Generalized pustular psoriasis: Advances in pathogenesis, diagnosis, and treatment

Generalized pustular psoriasis (GPP) is a rare but severe, potentially life-threatening condition characterized by widespread rashes and sterile pustule eruptions on nonacral skin. Flares often include systemic symptoms, such as high fever and malaise, which may lead to sepsis and multiorgan failure, with mortality rates between 4% and 24%. Reported prevalence rates differ widely, ranging from 1.76 to 198 cases per million people.[1] A variety of proinflammatory cytokines, particularly interleukin (IL)-36, are central to GPP pathogenesis. Its rapid onset and recurrent flares present significant management challenges. However, recent years have seen substantial progress in understanding GPP pathogenesis, development of targeted biological therapies, and clinical guideline updates, offering new hope for patients. Genetic factors play a crucial role in GPP pathogenesis [Supplementary Table 1, https://links.lww.com/CM9/C519]. Mutations in the IL36RN gene encoding the IL-36 receptor antagonist (IL-36Ra), are the key determinants. Loss-of-function mutations lead to unopposed IL-36 signaling, enhanced nuclear factor-kappa B (NF-κB) activation, increased neutrophil recruitment, and pustule formation.[2] Other identified GPP gene mutations are detailed in the Supplementary Material, https://links.lww.com/CM9/C519. GPP primarily involves the abnormal activation of the innate immune system through the IL-36 pathway, followed by the involvement of the adaptive immune system.[3] The IL-36-chemokine-neutrophil axis is central to the pathogenesis of GPP [Figure 1].Figure 1: Pre-IL-36 require processing by neutrophil-derived proteases, resulting in bioactive IL-36 agonists or antagonists. IL-36α/β/γ form complexes with IL-36R to recruit IL-1 receptor helper protein (IL-1RAcP) co-receptors. Then, binds to MyD88, activates NF-κB and mitogen-activated protein kinase signaling pathways, regulates downstream transcription of target genes, and generates inflammatory responses. This pathway can be antagonized by IL-36Ra. IL-36 cytokines also induce the expression of multiple cytokines (IL-1β, IL-17A, IL-23, and TNF-α), further spreading this pro-inflammatory cycle. CD4+: CD4+ T cells; CXCL: Chemokines (CXCL1, CXCL2, CXCL8) ; DC: Dendritic cells; Mon: Monocytes; MPO: Myeloperoxidase; NETs: Neutrophil extracellular traps; NF-κB: Nuclear factor-kappa B; Pre-IL-36: Precursor form of IL-36 cytokines; pDC: Plasmacytoid dendritic cells; SERPINA1/3: Serine protease inhibitors 1/3; TNF: Tumor necrosis factor.Consistent GPP diagnostic criteria are lacking due to its clinical heterogeneity. Consensus efforts (e.g., European Rare and Severe Psoriasis Expert Network [ERASPEN], National Psoriasis Foundation [NPF]) and national guidelines provide frameworks but differ on factors such as acral involvement, biopsy necessity, or duration of disease. Notably, a recent NPF consensus suggested that GPP can affect acral surfaces, may last less than 3 months, and does not require biopsy for diagnosis.[3] Details on the diagnosis, clinical characteristics, and course are provided in the Supplementary Material and Supplementary Table 2, https://links.lww.com/CM9/C519. GPP treatment aims for rapid flare control, sustained remission, inflammation reduction, flare prevention, and improved quality of life. Standardized international protocols are currently absent. Traditional options, including retinoids, cyclosporine, and methotrexate, have side effects and limited efficacy.[4] However, the advent of biologics has revolutionized GPP management. A large study confirmed that biologics lead to lower mortality and morbidity rates compared with conventional therapies.[5] Many biological agents approved for PV are also used for GPP, especially in regions such as Japan, and target the tumor necrosis factor (TNF), IL-17, and IL-23 pathways.[6] A comparison of PV and GPP treatments is provided in Supplementary Table 3, https://links.lww.com/CM9/C519. Approval of spesolimab, which is an IL-36R inhibitor directly targeting GPP core pathogenesis, was a landmark development in GPP treatment.[7] The EFFISAYIL 1 trial showed rapid efficacy; 54% of patients achieved clear skin at week 1 vs. 6% with placebo, with effects maintained for 12 weeks.[8] Real-world data confirmed rapid symptom relief.[9] Furthermore, the EFFISAYIL 2 trial showed that subcutaneous spesolimab significantly reduced flare frequency over 48 weeks compared with placebo.[10] Case reports suggest that this treatment is potentially safe during pregnancy.[11] Imsidolimab is another IL-36R inhibitor that is under investigation with promising phase 2 results.[12] TNF-α inhibitors adalimumab, infliximab, and certolizumab pegol, approved in Japan, indirectly suppress IL-36γ. TNF-α inhibitors have been used effectively in pregnant women and children, although careful monitoring is needed (e.g., to avoid low birth weight risk).[13,14] Infliximab showed favorable outcomes, including in pregnancy and pediatric cases.[15,16] Certolizumab pegol demonstrated sustained improvement and is often preferred during pregnancy due to minimal infant drug levels.[17] IL-17 inhibitors secukinumab, ixekizumab, brodalumab, and bimekizumab are also used. Secukinumab showed significant improvement in a phase III trial, and case reports support its pediatric use.[18,19] Ixekizumab demonstrated high psoriasis area and severity index (PASI75) rates in a real-world study.[20] Brodalumab achieved significant remission rates for 1 year.[21] Bimekizumab (anti-IL-17A/F) showed promise in case reports, sometimes succeeding after spesolimab failure.[22] IL-23 inhibitors guselkumab and risankizumab gained Japanese approval for adult GPP, showing high and sustained response rates in phase III trials.[23,24] Ustekinumab (anti-IL-12/23) efficacy is supported by case reports demonstrating sustained remission, including use during pregnancy and in children.[25,26] IL-1 inhibitors gevokizumab and anakinra target a cytokine implicated in IL-36 stimulation. Preliminary studies showed promising results, but larger trials are needed for further validation.[27,28] Emerging small molecule inhibitors, such as JAK and phosphodiesterase-4 inhibitors, are currently being investigated. Japanese guidelines recommend the tyrosine protein-kinase 2 (TYK2) inhibitor deucravacitinib for pustular psoriasis, with a recent trial showing improvement in GPP patients.[29] Phosphodiesterase-4 inhibitor apremilast’s use is documented in case reports, but attention to potential paradoxical GPP is needed.[30,31] In summary, significant progress in GPP management stems from understanding its distinct IL-36-driven pathogenesis and developing targeted therapies such as spesolimab. However, challenges remain. These include the need for standardized global diagnostic criteria to address clinical heterogeneity and the facilitation of research further exploring the genetic and molecular underpinnings to identify biomarkers and personalized approaches. Conducting large-scale, long-term trials and real-world studies is needed to confirm the efficacy and safety of treatment, especially focusing on flare prevention and long-term outcomes. Fundings This work was supported by grants from the Taishan Scholars Program of Shandong Province (No. tsqn201909141) and the National Natural Science Foundation of China (No. 82073441). Conflicts of interest None.