPP flares

	Patients (n = 34)
Age at enrollment with GPP flare, years, mean ± SD	47.1 ± 16.5
Male sex, n (%)	14	(41.2)
Weight, kg, mean ± SD	65.3 ± 16.4
BMI, kg/m2, mean ± SD		26.3 ± 5.85
BMI, kg/m2, categories, n (%)
Underweight (< 18.5)	3	(8.8)
Normal (18.5 to  < 24)	5	(14.7)
Overweight (24 to  < 27)	3	(8.8)
Obese (≥ 27)	9	(26.5)
Unknown	14	(41.2)
Smoking, n (%)
Current	2	(5.9)
Former	2	(5.9)
Never	13	(38.2)
Unknown or not reported	17	(50.0)
Alcohol use, n (%)
Current	0	(0)
Former	3	(8.8)
Never	14	(41.2)
Unknown or not reported	17	(50.0)
Family history, n (%)
PsO	1	(2.9)
GPP	0	(0)
None of the above	4	(11.8)
Unknown or not reported	29	(85.3)
Comorbidities, n (%)
Hypertension	7	(20.6)
Diabetes mellitus	5	(14.7)
Psoriatic arthritis	2	(2.9)
Fatty liver/hepatitis	3	(8.8)
Thyroid disease	2	(5.9)
Anxiety/ depression	1	(2.9)
Malignant tumor	3	(8.8)
Systemic lupus erythematosus	1	(2.9)
Multiple sclerosis	1	(2.9)
Rheumatoid arthritis	1	(2.9)
Gene analysis, n (%) (14 patients underwent gene analysis)
IL36RN mutation (among tested patients)	10	(71.4)a
Negative (among tested patients)	4	(28.6)a

^aThe percentage was calculated as the number patients with or without IL36RN mutation divided by the number undergoing gene analysis

BMI, body mass index; COPD, chronic obstructive pulmonary disease; GPP, generalized pustular psoriasis; IL36RN, interleukin 36 receptor antagonist; PsO, psoriasis; SD, standard deviation

Clinical Characteristics of GPP Flares

Of the 81 GPP flares in the CGRD cohort, 28.4% occurred in the spring, 23.5% in the summer, and 28.4% in the autumn. In the case of precipitating factors, 2.5% of the flares were due to infection or pregnancy. More than half of the GPP flares (58.0%) were severe, while 42.0% were moderate. The mean total GPPGA score was 3.6 ± 0.5 (median [IQR] = 4 [3–4]). Interestingly, 64.2% of the GPP flares were identified as recurrent. In terms of patient-reported outcomes, 25.9% of the GPP flares were accompanied by pain and 7.4% were associated with pruritus. In addition, 58.0% of the flares were associated with severe pustules and 32.1% with fever at diagnosis. Scaling was severe in 54.3% of the GPP flares. Histological findings varied, with 38.3% of patients having sub-corneal pustules with neutrophils, 14.8% having Kogoj’s spongiform pustules, and 8.6% showing eosinophil infiltration (Table 2).

Table 2.

Characteristics of moderate-to-severe flares in a cohort of GPP patients

	Flares (n = 81)
Season, n (%)
Spring (March–May)	23	(28.4)
Summer (June–August)	19	(23.5)
Autumn (September–November)	23	(28.4)
Winter (December–February)	16	(19.8)
Precipitating factors, n (%)
Infection	2	(2.5)
Medications	4	(4.9)
Overwork/stress	0	(0)
Drug withdrawal	1	(1.2)
Severe injury	0	(0)
Pregnancy	2	(2.5)
Others	2	(2.5)
Severity, n (%)
Moderate	34	(42.0)
Severe	47	(58.0)
GPPGA total score, mean ± SD; median (IQR)	3.6 ± 0.5;4 (3–4)
GPPGA sub-scores, mean ± SD
Erythema sub-score	3.7 ± 0.5
Pustule sub-score	3.6 ± 0.5
Scaling sub-score	3.5 ± 0.6
Type of GPP flare, n (%)
First-ever onset	29	(35.8)
Recurrent	52	(64.2)
Patient-reported symptoms at diagnosis, n (%)
Pruritus	6	(7.4)
Pain	21	(25.9)
Myalgia	0	(0)
Other symptoms at diagnosis, n (%)
Pustules, moderate	34	(42.0)
Pustules, severe	47	(58.0)
Fever	26	(32.1)
Malaise	1	(1.2)
Edema	6	(7.4)
Erythroderma	79	(97.5)
Scaling, mild	1	(1.2)
Scaling, moderate	36	(44.4)
Scaling, severe	44	(54.3)
Mucosal involvement	1	(1.2)
Involvement of organs other than skin (e.g., scalp, nails)	25	(30.9)
Histological findings, n (%)
Sub-corneal pustules with neutrophils	31	(38.3)
Kogoj’s spongiform pustules	12	(14.8)
Eosinophil infiltration	7	(8.6)
Unknown or not reported	50	(61.7)

