American Journal of Clinical Dermatology (2022) 23 (Suppl 1):S51–S64 https://doi.org/10.1007/s40257-021-00658-9 REVIEW ARTICLE Treatment Options and Goals for Patients with Generalized Pustular Psoriasis James Krueger1 · Lluís Puig2 · Diamant Thaçi3 Accepted: 14 November 2021 / Published online: 21 January 2022 © The Author(s) 2022 Abstract Generalized pustular psoriasis (GPP) is a rare, severe neutrophilic skin disorder characterized by sudden widespread erup- tion 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. Digital Features for this article can be found at https://​doi.​org/​ Key Points 10.​6084/​m9.​figsh​are.​16823​503. There are no generalized pustular psoriasis (GPP)- specific therapies approved in the USA or Europe for the treatment of GPP and management of GPP flares. The evidence supporting the use of non-biologic and * Diamant Thaçi biologic therapies for the treatment of patients with GPP diamant.thaci@uksh.de is limited and mainly based on case studies and small, 1 open-label, single-arm studies. Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, USA Advances in our understanding of the pathogenesis of 2 Department of Dermatology, Hospital de la Santa Creu i GPP have led to the development of targeted therapies, Sant Pau, Universitat Autònoma de Barcelona, Barcelona, such as interleukin-36 receptor inhibitors, which have Spain shown promising efficacy and acceptable safety in early- 3 Institute and Comprehensive Center for Inflammation phase clinical trials. Medicine, University of Lübeck, Lübeck, Germany Vol.:(0123456789) S52 J. Krueger et al. Graphical abstract Treatment Options and Goals for Generalized Pustular Psoriasis S53 1 Introduction IL-36 receptor is being evaluated for the treatment of GPP flares [19]. Generalized pustular psoriasis (GPP) is a rare, severe skin Advances in our understanding of the genetics and patho- disease characterized by sudden widespread eruption of genesis of GPP have revealed new opportunities to develop macroscopically visible primary sterile pustules on non- GPP-specific targeted therapeutic strategies. In this review, acral skin and may or may not be associated with systemic we highlight the currently available treatments and the inflammation [1, 2]. Approximately 65% of patients diag- emerging treatment options for GPP flares and long-term nosed with GPP have a prior diagnosis of plaque psoriasis management of GPP, and provide recommendations for [3]. According to the European Rare and Severe Psoriasis treatment goals. Expert Network (ERASPEN), the clinical course of GPP can be relapsing, at least once, or persistent for more than 3 months [2]. GPP flares can be life-threatening if untreated 2 Current Treatment Options for Patients due to potential systemic complications, such as bacterial with GPP infections [4], prerenal insufficiency [5], and cardiovascular failure [1]. GPP flares can be triggered by the use or dis- There are currently no GPP-specific treatments approved in continuation of corticosteroids [3, 6]. In addition, paradoxi- the USA or Europe [1]. All treatments discussed herein have cal incidence of GPP flares has been reported with the use no prescribing label for GPP except in Japan, where several of methotrexate, ustekinumab, and tumor necrosis factor biologics are currently approved for treatment of the disease, (TNF)-α blockers [3, 7]. Upper respiratory tract infections, including the TNFα-blocking agents adalimumab, infliximab, pregnancy, and stress have also been identified as triggers and certolizumab pegol; the IL-17/IL-17R inhibitors secuki- for GPP flares [4, 6, 8]. numab, brodalumab, and ixekizumab; and the IL-23 inhibi- The pathogenic mechanisms of GPP flares are poorly tors risankizumab and guselkumab [20–26]. Brodalumab is understood. However, recent advances in our understand- also approved in Taiwan and Thailand [20, 26, 27]. ing of the biology and genetic mechanisms of autoinflam- Current treatment options for GPP can be classified into mation and autoimmunity have led to the characterization biological and non-biological systemic agents. Based on the of critical genetic mutations associated with the incidence Japanese guidelines for the management of GPP and the and pathogenesis of GPP (these are discussed in greater Medical Board of the National Psoriasis Foundation, the detail in Chapter 2 [https://​doi.​org/​10.