Yukari Okubo ¹, Ryuhei Okuyama ², Shinichi Imafuku ³, Yayoi Tada ⁴, Keiichi Yamanaka ⁵, Kazumitsu Sugiura ⁶, Yukie Yamaguchi ⁷, Masahito Yasuda ⁸, Wataru Sakamoto ⁹, Morihisa Saitoh ⁹, Akimichi Morita ¹⁰; Study Investigators

Dermatol Ther (Heidelb). . 2025 Jul;15(7):1883-1899. doi: 10.1007/s13555-025-01429-8. Epub 2025 May 19.

Introduction: Generalized pustular psoriasis (GPP) is a rare, severe, and chronic inflammatory skin disease characterized by widespread pustules that leads to unpredictable and potentially serious disease flares. Information regarding treatment status for GPP and treatment patterns for flares is important but limited as a result of the rarity of the condition. We conducted a 10-year, retrospective, longitudinal chart review of treatment patterns at GPP referral hospitals in Japan.

Methods: Eligible patients with GPP had at least 6 months of continuous observation data within 10 years after the date of protocol approval. Data were collected from patient records and annual patient reports. Patient characteristics and treatment details, including in relation to flare occurrence, were analyzed.

Results: The median age of patients (N = 205) was 53 years; 48.3% were female and most had mild or moderate GPP (66.8%). Patients commonly received nonbiologic systemic therapy (86.3%) and a similar proportion received biologics (79.5%); 95.1% received topical treatment and 22.4% received systemic adrenal corticosteroids. Use of nonbiologic systemic therapy decreased, and use of biologics increased, over the study period. During the observation period, the proportion of patients receiving biologic therapy increased after a flare (from 41.4% receiving biologics when flares occurred to 62.9% initiating a new biologic post flare).

Conclusion: In Japanese clinical practice, the evolution of treatment practices for GPP has seen an increased use of biologic therapies over time. Biologic use was common after flares; however, some flares occurred during biologic therapy, indicating a need for improved treatment options to maintain stable disease and prevent flares.

Chisato Tawada ¹, Yoko Ueda ², Yoko Mizutani ¹, Xiaoyu Zang ¹, Kayoko Tanaka ¹, Hiroaki Iwata ¹

Exp Dermatol. 2025 Mar;34(3):e70076. doi: 10.1111/exd.70076.

Reactive oxygen species (ROS) are involved in the pathogenesis of generalised pustular psoriasis (GPP), but this involvement has not been fully elucidated. We performed the diacron-reactive oxygen metabolite (d-ROM) test and the biological antioxidant potential (BAP) test on sera from nine patients with active GPP who were hospitalised and treated at our hospital, (6/9 with GMA) including three patients with pustular psoriasis of pregnancy (PPP). The serum d-ROM and BAP levels were evaluated before treatment and at 1 month of treatment. We also performed immunostaining of 4-hydroxy-2-nonenal (4-HNE) in skin tissues. In the GPP patients, the average d-ROM levels were significantly reduced at 1 month of treatment (reduced to 343.0 ± 82.1 U.Carr from 423.2 ± 95.0 U.Carr, p = 0.005). The Generalised Pustular Psoriasis Area and Severity Index (GPPASI) score correlated with d-ROM levels (r = 0.57, p = 0.10), suggesting that those levels reflect the disease severity. In normal pregnancy, d-ROM values are known to increase from mid-term to late-term. The d-ROM values increased when GPP worsened in the case of PPP. Immunohistochemical staining of 4-HNE was positive for subcorneal pustules, neutrophils, and for the cytoplasm of epidermal keratinocytes, especially in upper epidermal layers. Our findings indicate that 4-HNE may play an important role in GPP and PPP.