GPP, generalized pustular psoriasis; SD, standard deviation; GPPGA, Generalized Pustular Psoriasis Global Assessment, IQR, interquartile ranges

Treatments and Clinical Outcomes of GPP Flares

Overall, 96.3% (n = 78) of the flares were treated with at least one type of systemic therapy, with acitretin being the most commonly used at 85.2%. Other common treatments included cyclosporine (45.7%) and methotrexate (18.5%). Biologics were used for < 10% of the flares, including etanercept for 9.9% of the flares, adalimumab for 7.4%, and brodalumab, secukinumab, and stekinumab for 2.5%. In the case of topical treatments, 95.1% (n = 77) of the flares were treated with at least one, with corticosteroids used by 84.0% of the cohort. Vitamin D analogs were also commonly used, with 66.7% of the flares treated with them. A smaller subset, 13.6% (n = 11), underwent phototherapy (Table 3).

Table 3.

Treatments for moderate-to-severe flares in a cohort of GPP patients

	Flares (n = 81)
Systemic treatments
Ever used at least one of the following systemic treatments	78	96.3
Acitretin	69	85.2
Cyclosporine	37	45.7
Methotrexate	15	18.5
Prednisolone	7	8.6
Etanercept	8	9.9
Adalimumab	6	7.4
Brodalumab	2	2.5
Secukinumab	2	2.5
Ustekinumab	2	2.5
Topical treatments
Ever used at least one of the following topical treatments	77	95.1
Corticosteroids: high potency, medium potency, low potency	68	84.0
Vitamin D analog	54	66.7
Tar	19	23.5
Tazarotene	1	1.2
Phototherapy	11	13.6
Other indications
Antibiotics	49	60.5
Psychiatric medications	8	9.9
Opioid pain medications	16	19.8
Sedatives	18	22.2

GPP, generalized pustular psoriasis

Figure 2 shows the evolution of treatment responses of the 81 GPP flares. On day 2, 84.0% of the flares did not show a response; however, the pattern shifted by week 12, with no responses dropping to 33.3%. There was a consistent rise in partial responses, reaching 39.5% by week 12. Concurrently, the proportion of patients with positive responses increased from 0% on day 2 to 6.2% by week 12.

Fig. 2.

Responses of the 81 moderate-to-severe flares to conventional treatments

After enrollment, the most common diagnosed comorbidities among GPP patients were hypertension (20.6%), diabetes mellitus (14.7%), and psoriatic arthritis (PsA; 2.9%). Eight patients (23.5%) had newly developed psoriasis and one patient (2.9%). Complications occurring within 12 weeks of GPP flares included arthritis (reported by 25.9% of the flares), skin infection (8.6%), and other infections (2.5%). No fatalities were reported.

Predictors of GPP Flare Rates

In our results, the following variables had a p value < 0.25 and were included in the multivariable regression model: BMI category, smoking status, alcohol consumption, genetic markers, family history of psoriasis, hypertension, DM, multiple sclerosis, liver disease, RA, and PsA. The final model included BMI category, smoking history, liver disease, rheumatoid arthritis, and psoriatic arthritis, as these remained significant. The outcomes of this analysis are presented in Table 4.

Table 4.

Multivariate Poisson regression model for predictors of GPP flare rates

	Rate ratio (95% CI)
BMI
Obese	0.21 (0.08–0.54)
Overweight	1.51 (0.46–5.03)
Normal	1.00
Underweight	1.50 (0.64–3.52)
Unknown	0.61 (0.28–1.33)
Smoking status
Current	0.70 (0.15–3.22)
Former	13.33 (2.87–61.78)
Never	1.00
Unknown or not reported	4.23 (1.95–9.17)
Presence of fatty liver/hepatitis	14.08 (3.04–65.29)
Presence of rheumatoid arthritis	0.07 (0.006–0.78)
Presence of psoriatic arthritis	34.84 (4.77–254.42)

GPP, generalized pustular psoriasis, BMI, body mass index, CI, confidence interval

Among these, former smokers show an increased rate of GPP flares, with an RR of 13.33 (95% confidence interval, CI 2.87–61.78), indicating their flare rate is substantially higher than that of individuals who have never smoked. In addition, the presence of psoriatic arthritis and liver disease was associated with an increased flare rate, with a RR of 34.84 (95% CI 4.77–254.42) and 14.08 (95% CI 2.87–61.78), respectively. However, the confidence intervals were wide given the limited sample size.