​1007/​s40257-​021-​ most commonly used treatments for patients with GPP are 00655-y] of this supplement). Most notably, IL36RN muta- retinoids, cyclosporine, and methotrexate (Table 1) [1, 20, tions have been identified in cases of sporadic and familial 28–31]. However, the evidence that supports the use of cur- GPP from around the world [9–14]. These loss-of-function rent therapies for GPP is largely ill-defined and mainly based mutations in the interleukin (IL)-36 receptor antagonist on small, open-label, single-arm studies and case reports. result in the hyperactivation of IL-36 signaling due to the Care should be taken when basing treatment decisions on unopposed stimulation of the IL-36 receptor by its ligands, data from case reports to avoid the risk of overinterpreting IL-36α, IL36β, and IL-36γ. The increased production of the findings. It is also important to note the potential for pub- IL-36 induces the production of chemokines by keratino- lication bias, as positive treatment results are predominantly cytes, leading to neutrophil epidermal accumulation, which reported and may not truly reflect the number of cases of drives the pathogenesis of GPP, and the formation of the unsuccessful treatment. With no therapies approved outside characteristic spongiform pustules of Kogoj [3, 15, 16]. The of Japan, there is a lack of up-to-date and globally relevant proinflammatory functions of IL-36 cytokines can be further GPP-specific treatment guidelines and goals despite the dis- potentiated by a positive feedback loop with the IL-17/IL-23 tinct pathologic and clinical features of the disease. There- axis. In addition, expression of IL-36γ has been found to cor- fore, treatment of GPP flares and long-term management relate with disease activity in psoriasis and was suppressed of patients with GPP remain urgent unmet medical needs. by TNFα inhibition [17]. Accordingly, several potential therapeutic targets have been identified based on our under- 2.1 Non‑Biologic Systemic Therapies standing of these mechanisms. Inhibition of TNFα, IL-1, and IL-17A, which stimulate IL-36α, IL-36β, and IL-36γ 2.1.1 Methotrexate synthesis in keratinocytes, may potentially disrupt inflam- matory pathways in GPP (Fig. 1) [18]. Similarly, targeting Methotrexate is a widely used drug for autoinflammatory and the IL-23 pathway, which regulates the synthesis of IL-17, autoimmune conditions and is recommended for use in GPP could potentially impact the IL-36 axis in patients with GPP according to the 2018 Japanese guidelines and the 2012 Medi- [1]. Among these pharmacologic targets, inhibition of the cal Board of the National Psoriasis Foundation guidelines [20, S54 J. Krueger et al. IL-36 IL-36Ra The unopposed activation of IL-36R in the presence of an IL36RN mutation results in IL-36R hyperactivation of the IL-36 Neutrophils pathway in GPP NFκB MAPK Chemotaxis of neutrophils Secretion of cytokines: IL-36, IL-1, IL-8, Secretion of NFκB AP-1 CXCL1, CXCL2, TNF, IL-23 Gene CXCL8, CXCL20 expression Dendritic cells Secretion of IFN, IL-17A Keratinocyte T cells TNF and IL-17A synergize with IL-36 to further increase IL-36 production in keratinocytes Fig. 1  Hyperactivation of IL-36 plays a central role in the pathogenesis of GPP by driving neutrophilic involvement. GPP generalized pustular psoriasis, IFN interferon, IL interleukin, R receptor, TNF tumor necrosis factor. Adapted from Zhou et al. [18] 28, 29]. However, there are no clinical studies that demonstrate function, gastrointestinal symptoms, and increased risk of the efficacy of methotrexate for the treatment or prevention of infection [29]. GPP flares. Although the mechanism of action of methotrexate for the treatment of GPP is not well defined, recent findings in 2.1.2 Calcineurin Inhibitors psoriasis suggest that it restores the immunosuppressive func- tion of regulatory T cells through inhibition of the mammalian Cyclosporine is commonly used to treat patients with GPP target of rapamycin (mTOR) pathway [29, 32]. [28]. It acts as an immunosuppressive agent through the In patients with psoriasis, methotrexate has a slow onset inhibition of calcineurin phosphatase signaling [30]. In a of action. In a retrospective study that included 157 patients retrospective study of 102 patients with GPP, cyclosporine with several types of psoriasis, including 12 with GPP, meth- treatment resulted in a response in eight patients, but recur- otrexate resulted in skin clearance in 31% of the enrolled rence was common and the clinical disease measures were patients within 3–5 months [29]. In this study, the treatment not defined [6]. Cyclosporine is associated with adverse goal was to achieve adequate disease control rather than events such as hypertension, nephrotoxicity, and increased complete clearance. In a case study involving two patients risk of infection, limiting its long-term use for the mainte- with GPP, methotrexate was combined with anti-TNFα nance treatment of GPP [6]. inhibitors such as infliximab and adalimumab for long-term control of GPP [33]. In this report, the Psoriasis Area and 2.1.3 Retinoids Severity Index (PASI), a disease measure established for plaque