Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
American Journal of Clinical Dermatology
Published in: American Journal of Clinical Dermatology 1/2022

Open Access 01-01-2022 | Generalized Pustular Psoriasis | Review Article

Treatment Options and Goals for Patients with Generalized Pustular Psoriasis

Authors: James Krueger, Lluís Puig, Diamant Thaçi

Published in: American Journal of Clinical Dermatology | Special Issue 1/2022

Login to get access

Abstract

Generalized pustular psoriasis (GPP) is a rare, severe neutrophilic skin disorder characterized by sudden widespread eruption of superficial sterile pustules with or without systemic inflammation. GPP flares can be life-threatening if untreated due to potential severe complications such as cardiovascular failure and serious infections. Currently, there are no GPP-specific therapies approved in the USA or Europe. Retinoids, cyclosporine, and methotrexate are the most commonly used non-biologic therapies for GPP. The evidence that supports the currently available treatment options is mainly based on case reports and small, open-label, single-arm studies. However, recent advances in our understanding of the pathogenic mechanisms of GPP and the identification of gene mutations linked to the disease have paved the way for the development of specific targeted therapies that selectively suppress the autoinflammatory and autoimmune mechanisms induced during GPP flares. Several biologic agents that target key cytokines involved in the activation of inflammatory pathways, such as tumor necrosis factor-α blockers and interleukin (IL)-17, IL-23, and IL-12 inhibitors, have emerged as potential treatments for GPP, with several being approved in Japan. The evidence supporting the efficacy of these agents is mainly derived from small, uncontrolled trials. A notable recent advance is the discovery of IL36RN mutations and the central role of IL-36 receptor ligands in the pathogenesis of GPP, which has defined key therapeutic targets for the disease. Biologic agents that target the IL-36 pathway have demonstrated promising efficacy in patients with GPP, marking the beginning of a new era of targeted therapy for GPP.