On the other hand, obesity was linked to a lower flare rate, with an RR of 0.21 (95% CI 0.08–0.54), indicating a significant reduction compared to individuals with normal BMI. Furthermore, individuals with rheumatoid arthritis exhibit a reduced flare rate, with an RR of 0.07 (95% CI 0.006–0.78).

Discussion

Generalized pustular psoriasis imposes a substantial clinical and economic burden on the public health system and significantly impairs patients’ clinical outcomes and quality of life [21]. Nonetheless, the clinical presentations and outcomes of GPP flares have been poorly studied [3]. This study presents a detailed examination of the clinical characteristics, treatment patterns, and outcomes associated with GPP flares to offer a multifaceted understanding of this condition. We also constructed a multivariate regression model to investigate different predictors of GPP flare rates.

In the case of population characteristics, we found a slight predominance of females (58.8%), with a mean age of 47.1 ± 16.5 years at GPP diagnosis. This finding is consistent with those of recent case series from Asian countries [15, 22, 23]. A multicenter study from Italy reported a male-to-female ratio of 0.5 and a mean age at diagnosis of 58.1 years [24]. However, a study from Turkey reported a male-to-female ratio of 0.6 [25]. While former smoking was associated with higher GPP flare rates, obesity was associated with lower flare rates. This may imply significant risk factors for GPP and necessitates further studies. Nevertheless, this should be interpreted cautiously given the limited sample size.

Generalized pustular psoriasis is increasingly recognized as being associated with various comorbidities that may complicate patients’ clinical course [3]. In this study, 45% (9/20) of patients were obese, 21% had hypertension, and 14% had diabetes mellitus. A previous study also showed that the prevalence of obesity, hypertension, and diabetes mellitus among patients with GPP was 43%, 26%, and 24%, respectively [19]. Our study highlights the development of various comorbidities in patients with GPP during the course of their disease. For example, psoriasis and PsA were the most common newly developed comorbidities; this result is similar to those of previous studies that found a 25–35% incidence of joint involvement (arthralgia or arthritis) in patients with GPP [22, 25, 26]. In addition, patients with liver disease and PsA had higher flare rates, while patients with rheumatoid arthritis had lower flare rates.

The relationship among GPP, psoriasis vulgaris (PsO), and PsA is complex and has not been fully elucidated yet. Our findings demonstrate that the incidence of both PsO (23.5%) and PsA (8.8%) in patients with GPP is significantly higher than the incidence of both conditions in the general population. The global age-standardized incidence of PsO is 57.8 per 100,000 people [27]. The high incidence of PsO and PsA among GPP patients is consistent with the incidences given in previous studies [28] and underscores the interplay between these psoriasis variants. GPP patients’ elevated risk of PsO and PsA suggests that GPP may serve as a prodromal symptom or a clinical precursor of these conditions. GPP is often associated with a more severe and widespread inflammatory response, implicating potentially heightened immune dysregulation that can predispose individuals to the development of PsO and PsA [29]. In addition, genetic factors, such as specific HLA alleles, have been implicated in the pathogenesis of both GPP and PsO, suggesting shared genetic susceptibility [30].

As in other forms of psoriasis, genetic factors contribute significantly to the predisposition to GPP. The IL36RN gene has emerged as one of the most significant genetic contributors to GPP. Loss-of-function mutations in the IL36RN gene result in uncontrolled IL-36 signaling, which promotes excessive inflammation and has been strongly linked to GPP development [6]. CARD14 is another gene whose disruption can enhance nuclear factor kappa B (NF-κB) signaling and subsequent inflammation. A few studies have identified mutations in CARD14 in patients with GPP [31]. In addition, mutations in AP1S3 have been linked to GPP in specific populations [5]. The CGRD cohort in our study offers unique insights into the genetic landscape of GPP, with 71.4% (10/14) of the patients having a mutation in IL36RN. This finding supports previous studies that have linked IL36RN mutations to GPP severity [6].

The primary treatment options for GPP include systemic (e.g., acitretin, methotrexate, and cyclosporine), biological (e.g., infliximab, adalimumab, and ustekinumab), and other (e.g., colchicine, dapsone, and tetracyclines) therapies [32]. Since there is little consensus on managing GPP, previous studies have shown notable variability in treatment regimens [7, 33, 34]. Acitretin was the most prescribed drug for the CGRD cohort. These variations might reflect differences in clinical guidelines, healthcare systems, or physician experiences and preferences and lead to unfavorable treatment outcomes. Previous research indicated that the effectiveness of the current treatment regimen is limited, with a response rate of only 41.3% [11]. Our findings underscore the complexity of managing GPP and suggest that treatment should be tailored to the patient’s condition. Therefore, building a consensus on the appropriate treatment regimen is warranted. Camela et al. highlighted the importance of using holistic approach in the treatment of psoriatic patients [35]. For instance, novel biological agents target a common pathological pathway in the pathogenesis of psoriasis, helping to treat comorbidities linked to that particular pathway including psoriatic arthritis and metabolic impairment. This greatly aids in reducing the bill burden, cost, and drug interactions of polypharmacy with improved patient’s compliance, wellbeing, and quality of life [35].

