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Generalized Pustular Psoriasis (GPP)

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Experimental Therapies

Generalized pustular psoriasis (GPP) is a rare and sometimes fatal skin disorder characterized by widespread pustular eruptions over erythematous plaques, usually in association with fever and malaise. GPP can lead to serious complications, including sepsis, renal disease, and acute respiratory distress syndrome. This acute stage can lead to fatality without complete and effective treatment.1

Retinoids, cyclosporine, and methotrexate are various conventional therapies that have proven effective in patients with GPP; however, these medications have a risk of toxicity. The effectiveness and safety of biologics for this disease have been investigated in numerous clinical trials.1 The US Food and Drug Administration (FDA) approved one biologic, Spevigo® (spesolimab), as the first treatment specifically for GPP in adults in September 2022. It is a monoclonal antibody therapy that targets the interleukin (IL)-36 pathway. Many other targeted therapies are currently under experimental study.2

Other Anti-IL-36 Pathway Therapies

Imsidolimab (ANB019), an antibody that blocks the ability of IL-36 receptor (IL-36R) to function, is being researched as a potential first-in-class treatment for patients with GPP. Imsidolimab was granted Orphan Drug designation by the FDA in July 2020 for its use in patients with GPP.3 A phase 3 clinical trial is currently assessing the safety and efficacy of imsidolimab over 4- and 24-week periods.2,4

Small compounds that block IL-36γ are currently being created, and they might be used to treat GPP. Letairis® (ambrisentan), an endothelin receptor A antagonist, has been found to be an effective inhibitor of IL-36γ in humans. It works by causing IL-36γ to undergo a number of inhibitory chemical and structural changes that reduce IL-36γ’s capacity to bind to receptors.2 

IL-1 receptor accessory protein (IL-1RAcP) antibodies are also being studied as an experimental treatment option for GPP. Agonist-induced binding of IL-36R results in dimerization with IL-1RAcP and activation of the downstream Myd88 pathway. The Myd88 pathway can then activate a number of transcription factors involved in inflammation, including NF-κB, AP-1, and STAT3. Overactivation of the IL-36 pathway and the subsequent inflammation cascade could be avoided by inhibiting IL-1RAcP’s capacity to dimerize with IL-36R.2 

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TNF-α Inhibitors

Humira® (adalimumab), Remicade® (infliximab), and Cimzia® (certolizumab) are tumor necrosis factor (TNF)-α inhibitors that are currently approved for the treatment of GPP in Japan.2 In a case study on a woman with GPP and psoriatic arthritis (PA) in Japan, the patient’s pustular lesions disappeared within 48 hours of receiving a single 3 mg/kg Remicade injection. A second injection of 3 mg/kg had a major effect on the patient’s ability to move her joints. The patient continued to receive a 3 mg/kg Remicade injection every 8 weeks over a 12-month period, and there was no incidence of GPP relapse or PA symptoms.2,5

IL-17 Inhibitors

IL-17A and IL-17 receptor A (IL-17RA) inhibitors include the biologics, Cosentyx® (secukinumab), Taltz® (ixekizumab), and Siliq® (brodalumab). These 3 medications are approved for use in patients with GPP in Japan, and Siliq is also approved for GPP in Thailand and Taiwan.2 

A clinical study assessed the efficacy of Siliq and concluded that 83.3% of 12 patients with GPP showed significant remission of symptoms after 12 weeks of treatment. After 1 year, 91.6% showed remission or improvement in GPP symptoms.6 

In a phase 3 trial on Taltz, 5 individuals with GPP were evaluated, of whom 40% had fully clear skin and 80% had a Psoriasis Area and Severity Index (PASI) score of at least 75 after 12 weeks. The PASI scores of all patients who received Taltz treatment showed improvements.2,7 

Twelve patients with GPP participated in a phase 3 study on Cosentyx. Of these, 72.7% had a PASI score of at least 75 after 3 to 4 weeks, while 83.3% had a PASI score of at least 75 after 16 weeks, showing good efficacy.2, 8

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IL-23 Inhibitors

IL-23 controls the synthesis of IL-17, which in turn triggers the synthesis of proinflammatory IL-36R agonists, further leading to overactivation of the IL-36 pathway. IL-23 inhibitors include Tremfya® (guselkumab) and Skyrizi®(risankizumab), which are currently approved for use in patients with GPP in Japan.2

The safety and efficacy of Tremfya were assessed in a phase 3, single-arm, open-label study including patients with GPP from 23 sites across Japan. The Clinical Global Impression (CGI) scores of “very much improved” (22.2%), “much improved” (22.2%), and “minimally improved” (33.3%) at week 16 indicated that 77.8% of patients with GPP experienced treatment success.9,10

In a phase 3 trial on Skyrizi, 88% of 225 Japanese participants who received a subcutaneous dose of 150 mg achieved a Static Physician’s Global Assessment (sPGA) score of 0 or 1, and severe infections were not associated with Skyrizi use.2

Phototherapy

The use of phototherapy during flare-ups (acute phase) of GPP is not advised based on the available research. However, there have been studies on the effectiveness of PUVA (psoralen + ultraviolet A) phototherapy during the maintenance phase following the management of the acute phase.11 

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References

  1. Emerging treatment options for pustular psoriasis. myCME. May 31, 2022. Accessed May 31, 2023. 
  2. 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
  3. Imsidolimab. AnaptysBio. Accessed May 31, 2023. 
  4. A study to evaluate the efficacy and safety of imsidolimab (ANB019) in adults with generalized pustular psoriasis (GPP). ClinicalTrials.gov. August 8, 2018. Updated March 29, 2022. Accessed May 31, 2023. 
  5. Kim HS, You HS, Cho HH, et al. Two cases of generalized pustular psoriasis: successful treatment with infliximab. Ann Dermatol. 2014;26(6):787-788. doi:10.5021/ad.2014.26.6.787
  6. Yamasaki K, Nakagawa H, Kubo Y, Ootaki K; Japanese Brodalumab Study Group. 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):741-751. doi:10.1111/bjd.14702
  7. Saeki H, Nakagawa H, Nakajo K, et al; Japanese Ixekizumab Study Group. 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):355-362. doi:10.1111/1346-8138.13622
  8. Imafuku S, Honma M, Okubo Y, 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):1011-1017. doi:10.1111/1346-8138.13306
  9. Tremfya – treatment of generalized pustular psoriasis. Janssen Science. Updated January 31, 2023. Accessed May 31, 2023.
  10. 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):529-539. doi:10.1111/1346-8138.14294
  11. Romiti R, Hirayama ALDS, Arnone M, Magalhães RF. Generalized pustular psoriasis (von Zumbusch). An Bras Dermatol. 2022;97(1):63-74. doi:10.1016/j.abd.2021.05.011

Reviewed by Kyle Habet, MD, on 5/31/2023.

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