Miho Takahashi*, Hitoshi Tsuchihashi and Rei Watanabe

J. Cutan. Immunol. Allergy, 13 March 2025 Volume 8 – 2025 | https://doi.org/10.3389/jcia.2025.14441

A 41-year-old woman had been diagnosed with generalized pustular psoriasis (GPP) for 4 years. Her symptoms had been stabilized with cyclosporine (2 mg/kg/day). Despite increasing the cyclosporine dosage to 3 mg/kg/day, the skin lesions did not improve and the patient developed a fever.  A CT scan revealed a mass lesion measuring 2.5 cm × 4 cm in the right breast and axillary lymphadenopathy. Based on the CT findings, the patient was suspected of having left breast cancer. To manage GPP, granulocyte and monocyte adsorption (GMA) was initiated to minimize the possible adverse effects on the suspected cancer. During the five courses of GMA, the patient’s body temperature returned to a normal degree and the pustules and erythema gradually improved. However, the erythema on her trunk remained. GMA was selected as the initial treatment because the therapeutic strategy for the breast cancer had not yet been determined. Meanwhile, etretinate, corticosteroids, biologics, and their combination are also strong candidates for acute exacerbated GPP. Subsequently, subcutaneous brodalumab administration was introduced; brodalumab allowed the patient to concurrently undergo chemotherapy for breast cancer. The patient underwent a left breast mastectomy and was diagnosed with right breast cancer with right axillary lymph node metastasis. The patient started hormonal therapy, and tumor markers showed a decreasing trend. However, she gradually developed skin metastases, which grew despite treatment. The patient died of breast cancer 4 years after diagnosis. Brodalumab was continued for 4 years, during which no recurrence of GPP was observed.

In conclusion, due to the rarity of the disease, selecting an appropriate therapy for GPP is often challenging especially considering the management of complications. Further accumulation of the treatment experience would be desirable.

Masashi Akiyama ¹

J Dermatol. 2025 Mar;52(3):400-407. doi: 10.1111/1346-8138.17585. Epub 2024 Dec 19.

Generalized pustular psoriasis (GPP) is a severe autoinflammatory keratinization disease (AiKD) characterized by acute flares of widespread sterile pustules and high fever. GPP is potentially life-threatening. Recently clarified genetic predisposing factors for GPP suggest that the excessive activation of innate immune pathways in the skin, including of interleukin (IL)-1 and IL-36 signaling, plays a significant role in the GPP pathogenesis. IL36RN, CARD14, AP1S3, MPO, SERPINA3, BTN3A3, and MEFV have been identified as GPP-related genes. The pathogenesis of GPP provoked by variants in these seven genes is tightly associated with the excessive activation of innate immune pathways and the resulting autoinflammation in the skin. Various biologics, including inhibitors for the tumor necrosis factor, IL-17, and IL-23 pathways, are used as treatments for GPP. The new understanding of the genetic background of GPP, mentioned above, indicates that the genetic predisposing factors are predominantly related to the excessive activation of innate immunity and autoinflammation. In this context, inhibitors of inflammatory signaling, including of the IL-1 and IL-36 pathways, have been used in clinical practice and investigated as potential future therapies.

Ludovica Franceschin ¹, Alessia Guidotti ¹, Roberto Mazzetto ¹, Jacopo Tartaglia ¹, Christian Ciolfi ¹, Mauro Alaibac ¹, Alvise Sernicola ¹

Biomolecules. 2024 Nov 27;14(12):1515. doi: 10.3390/biom14121515.

Neutrophil-mediated inflammation is a key feature of immune-mediated chronic skin disorders, but the mechanistic understanding of neutrophil involvement in these conditions remains incomplete. Dapsone, colchicine, and tetracyclines are established drugs within the dermatologist’s therapeutic armamentarium that are credited with potent anti-neutrophilic effects. Anti-neutrophilic drugs have established themselves as versatile agents in the treatment of a wide range of dermatological conditions. Some of these agents are approved for the management of specific dermatologic conditions, but most of their current uses are off-label and only supported by isolated reports or case series. Their anti-inflammatory and immunomodulatory properties make them particularly valuable in managing auto-immune bullous diseases, neutrophilic dermatoses, eosinophilic dermatoses, interface dermatitis, and granulomatous diseases that are the focus of this review. By inhibiting inflammatory pathways, reducing cytokine production, and modulating immune responses, they contribute significantly to the treatment and management of these complex skin conditions. Their use continues to evolve as our understanding of these diseases deepens, and they remain a cornerstone of dermatological therapy.