Generalized pustular psoriasis flares show substantial variation in severity and duration [36]. A major challenge is the lack of consensus on what constitutes a “moderate” versus a “severe” GPP flare. Clinicians and researchers may use different criteria for grading the severity of GPP flares based on subjective clinical assessment, patient-reported symptoms, and objective laboratory or imaging findings [2]. As recently proposed, the GPPGA is an effective measure for assessing the severity of GPP [37].

This study has several clinical and healthcare policy implications. Its detailed characterization of the clinical features of GPP flares and their outcomes adds to the current body of evidence informing patient management. Its data on comorbidity profiles, treatment regimens, and associated outcomes can serve as a valuable reference for clinicians in various settings. Its findings emphasize the need to closely monitor patients with GPP for the appearance of comorbidities and highlight the importance of tailored treatment strategies based on individual patient characteristics. The recognition of GPP as a potential prodromal symptom of PsO has important clinical implications. Early detection of and intervention for GPP may help mitigate the progression to PsO or PsA and improve overall outcomes. In addition, understanding the shared pathogenic mechanisms and genetic predispositions between these conditions may lead to targeted therapies and personalized treatment strategies. This study could serve as a call to action for creating consensus guidelines that provide clear recommendations for managing GPP flares.

Limitations of the Study

A key strength of our analysis is its use of extensive real-world data. However, our study has some limitations. Its retrospective nature might have introduced bias, and there is a risk that unrecorded confounding variables might have affected the validity of the results. We could not account for important potential confounders, including lifestyle habits, socioeconomic status, and adherence to treatment regimens. In addition, there was a risk of misclassification bias in the electronic medical records. For example, the ICD-10-CM code for GPP is L40.1, which was historically diagnosed as psoriasis vulgaris. Therefore, some patients might have been misdiagnosed and not accurately captured. Another limitation is the lack of a control group, e.g., patients without GPP or patients with GPP without flares, which restricts the ability to assess the relative risks and impacts of various comorbidities and treatments on GPP flares. Our analysis did not capture the long-term effects and outcomes of GPP flares and their management due to limited follow-up time. The relatively small sample size hinders the generalizability of the multivariate regression model for potential predictors of GPP flare rates that we built. Finally, few patients in the cohort were tested for mutations in the IL36RN gene. Specifically, only 14 patients underwent genetic testing, and among them, 10 were found to test positive for the IL36RN gene mutation. This limitation has several implications that need to be considered when interpreting our findings and discussing their broader relevance. Further prospective studies are needed to understand the genetic involvement in GPP.

Conclusions

This study provides valuable insights into the presentations and outcomes of GPP flares in Taiwan. Its findings highlight the complexity of GPP and the necessity for targeted treatments to alleviate the impact of the condition on patients and achieve individualized, patient-centered care. Future research involving more detailed genetic analyses, aiming to understand the underlying factors contributing to the observed differences in the presentations and outcomes of GPP flares, is warranted.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Chun-Wei Lu, Chien-Yu Tseng, and Chuang-Wei Wang conceptualized the study. All authors were involved in data acquisition. Chien-Yu Tseng, Chun-Bing Chen, Chung-Yee Rosaline Hui, Ching-Chi Chi, and Fang-Ju Lin analyzed and interpreted the data. Chun-Wei Lu, Chien-Yu Tseng, Chuang-Wei Wang, Shang-Hung Lin, Chun-Bing Chen, Chung-Yee Rosaline Hui, Ching-Chi Chi, Yu-Huei Huang, and Wen-Hung Chung drafted the manuscript. Chun-Wei Lu, Chien-Yu Tseng, and Wen-Hung Chung revised the manuscript for important intellectual content. Wen-Hung Chung provided administrative, technical, or logistic support. All authors read and approved the final manuscript.

Funding

No funding or sponsorship was received for this study or publication of this article. The Rapid Service Fee was funded by the authors.

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Conflict of interest

The authors (Chun-Wei Lu, Chien-Yu Tseng, Chuang-Wei Wang, Shang-Hung Lin, Chun-Bing Chen, Chung-Yee Rosaline Hui, Ching-Chi Chi, Yu-Huei Huang, Chih-Hung Lee, Fang-Ju Lin, Wen-Hung Chung) declare that they have no potential conflicts of interest.

Ethical approval

The study protocol was approved by the Institutional Review Board of Chang Gung Medical Foundation (No. 202200813B0, dated 18/06/2022). This is an IRB-approved retrospective study, all patient information was deidentified and patient consent was waived.