Generalized pustular psoriasis (GPP) is a severe and rare inflammatory skin disorder that can potentially be life-threatening. This condition is characterized by recurring episodes of inflamed, red, and tender skin with widespread pustules all over the body, accompanied by systemic symptoms such as fever, chills, headache, rapid pulse rate, loss of appetite, nausea, and muscle weakness.1 These flare-ups can affect large areas of the body and can last for several weeks before spontaneous remission occurs, leading to partial or complete clearance of the skin.2 GPP most commonly affects adults, although the condition may sometimes develop in children too.2 It is estimated that GPP affects fewer than 5000 individuals in the United States.1
GPP is a complex condition that arises from a combination of genetic and environmental factors. As a genetic disorder, several mutations have been linked to the development of GPP. One such mutation is found in the IL36RN gene, which results in a deficiency of the interleukin-36 receptor antagonist (IL-36Ra).3,4 This deficiency leads to the expression of pro-inflammatory cytokines, which are regulated by transcription factor NF-kB and MAPK. These cytokines include IL-8, CXCL1-3, IL-1, and IL-36, which form a cycle of inflammation. IL-8 and CXCL1-3 are potent neutrophil chemokines that upregulate their expression, causing neutrophils to infiltrate the skin pustules and leading to systemic inflammation in patients with GPP.4
While IL36RN mutations are the most common genetic cause of GPP, mutations in other genes like CARD14, AP1S3, and MPO have also been associated with this condition, although at a lower prevalence.5 The CARD14 gene, also known as CARMA2, is responsible for encoding caspase recruitment domain family member 14 (CARD14). This process mediates the activation of TRAF2-dependent NF-κB signaling in keratinocytes. While mutations in the CARD14 gene are believed to be involved in GPP progression, the exact correlation between CARD14 gene mutations and the onset of GPP requires further investigation.4 The AP1S3 gene encodes the core subunit σ1C of adaptor protein complex 1 (AP-1), which stabilizes AP-1 heterotetramers involved in vesicular trafficking between the trans-Golgi network and endosomes. Studies have shown that loss-of-function mutations in the AP1S3 gene can also be relevant to GPP.4 In 2020, myeloperoxidase (MPO) deficiency was identified as a genetic risk factor for GPP.6 Mutations in the MPO gene, which encodes MPO, have been identified as playing a role in the pathogenesis of GPP.4
Several factors can trigger or worsen GPP, including infections, medication use, psychological stress, and hypocalcemia.5 Medication-related triggers are common, including steroid withdrawal, antimalarials, beta-blockers, angiotensin-converting enzyme inhibitors, and lithium. Other triggers include pregnancy, menstruation, upper respiratory tract infections, and bacterial infections.5 Recently, a study has reported a link between COVID-19 infection and the subsequent diagnosis or worsening of GPP, with an average time of 19 days between COVID-19 infection and the eruption of pustules.7
Screening and Diagnosis
Physicians should suspect the condition in patients with an acute onset of erythema and pustulosis and evaluate it by correlating clinicopathologic findings from physical examination, patient history, review of symptoms, and histopathology.8 GPP is characterized by a sudden onset of widespread, inflamed skin with sterile pustules, accompanied by systemic symptoms such as fever and malaise. Patients with GPP may also exhibit mucosal findings such as a geographic or fissured tongue, cheilitis, and ocular involvement.8 Although a history of concurrent or previous psoriasis may assist in diagnosis, not all patients have a history of the condition. A thorough history is crucial as GPP can be triggered by several patient specific factors.8 GPP may be associated with various medical conditions such as infections including Epstein-Barr virus or varicella-zoster virus, Turner syndrome, hypoparathyroidism, hypocalcemia, allogeneic stem cell transplantation, rheumatoid arthritis, and cardiomyopathy.8
The classification and diagnosis of GPP present challenges, and consensus guidelines with clear definitions and diagnostic criteria have been proposed by international groups. In 2017, the European Rare and Severe Psoriasis Expert Network (ERASPEN) published diagnostic criteria that define GPP as primary, macroscopically visible, and sterile epidermal pustules on non-acral skin. These guidelines state that GPP can occur with or without systemic inflammation, with or without psoriasis vulgaris, and may be either relapsing (>1 episode) or persistent (>3 months).9 The Japanese Dermatological Association (JDA) published diagnostic criteria for GPP in 2018, based on four factors: (1) systemic symptoms such as fever or fatigue; (2) systemic or extensive flush accompanied by multiple sterile pustules; (3) histological evidence of neutrophilic subcorneal pustules, characterized by Kogoj spongiform pustules; and (4) recurrence of these clinical and histologic findings. In Japan, a definitive diagnosis of GPP can be made in patients who meet all four criteria, and GPP should be suspected in those who meet criteria 2 and 3.10
The evidence base for these guidelines for GPP diagnosis is limited due to the rarity of the condition and lack of large-scale clinical trials. Recently, a global Delphi panel study was conducted to gain further insights into the diagnosis of GPP.11 The study found a consensus among the panelists that the ERASPEN and JDA diagnostic criteria can be used to classify and define GPP, respectively.