GMA is a promising alternative in patients who have failed conventional therapies for generalized pustular psoriasis, pyoderma gangrenosum, Behçet’s disease, and hidradenitis suppurativa. The strengths of GMA lie in its favorable tolerability and peculiar mode of action that is able to deplete inflammation without causing immunodeficiency.

Siew Eng Choon ¹, Peter Anthony Foley ^2 3, Pravit Asawanonda ⁴, Hideki Fujita ⁵, Seong-Jin Jo ⁶, Yu-Ling Shi ^7 8, Colin Theng ⁹, Azura Mohd Affandi ¹⁰, Chul Hwan Bang ¹¹, Maria Lorna Frez ¹², Huang Yu Huei ^13 14, Doanh Le Huu ¹⁵, Tae-Gyun Kim ¹⁶, Akimichi Morita ¹⁷, Hazel H Oon ^18 19, Pablo Fernández-Peñas ^20 21, Natta Rajatanavin ²², Suganthy Robinson ¹⁰, Latha Selvarajah ²³, Tsen-Fang Tsai ²⁴

J Dermatol. 2024 Dec;51(12):1579-1595. doi: 10.1111/1346-8138.17471. Epub 2024 Oct 10.

Generalized pustular psoriasis (GPP) is a rare, chronic, heterogeneous, and potentially life-threatening disease characterized by primary, sterile, and macroscopically visible pustules with or without systemic symptoms. There are ethnic differences in the genetic mutations associated with GPP that might affect the clinical manifestations and treatment responses. Currently, there is limited evidence from the patient population in the Asia-Pacific (APAC) region, resulting in a general paucity of information on the effective management of patients with GPP in this region. This modified Delphi panel study aimed to identify current evidence and gain advanced insights to facilitate the development of a regionally tailored APAC consensus on the management of GPP. A systematic literature review (SLR) was conducted to identify published literature and develop consensus statements on (i) definition and clinical course, (ii) diagnosis of GPP, (iii) treatment outcomes, goals, and monitoring measures, and (iv) optimal management strategies and clinical practices. Statements were rated by a panel of dermatologists in two rounds, with the threshold for consensus at ≥80% agreement. Twenty experts from the APAC region reached consensus on 106 statements that were developed based on the SLR and experts’ collective expertise. The experts agreed that GPP is a rare, severe, and potentially life-threatening condition that is distinct from plaque psoriasis. This consensus emphasized the importance of a tailored treatment strategy taking into account the GPP flare severity and each patient’s unique clinical circumstances. The experts reached consensus on the severity classification of GPP flares and recommended first-line and maintenance treatment options for adult GPP, childhood GPP, and GPP in pregnancy. These consensus outcomes have been synthesized into treatment algorithms to guide dermatologists in the APAC region in their clinical decision-making processes.

Non-pharmacological treatments, such as GMA and IVIG, can be considered based on their availability in individual countries

Lluís Puig ¹, Hideki Fujita ², Diamant Thaçi ³, Min Zheng ⁴, Ana Cristina Hernandez Daly ⁵, Craig Leonardi ⁶, Mark G Lebwohl ⁷, Jonathan Barker ⁸

Dermatol Ther (Heidelb). 2024 Sep;14(9):2331-2378. doi: 10.1007/s13555-024-01230-z. Epub 2024 Aug 1.

Generalized pustular psoriasis (GPP) is a rare, chronic and potentially life-threatening autoinflammatory skin disease characterized by widespread eruption of sterile pustules, with or without systemic inflammation. GPP can significantly reduce patients’ quality of life (QoL). Several therapeutic approaches have been described in the literature, but there is no consensus on optimal treatment. In this review, we summarize published literature on efficacy, safety and QoL outcomes associated with current treatment of GPP with both approved and non-approved products. Embase and MEDLINE databases were searched (1980-September 2023). A search protocol was designed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered on the PROSPERO database (CRD42021215437). Details on publication, population, intervention, efficacy, safety and QoL were captured and checked by independent reviewers. In total, 118 publications were included, with only 19% of publications reporting on the results of clinical trials. Treatment modalities reported for GPP included non-biologic systemic therapies such as retinoids, cyclosporine and methotrexate, topical agents, biologics and small molecules, among others. Results were highly heterogeneous and methodological quality was very low, with only the interleukin-36R inhibitor spesolimab reporting results from placebo-controlled randomized trials; based on this, spesolimab is now approved for GPP treatment in regions including the USA, Japan, China, the EU and several other countries. Some other biologics are approved exclusively in Japan and Taiwan for the treatment of GPP based on open-label studies with small patient numbers in lieu of double-blind studies. Non-standardization of clinical outcomes across studies remains a major hurdle in reaching a consensus on optimal treatment. However, recently trials have been conducted using well-defined, disease-specific endpoints to evaluate GPP-targeted treatments, which will hopefully advance patient care. In conclusion, this review highlights the need for prospective randomized studies with GPP-specific endpoints to determine the optimal treatment strategy.