Graphical abstract

Literature
1.
Gooderham MJ, Van Voorhees AS, Lebwohl MG. An update on generalized pustular psoriasis. Expert Rev Clin Immunol. 2019;15(9):907–19.PubMed
2.
Navarini AA, Burden AD, Capon F, Mrowietz U, Puig L, Koks S, et al. European consensus statement on phenotypes of pustular psoriasis. J Eur Acad Dermatol Venereol. 2017;31(11):1792–9.PubMed
3.
Benjegerdes KE, Hyde K, Kivelevitch D, Mansouri B. Pustular psoriasis: pathophysiology and current treatment perspectives. Psoriasis (Auckl). 2016;6:131–44.PubMedPubMedCentral
4.
Zelickson BD, Muller SA. Generalized pustular psoriasis. A review of 63 cases. Arch Dermatol. 1991;127(9):1339–45.PubMed
5.
Takedai T, Yamamoto I, Tokeshi J. Acute generalized pustular psoriasis presenting with erythroderma associated with shock and acute renal failure. Hawaii Med J. 2003;62(12):278–81.PubMed
6.
Choon SE, Lai NM, Mohammad NA, Nanu NM, Tey KE, Chew SF. Clinical profile, morbidity, and outcome of adult-onset generalized pustular psoriasis: analysis of 102 cases seen in a tertiary hospital in Johor, Malaysia. Int J Dermatol. 2014;53(6):676–84.PubMed
7.
Brunasso AM, Laimer M, Massone C. Paradoxical reactions to targeted biological treatments: a way to treat and trigger? Acta Derm Venereol. 2010;90(2):183–5.PubMed
8.
Baker H, Ryan TJ. Generalized pustular psoriasis. A clinical and epidemiological study of 104 cases. Br J Dermatol. 1968;80(12):771–93.PubMed
9.
Marrakchi S, Guigue P, Renshaw BR, Puel A, Pei XY, Fraitag S, et al. Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis. N Engl J Med. 2011;365(7):620–8.PubMed
10.
Onoufriadis A, Simpson MA, Pink AE, Di Meglio P, Smith CH, Pullabhatla V, 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):432–7.PubMedPubMedCentral
11.
Farooq M, Nakai H, Fujimoto A, Fujikawa H, Matsuyama A, Kariya N, et al. Mutation analysis of the IL36RN gene in 14 Japanese patients with generalized pustular psoriasis. Hum Mutat. 2013;34(1):176–83.PubMed
12.
Sugiura K, Takemoto A, Yamaguchi M, Takahashi H, Shoda Y, Mitsuma T, et al. The majority of generalized pustular psoriasis without psoriasis vulgaris is caused by deficiency of interleukin-36 receptor antagonist. J Invest Dermatol. 2013;133(11):2514–21.PubMed
13.
Wang TS, Chiu HY, Hong JB, Chan CC, Lin SJ, Tsai TF. Correlation of IL36RN mutation with different clinical features of pustular psoriasis in Chinese patients. Arch Dermatol Res. 2016;308(1):55–63.PubMed
14.
Tauber M, Bal E, Pei XY, Madrange M, Khelil A, Sahel H, et al. IL36RN mutations affect protein expression and function: a basis for genotype-phenotype correlation in pustular diseases. J Invest Dermatol. 2016;136(9):1811–9.PubMed
15.
Bachelez H. Pustular psoriasis: the dawn of a new era. Acta Derm Venereol. 2020;100(3):adv00034.PubMed
16.
Arakawa A, Vollmer S, Besgen P, Galinski A, Summer B, Kawakami Y, et al. Unopposed IL-36 activity promotes clonal CD4(+) T-cell responses with IL-17A production in generalized pustular psoriasis. J Invest Dermatol. 2018;138(6):1338–47.PubMed
17.
18.
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):118.PubMedPubMedCentral
19.
Bachelez H, Choon SE, Marrakchi S, Burden AD, Tsai TF, Morita A, et al. Inhibition of the interleukin-36 pathway for the treatment of generalized pustular psoriasis. N Engl J Med. 2019;380(10):981–3.PubMed
20.
Fujita H, Terui T, Hayama K, Akiyama M, Ikeda S, Mabuchi T, et al. Japanese guidelines for the management and treatment of generalized pustular psoriasis: the new pathogenesis and treatment of GPP. J Dermatol. 2018;45(11):1235–70.PubMed
21.
Imafuku S, Honma M, Okubo Y, Komine M, Ohtsuki M, Morita A, et al. Efficacy and safety of secukinumab in patients with generalized pustular psoriasis: a 52-week analysis from phase III open-label multicenter Japanese study. J Dermatol. 2016;43(9):1011–7.PubMed
22.
Saeki H, Nakagawa H, Nakajo K, Ishii T, Morisaki Y, Aoki T, et al. Efficacy and safety of ixekizumab treatment for Japanese patients with moderate to severe plaque psoriasis, erythrodermic psoriasis and generalized pustular psoriasis: results from a 52-week, open-label, phase 3 study (UNCOVER-J). J Dermatol. 2017;44(4):355–62.PubMed
23.