Several laboratory tests are helpful in diagnosing GPP, including complete blood cell count, erythrocyte sedimentation rate, C-reactive protein levels, and blood chemistries. In cases where genetic testing is available, screening for IL36RN mutations is recommended for GPP diagnosis, while screening for other mutations associated with GPP may also be considered.11
When diagnosing GPP, experts agree that a histopathologic examination of a skin biopsy is useful in differential diagnoses to confirm the diagnosis. The histologic features of GPP include neutrophilic subcorneal pustules characterized by Kogoj spongiform pustules, intense neutrophilic epidermal and dermal infiltration, intraepidermal pustules, and Munro micro-abscesses.11 The panel agree that parakeratosis, acanthosis, hyperkeratosis, elongation of rete ridges, diminished stratum granulosum, and capillary dilation of the papillary dermis are histologic findings of plaque psoriasis, which may also be present in GPP.11
Treatment and Management
Treatment options for GPP include topical, biological, and non-biological therapies. However, there is a lack of well-established treatment guidelines due to limited evidence for their effectiveness and the absence of large clinical trials. Treatment plans for GPP often involve inpatient admission and supportive care, and the choice of treatment should be individualized based on the patient's specific comorbidities and the severity of their disease.5
Spesolimab, an anti-IL-36R antibody, is currently the only medication specifically approved for the treatment of GPP by the FDA.12 The approval was based on the results of the randomized phase II EFFISAYIL trial, which demonstrated that 54% of individuals treated with spesolimab showed no visible pustules compared with 6% taking the placebo. However, it is important to note that spesolimab has been associated with risk of infections and systemic medication reactions.13 To address this, EFFISATYI 2 is currently investigating the long-term management of patients with GPP using spesolimab.14
Investigations are currently being conducted on other therapies that target the anti-IL-36 pathway for GPP treatment. In particular, imsidolimab is being evaluated in the phase III GEMINI1 trial, which aims to assess its safety and effectiveness in comparison with a placebo among adult patients with GPP.15 Furthermore, small molecule anti-IL-36 therapies like the endothelin receptor A antagonist ambrisentan (A-552) and interleukin-1 receptor accessory protein (IL-1RAcP) antibodies may serve as potential future therapies for GPP management, but additional studies are required to determine their long-term safety and efficacy.5
According to the treatment guidelines developed by the American Academy of Dermatology and National Psoriasis Foundation, biological therapies such as adalimumab, ustekinumab, secukinumab, ixekizumab, brodalumab, and infliximab are listed as potential options for treating GPP.16 Non-biological therapies, such as methotrexate and cyclosporine, are also recommended.17 In addition, phototherapy may be used in conjunction with methotrexate.18
GPP is a rare and severe skin condition characterized by painful and disfiguring pustules, which pose a threat to the patient's life. Treatment options have historically been limited because of a lack of clinical trials, mainly due to the low survival rate of the disease and the limited number of cases diagnosed. However, recent research has provided new insights into the pathogenesis of GPP, leading to the development of a new FDA-approved GPP-specific medication. Despite this progress, further research is necessary to identify additional biologic treatment options for GPP and establish effective long-term management strategies for chronic GPP.