psoriasis, was used to assess treatment success in Retinoids are non-immunosuppressive drugs used for the patients with GPP; however, it is worth noting that defined treatment of psoriasis [34]; however, the evidence that quantitative disease measures were not used. It is well supports the use of retinoids for the treatment of patients known that methotrexate has an unacceptable safety pro- with GPP is limited. In a retrospective study that included file in some patients, including liver toxicity that may lead 15 patients with pustular psoriasis, including 10 patients to treatment discontinuation or limited use. Other adverse with GPP, acitretin resulted in a good response (defined as events associated with methotrexate include abnormal liver 60–90% clearance of skin lesions) based on prevention of new pustule formation within 3 days of treatment, and most Table 1  Non-biologic systemic therapies for generalized pustular psoriasis Drug Mechanism of action Efficacy and onset of action General safety considerations Methotrexate The exact mechanism is unknown. It is proposed to sup- Efficacy in GPP has been demonstrated in several Contraindicated during pregnancy [29] press DNA synthesis and induce apoptosis of keratino- retrospective studies and case reports. Clearance of skin May cause hepatotoxicity and hematotoxicity [29] cytes [1] lesions could be achieved within 3–5 months [29] Cyclosporine Inhibits the production of inflammatory cytokines by Efficacy is comparable with that of other non-biologics, Pregnancy category C [1] T cells through inhibition of calcineurin [6, 77] based on case reports and retrospective studies [6, 30] Long-term use is associated with hypertension and renal dysfunction [6, 30] Retinoids Normalizes keratinization and epidermal cell prolifera- The efficacy of acitretin has been demonstrated in case Teratogenic; contraindicated in pregnancy [1] tion and may suppress the production of proinflamma- reports and retrospective studies. A retrospective study Long-term use may be associated with osteoarticular tory cytokines, including TNFα, IL-1, and IL-6 [78] demonstrated that acitretin disrupted the formation of symptoms and adversely affect bone growth in children new pustules within 3 days, and skin lesion remission [1, 31] was observed within 5–7 days [35] Treatment Options and Goals for Generalized Pustular Psoriasis In a retrospective study conducted in 1350 patients with GPP from a national Japanese registry, orally admin- istered etretinate exhibited higher efficacy rates than cyclosporine, methotrexate, or corticosteroids; however, the efficacy measures were not defined [20] MMF Immunosuppressive agent that acts through inhibition of MMF (2 g⁄day) improved the cutaneous status of patients The most commonly reported AEs associated with MMF de novo purine synthesis [79] within 1 week of treatment. The patients remained well, are GI-related, including nausea, vomiting, diarrhea, without requiring any treatment during follow-up for abdominal cramps, constipation, soft stools, and frequent 4 months [25, 39] stools [79] Hydroxyurea Antimetabolite that is considered an effective treatment The evidence that supports the use of hydroxyurea is All patients showed lesional pigmentation [40] for chronic psoriasis [80] limited. In a prospective, non-randomized study that included 80 patients with chronic plaque psoriasis and GPP with more than 20% body surface area involve- ment and psoriatic erythroderma, a good treatment response (up to 50% reduction in PASI score) was reported in 59/76 patients (77.6%) [40] Apremilast Inhibits phosphodiesterase-4 in immune cells, leading In a case report, improvement of plaque psoriasis and Mild-to-moderate AEs have been reported, including to decreased levels of proinflammatory cytokines and GPP was noted after 2–3 weeks of treatment. Complete diarrhea, nausea, headache, and nasopharyngitis [41] chemokines [41] clearance of plaque psoriasis and GPP was noted 6 weeks after starting apremilast, with sustained remis- sion of psoriatic plaques and pustular flares for 9 months at the time of this writing [41] AE adverse event, GI gastrointestinal, GPP generalized pustular psoriasis, IL interleukin, MMF mycophenolate mofetil, PASI Psoriasis Area and Severity Index, TNF tumor necrosis factor S55 S56 J. Krueger et al. skin lesions resolved within 4–6 weeks [35]. However, it is ultraviolet light [28]. In addition, granulocyte/monocyte important to note that relapse can be observed upon acitretin adsorption apheresis has been used in Japan; however, evi- withdrawal [35]. dence of its efficacy is mainly based on case reports [20]. All systemic retinoids are teratogenic [31] and may cause hepatotoxicity [36], mucocutaneous and skeletal toxicities, 2.2 Biologic