Sano S, Kubo H, Morishima H, Goto R, Zheng R, Nakagawa H. Guselkumab, a human interleukin-23 monoclonal antibody in Japanese patients with generalized pustular psoriasis and erythrodermic psoriasis: efficacy and safety analyses of a 52-week, phase 3, multicenter, open-label study. J Dermatol. 2018;45(5):529–39.PubMedPubMedCentral
24.
25.
Wilsmann-Theis D, Schnell LM, Ralser-Isselstein V, Bieber T, Schon MP, Huffmeier U, et al. Successful treatment with interleukin-17A antagonists of generalized pustular psoriasis in patients without IL36RN mutations. J Dermatol. 2018;45(7):850–4.PubMed
26.
Yamasaki K, Nakagawa H, Kubo Y, Ootaki K, Japanese Brodalumab Study G. Efficacy and safety of brodalumab in patients with generalized pustular psoriasis and psoriatic erythroderma: results from a 52-week, open-label study. Br J Dermatol. 2017;176(3):741–51.PubMed
27.
28.
Robinson A, Van Voorhees AS, Hsu S, Korman NJ, Lebwohl MG, Bebo BF Jr, et al. Treatment of pustular psoriasis: from the Medical Board of the National Psoriasis Foundation. J Am Acad Dermatol. 2012;67(2):279–88.PubMed
29.
Haustein UF, Rytter M. Methotrexate in psoriasis: 26 years’ experience with low-dose long-term treatment. J Eur Acad Dermatol Venereol. 2000;14(5):382–8.PubMed
30.
Zhou LL, Georgakopoulos JR, Ighani A, Yeung J. Systemic monotherapy treatments for generalized pustular psoriasis: a systematic review. J Cutan Med Surg. 2018;22(6):591–601.PubMed
31.
David M, Hodak E, Lowe NJ. Adverse effects of retinoids. Med Toxicol Adverse Drug Exp. 1988;3(4):273–88.PubMed
32.
Yan K, Xu W, Huang Y, Zhang Z, Huang Q, Xin KZ, et al. Methotrexate restores the function of peripheral blood regulatory T cells in psoriasis vulgaris via the CD73/AMPK/mTOR pathway. Br J Dermatol. 2018;179(4):896–905.PubMed
33.
Kawakami H, Maeda T, Abe N, Matsumoto Y, Mitsuhashi Y, Tsuboi R, et al. Efficacy of adalimumab and methotrexate combination therapy on generalized pustular psoriasis patients unresponsive to infliximab monotherapy due to anti-infliximab antibody development. J Dermatol. 2015;42(1):94–5.PubMed
34.
Kang S, Li XY, Voorhees JJ. Pharmacology and molecular action of retinoids and vitamin D in skin. J Investig Dermatol Symp Proc. 1996;1(1):15–21.PubMed
35.
Chen P, Li C, Xue R, Chen H, Tian X, Zeng K, et al. Efficacy and safety of acitretin monotherapy in children with pustular psoriasis: results from 15 cases and a literature review. J Dermatol Treat. 2018;29(4):353–63.
36.
Otley CC, Stasko T, Tope WD, Lebwohl M. Chemoprevention of nonmelanoma skin cancer with systemic retinoids: practical dosing and management of adverse effects. Dermatol Surg. 2006;32(4):562–8.PubMed
37.
Lee CS, Li K. A review of acitretin for the treatment of psoriasis. Expert Opin Drug Saf. 2009;8(6):769–79.PubMed
38.
Yang H, Tan Q, Chen GH, Chen JS, Fu Z, Ren FL, et al. Plasma retinol as a predictive biomarker of disease activity and response to acitretin monotherapy in children with generalized pustular psoriasis. J Eur Acad Dermatol Venereol. 2020;34(6):e270–2.PubMed
39.
Ji YZ, Geng L, Ma XH, Wu Y, Zhou HB, Li B, et al. Severe generalized pustular psoriasis treated with mycophenolate mofetil. J Dermatol. 2011;38(6):603–5.PubMed
40.
Das S, Das S. Hydroxyurea—an experience in the management of psoriasis. J Pak Assoc Dermatol. 2013;23(4):401–6.
41.
Jeon C, Nakamura M, Sekhon S, Yan D, Wu JJ, Liao W, et al. Generalized pustular psoriasis treated with apremilast in a patient with multiple medical comorbidities. JAAD Case Rep. 2017;3(6):495–7.PubMedPubMedCentral
42.
Kromer C, Loewe E, Schaarschmidt ML, Pinter A, Gerdes S, Herr R, et al. Drug survival in the treatment of generalized pustular psoriasis: a retrospective multicenter study. Dermatol Ther. 2021;34(2):e14814.PubMed
43.
Zachariae H, Kragballe K, Herlin T. Colchicine in generalized pustular psoriasis: clinical response and antibody-dependent cytotoxicity by monocytes and neutrophils. Arch Dermatol Res. 1982;274(3–4):327–33.PubMed
44.
45.
Huffmeier U, Watzold M, Mohr J, Schon MP, Mossner R. Successful therapy with anakinra in a patient with generalized pustular psoriasis carrying IL36RN mutations. Br J Dermatol. 2014;170(1):202–4.PubMed
46.