GMA was approved for the treatment of GPP in Japan in 2012 

João Vilaça ¹, Orhan Yilmaz ², Tiago Torres ^1 3

Pharmaceutics. . 2024 Jul 6;16(7):908. doi: 10.3390/pharmaceutics16070908.

Generalized Pustular Psoriasis (GPP) is a rare and severe subtype of psoriasis that significantly impacts patients’ quality of life. Until recently, no specific treatment modalities were available, and treatment for GPP followed the guidelines for the treatment of plaque psoriasis, consisting of conventional treatments, such as retinoids, methotrexate, and even biologics, which although effective in some cases, may be associated with significant side effects, necessitating more effective and safe options. The pathophysiology of Generalized Pustular Psoriasis is complex and not fully understood, but there is some overlap with the pathogenesis of Plaque Psoriasis. In GPP, the innate immune system seems to play a more significant role, with the interleukin (IL)-36 pathway being fundamentally involved. Spesolimab and imsidolimab, two recently developed therapeutic agents, target the IL-36 inflammatory pathway by binding to the IL-36 receptor (IL-36R). Both biologics have already been evaluated in phase 1 and 2 clinical trials and have shown promising results in terms of safety and efficacy. IL-36 receptor inhibitors demonstrated great efficacy and good safety profile in the management of patients with GPP, demonstrating their potential to emerge as a leading treatment option. This review aims to explore and summarize the current scientific literature on the most recently developed treatments for GPP.

Dimitrii Pogorelov ¹, Anne Tschesche ¹, Galina Balakirski ¹, Silke C Hofmann ¹

Cureus. 2024 May 7;16(5):e59832. doi: 10.7759/cureus.59832. eCollection 2024 May.

Generalized pustular psoriasis of pregnancy (GPPP) is a rare dermatological condition that significantly affects maternal health and pregnancy outcomes. The treatment of this disease might be very challenging, as only a limited number of effective therapeutic options are available. If the use of systemic drugs is considered, they should ideally effectively control the systemic inflammation without harming the fetus. Here, we report the successful treatment of a severe case of GPPP in a 28-year-old woman using the tumor necrosis factor-alpha inhibitor (TNFi) certolizumab pegol. Additionally, we review the existing literature on the use of this class of drugs for treating GPPP. To date, there are only 11 reported cases of this severe skin condition treated with a TNFi. We also discuss the pathogenesis of GPPP and the rationale behind using TNFi for its treatment.

Mingdan Zhao, Fujun Huang, Lei Tang, Xun Zhou,Miao Zhang, Mengxue Liao,Lirong Liu,Mengya Huang, Front. Immunol. 2024, 15,doi.org=10.3389/fimmu.2024.1354578

Acute generalized pustular psoriasis (GPP) is a serious illness. Despite various treatment methods, there is still lack of effective treatment plans for refractory cases with multiple comorbidities. This case report presents a 67-year-old woman with acute GPP, stage 4 chronic kidney disease (CKD), type 2 diabetes, and cardiovascular disease, in whom skin symptom disappearance and kidney function improvement were observed after the use of oral tacrolimus as the sole therapy. This is the first report on the application of tacrolimus in the treatment of acute GPP, especially refractory acute GPP. The successful treatment indicates that there are shared immune pathways between acute GPP and CKD, and the pathways can be interdicted by tacrolimus. Further studies are needed to optimize the therapy to maximize efficacy and minimize toxicity.