- Generalized pustular psoriasis. National Center for Advancing Translational Sciences. Updated February 2023. Accessed April 25, 2023. https://rarediseases.info.nih.gov/diseases/12819/generalized-pustular-psoriasis
- Generalized pustular psoriasis. National Psoriasis Foundation. Accessed April 25, 2023. https://www.psoriasis.org/generalized-pustular-psoriasis/
- Onoufriadis A, Simpson MA, Pink AE, et al. Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. Am J Hum Genet. 2011;89(3):432-437. doi:10.1016/j.ajhg.2011.07.022.
- Zhou J, Luo Q, Cheng Y, Wen X, Liu J. An update on genetic basis of generalized pustular psoriasis (review). Int J Mol Med. 2021;47(6):1-12. doi:10.3892/ijmm.2021.4951.
- Kodali N, Blanchard I, Kunamneni S, Lebwohl MG. Current management of generalized pustular psoriasis. Exp Dermatol. Published online February 13, 2023. doi:10.1111/exd.14765.
- Haskamp S, Bruns H, Hahn M, et al. Myeloperoxidase modulates inflammation in generalized pustular psoriasis and additional rare pustular skin diseases. Am J Hum Genet. 2020;107(3):527-538. doi:10.1016/j.ajhg.2020.07.001.
- Goyal PK, Mohammed TO, Mahmoud A, Zaidi AJ, Nguyen CV. COVID-19 infection leading to acute pustular dermatoses. Arch Dermatol Res. 2023;315(4):685-697. doi:10.1007/s00403-022-02450-z.
- Ly K, Beck KM, Smith MP, Thibodeaux Q, Bhutani T. Diagnosis and screening of patients with generalized pustular psoriasis. Psoriasis (Auckl). 2019;9:37-42. doi:10.2147/PTT.S181808.
- Navarini AA, Burden AD, Capon F, et al; ERASPEN Network. European consensus statement on phenotypes of pustular psoriasis. J Eur Acad Dermatol Venereol. 2017;31(11):1792-1799. doi:10.1111/jdv.14386.
- Fujita H, Terui T, Hayama K, et al; The Japanese Dermatological Association Guidelines Development Committee for the Guidelines for the Management and Treatment of Generalized Pustular Psoriasis. Japanese guidelines for the management and treatment of generalized pustular psoriasis: the new pathogenesis and treatment of GPP. J Dermatol. 2018;45(11):1235-1270. doi:10.1111/1346-8138.114523.
- Puig L, Choon SE, Gottlieb AB, et al. Generalized pustular psoriasis: A global Delphi consensus on clinical course, diagnosis, treatment goals and disease management. J Eur Acad Dermatol Venereol. 2023;37(4):737-752. doi:10.1111/jdv.18851.
- Spevigo prescribing information. Food and Drug Administration. Updated September 2022. Accessed April 26, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761244s000lbl.pdf
- Bachelez H, Choon SE, Marrakchi S, et al. Trial of spesolimab for generalized pustular psoriasis. N Engl J Med. 2021;385(26):2431-2440. doi:10.1056/NEJMoa2111563.
- Morita A, Choon SE, Bachelez H, et al. Design of EffisayilTM 2: a randomized, double-blind, placebo-controlled study of spesolimab in preventing flares in patients with generalized pustular psoriasis. Dermatol Ther. 2023;13(1):347-359. doi:10.1007/s13555-022-00835-6.
- A phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of imsidolimab (ANB019) in the treatment of adult subjects with generalized pustular psoriasis. Clinicaltrials.gov. April 29, 2022. Accessed April 25, 2023. Clinicaltrials.gov identifier NCT05352893. https://clinicaltrials.gov/ct2/show/NCT05352893
- Menter A, Strober BE, Kaplan DH, et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with biologics. J Am Acad Dermatol. 2019;80(4):1029-1072. doi:10.1016/j.jaad.2018.11.057.
- Menter A, Gelfand JM, Connor C, et al. Joint American Academy of Dermatology–National Psoriasis Foundation guidelines of care for the management of psoriasis with systemic nonbiologic therapies. J Am Acad Dermatol. 2020;82(6):1445-1486. doi:10.1016/j.jaad.2020.02.044.
- Elmets CA, Lim HW, Stoff B, et al. Joint American Academy of Dermatology–National Psoriasis Foundation guidelines of care for the management and treatment of psoriasis with phototherapy. J Am Acad Dermatol. 2019;81(3):775-804. doi:10.1016/j.jaad.2019.04.042.