Husson B, Barbe C, Hegazy S, Seneschal J, Aubin F, Mahe E, et al. Efficacy and safety of TNF blockers and of ustekinumab in palmoplantar pustulosis and in acrodermatitis continua of Hallopeau. J Eur Acad Dermatol Venereol. 2020;34(10):2330–8.PubMed
47.
Johnston A, Xing X, Wolterink L, Barnes DH, Yin Z, Reingold L, et al. IL-1 and IL-36 are dominant cytokines in generalized pustular psoriasis. J Allergy Clin Immunol. 2017;140(1):109–20.PubMed
48.
Mansouri B, Richards L, Menter A. Treatment of two patients with generalized pustular psoriasis with the interleukin-1beta inhibitor gevokizumab. Br J Dermatol. 2015;173(1):239–41.PubMed
49.
Skendros P, Papagoras C, Lefaki I, Giatromanolaki A, Kotsianidis I, Speletas M, et al. Successful response in a case of severe pustular psoriasis after interleukin-1beta inhibition. Br J Dermatol. 2017;176(1):212–5.PubMed
50.
Storan ER, O’Gorman SM, Markham T. Generalized pustular psoriasis treated with ustekinumab. Clin Exp Dermatol. 2016;41(6):689–90.PubMed
51.
52.
Bachelez H CS, Marrakchi S, Burden AD, Tsai TF, Morita A, et al. Effisayil 1: a multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, and tolerability of spesolimab in patients with a generalized pustular psoriasis flare. The World Psoriasis and Psoriatic Arthritis Conference. Stockholm; 30 June–3 July 2021. p. 35129.
53.
Saeki H, Nakagawa H, Ishii T, Morisaki Y, Aoki T, Berclaz PY, et al. Efficacy and safety of open-label ixekizumab treatment in Japanese patients with moderate-to-severe plaque psoriasis, erythrodermic psoriasis and generalized pustular psoriasis. J Eur Acad Dermatol Venereol. 2015;29(6):1148–55.PubMed
54.
Tsai YC, Tsai TF. Anti-interleukin and interleukin therapies for psoriasis: current evidence and clinical usefulness. Ther Adv Musculoskelet Dis. 2017;9(11):277–94.PubMedPubMedCentral
55.
Viguier M, Aubin F, Delaporte E, Pages C, Paul C, Beylot-Barry M, et al. Efficacy and safety of tumor necrosis factor inhibitors in acute generalized pustular psoriasis. Arch Dermatol. 2012;148(12):1423–5.PubMed
56.
Wang WM, Jin HZ. Biologics in the treatment of pustular psoriasis. Expert Opin Drug Saf. 2020;19(8):969–80.PubMed
57.
Cuperus E, Koevoets R, van der Smagt JJ, Toonstra J, de Graaf M, Frenkel J, et al. Juvenile interleukin-36 receptor antagonist deficiency (DITRA) with c.80T>C (p.Leu27Pro) mutation successfully treated with etanercept and acitretin. JAAD Case Rep. 2018;4(2):192–5.PubMedPubMedCentral
58.
Esposito M, Mazzotta A, Saraceno R, Schipani C, Chimenti S. Influence and variation of the body mass index in patients treated with etanercept for plaque-type psoriasis. Int J Immunopathol Pharmacol. 2009;22(1):219–25.PubMed
59.
Fialova J, Vojackova N, Vanousova D, Hercogova J. Juvenile generalized pustular psoriasis treated with etanercept. Dermatol Ther. 2014;27(2):105–8.PubMed
60.
Fiorentino D, Ho V, Lebwohl MG, Leite L, Hopkins L, Galindo C, et al. Risk of malignancy with systemic psoriasis treatment in the Psoriasis Longitudinal Assessment Registry. J Am Acad Dermatol. 2017;77(5):845-54 e5.PubMed
61.
Kamarashev J, Lor P, Forster A, Heinzerling L, Burg G, Nestle FO. Generalised pustular psoriasis induced by cyclosporin a withdrawal responding to the tumour necrosis factor alpha inhibitor etanercept. Dermatology. 2002;205(2):213–6.PubMed
62.
Yost J, Gudjonsson JE. The role of TNF inhibitors in psoriasis therapy: new implications for associated comorbidities. F1000 Med Rep. 2009;1:30.PubMedPubMedCentral
63.
Routhouska SB, Sheth PB, Korman NJ. Long-term management of generalized pustular psoriasis with infliximab: case series. J Cutan Med Surg. 2008;12(4):184–8.PubMed
64.
Poulalhon N, Begon E, Lebbe C, Liote F, Lahfa M, Bengoufa D, et al. A follow-up study in 28 patients treated with infliximab for severe recalcitrant psoriasis: evidence for efficacy and high incidence of biological autoimmunity. Br J Dermatol. 2007;156(2):329–36.PubMed
65.
Adachi A, Komine M, Hirano T, Tsuda H, Karakawa M, Murata S, et al. Case of generalized pustular psoriasis exacerbated during pregnancy, successfully treated with infliximab. J Dermatol. 2016;43(12):1439–40.PubMed
66.
Trent JT, Kerdel FA. Successful treatment of Von Zumbusch pustular psoriasis with infliximab. J Cutan Med Surg. 2004;8(4):224–8.PubMed
67.
Morita A, Yamazaki F, Matsuyama T, Takahashi K, Arai S, Asahina A, et al. Adalimumab treatment in Japanese patients with generalized pustular psoriasis: results of an open-label phase 3 study. J Dermatol. 2018;45(12):1371–80.PubMedPubMedCentral
68.
Esposito M, Mazzotta A, Casciello C, Chimenti S. Etanercept at different dosages in the treatment of generalized pustular psoriasis: a case series. Dermatology. 2008;216(4):355–60.PubMed
69.
Okubo Y, Mabuchi T, Iwatsuki K, Elmaraghy H, Torisu-Itakura H, Morisaki Y, et al. Long-term efficacy and safety of ixekizumab in Japanese patients with erythrodermic or generalized pustular psoriasis: subgroup analyses of an open-label, phase 3 study (UNCOVER-J). J Eur Acad Dermatol Venereol. 2019;33(2):325–32.PubMed
70.
Arakawa A, Ruzicka T, Prinz JC. Therapeutic efficacy of interleukin 12/interleukin 23 blockade in generalized pustular psoriasis regardless of IL36RN mutation status. JAMA Dermatol. 2016;152(7):825–8.PubMed
71.
72.
Gudjonsson J RA, Barker J, Pink A, Reynolds N, Griffiths C, et al. Imsidolimab, an anti-IL-36 receptor monoclonal antibody, in the treatment of generalized pustular psoriasis: results from a phase 2 trial. 30th EADV Congress; 29 September–2 October 2021.
73.
Todorovic V, Su Z, Putman CB, Kakavas SJ, Salte KM, McDonald HA, et al. Small molecule IL-36 gamma antagonist as a novel therapeutic approach for plaque psoriasis. Sci Rep. 2019;9(1):9089.PubMedPubMedCentral
74.
75.
Strober B, Kotowsky N, Medeiros R, Mackey RH, Harrold LR, Valdecantos WC, et al. Unmet medical needs in the treatment and management of generalized pustular psoriasis flares: evidence from a survey of corrona registry dermatologists. Dermatol Ther (Heidelb). 2021;11(2):529–41.PubMedPubMedCentral
76.
Trivedi MK, Vaughn AR, Murase JE. Pustular psoriasis of pregnancy: current perspectives. Int J Womens Health. 2018;10:109–15.PubMedPubMedCentral
77.
Ho S, Clipstone N, Timmermann L, Northrop J, Graef I, Fiorentino D, et al. The mechanism of action of cyclosporin A and FK506. Clin Immunol Immunopathol. 1996;80(3 Pt 2):S40–5.PubMed
78.
Umezawa Y, Ozawa A, Kawasima T, Shimizu H, Terui T, Tagami H, et al. Therapeutic guidelines for the treatment of generalized pustular psoriasis (GPP) based on a proposed classification of disease severity. Arch Dermatol Res. 2003;295(Suppl 1):S43-54.PubMed
79.
Park H. The emergence of mycophenolate mofetilin dermatology: from its roots in the world of organ transplantation to its versatile role in the dermatology treatment room. J Clin Aesthet Dermatol. 2011;4(1):18–27.PubMedPubMedCentral
80.
Lee ES, Heller MM, Kamangar F, Park K, Liao W, Koo J. Hydroxyurea for the treatment of psoriasis including in HIV-infected individuals: a review. Psoriasis Forum. 2011;17(3):180–7.PubMedPubMedCentral
81.
Penso L, Dray-Spira R, Weill A, Pina Vegas L, Zureik M, Sbidian E. Association between biologics use and risk of serious infection in patients with psoriasis. JAMA Dermatol. 2021;157(9):1056–65.PubMed
82.
Lebwohl M, Strober B, Menter A, Gordon K, Weglowska J, Puig L, et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Engl J Med. 2015;373(14):1318–28.PubMed
Metadata
Title
Treatment Options and Goals for Patients with Generalized Pustular Psoriasis
Authors
James Krueger
Lluís Puig
Diamant Thaçi
Publication date
01-01-2022
Publisher
Springer International Publishing
Published in
American Journal of Clinical Dermatology / Issue Special Issue 1/2022
Print ISSN: 1175-0561
Electronic ISSN: 1179-1888
DOI
https://doi.org/10.1007/s40257-021-00658-9

Other articles of this Special Issue 1/2022

American Journal of Clinical Dermatology 1/2022 Go to the issue

Review Article

Clinical Disease Measures in Generalized Pustular Psoriasis

Original Research Article

Impact of Generalized Pustular Psoriasis from the Perspective of People Living with the Condition: Results of an Online Survey

Review Article

The Prevalence and Disease Characteristics of Generalized Pustular Psoriasis

Review Article

Diagnosis of Generalized Pustular Psoriasis

Announcement

American Journal of Clinical Dermatology

Review Article

Pathophysiology of Generalized Pustular Psoriasis