Systemic Therapies and hyperlipidemia [37]. Due to the potential toxicity of acitretin and the possibility of disease recurrence follow- Increased understanding of the inflammatory and autoin- ing its withdrawal, several study groups have attempted to flammatory mechanisms involved in the pathogenesis of identify reliable response biomarkers to predict benefit and GPP has provided the rationale for use of targeted biologics recurrence following acitretin treatment. A recent study to treat GPP (Table 2) [7, 19, 21–23, 26, 33, 34, 44–61]. demonstrated that acitretin treatment resulted in a rise in plasma retinol and a reduction in PASI score, suggesting the 2.2.1 TNFα Blocking Agents potential use of plasma retinol as a biomarker of response to acitretin. Additional studies are needed to validate these TNFα is a proinflammatory cytokine that plays a central role findings [38]. in the regulation and amplification of inflammatory path- ways [62]. The TNFα inhibitors adalimumab, infliximab, 2.1.4 Other Non‑Biologic Agents and certolizumab pegol are currently approved in Japan for the treatment of GPP [20]. Several case reports have Several other non-biologic immunomodulatory agents demonstrated the efficacy of TNFα inhibitors in the man- have been used for the treatment of GPP. The evidence that agement of patients with GPP [63–65]. In a retrospective supports their benefit is mainly based on case reports and study that involved four patients experiencing GPP flares, non-randomized studies. Mycophenolate mofetil has dem- treatment with 5 mg/kg infliximab intravenous infusion onstrated efficacy in a case study in which it improved the at Weeks 0, 2, and 6, followed by a monthly regimen, was cutaneous status of a patient with GPP within 1 week of effective. During the first 24 h after the infliximab infusion, treatment. The patient remained in remission with no use of the patients’ condition stabilized, as evidenced by the resolu- additional therapies for up to 4 months [39]. Hydroxyurea tion of pustules and suppression of eruption of new pustules has also been used despite limited evidence of efficacy. In a within 24–48 h of infliximab infusion [66]. In an open-label prospective, non-randomized study that included 80 patients study of infliximab that included 10 patients with GPP flares, with chronic plaque psoriasis and GPP with > 20% body the time to pustular clearance ranged 1–8 days [55]. surface area involvement and psoriatic erythroderma, a good Adalimumab was found to be effective and well treatment response (up to 50% reduction in PASI score) tolerated for up to 52 weeks for the treatment of 10 Japa- was reported in 59/76 patients (77.6%) [40]. Apremilast, nese patients with GPP, including those who did not respond a phosphodiesterase-4 inhibitor approved for the treatment to prior treatment with infliximab [67]. In another study of moderate-to-severe plaque psoriasis, has also been used that included three patients with GPP treated with adali- in a patient with GPP and resulted in improvement in GPP mumab, time to remission was between 7 and 28 days [55]. symptoms within 2–3 weeks of treatment, and complete skin Adalimumab has also shown efficacy in combination with clearance by Week 6, with sustained remission of psoriatic acitretin and methotrexate in a case study of two patients plaques and pustules for up to 9 months [41]; however, the [33]. In addition, case reports showed that etanercept was evidence for its activity is based on a limited number of effective in patients with GPP [56], and a case series that patients [42]. The positive use of colchicine for the treat- included six patients with GPP showed that etanercept ment of patients with GPP has also been reported in two treatment normalized laboratory findings and markers of case studies [20, 43]; however, no clinical studies have been systemic inflammation and reduced PASI scores [68]. Para- conducted to investigate the use of colchicine. doxically, cases of induction of pustular psoriasis flares by In certain cases, topical treatments such as calcipot- TNFα inhibitors have been reported; however, the mecha- riene and tacrolimus have been combined with systemic nisms remain to be fully elucidated [7]. therapies to treat severe disease or used as monotherapy in patients with localized disease [28]. Topical treatments are 2.2.2 IL‑17A and IL‑17 Receptor Inhibitors not recommended for GPP flares; however, they have been proposed in Japanese guidelines for use as maintenance IL-17 is a key cytokine produced by T-helper 17 cells therapy after flares or as adjuvant therapy to manage pso- and plays an important role in the pathogenesis of inflam- riasis-like symptoms [20]. Alternative treatment modali- matory skin diseases. Moreover, IL-17A acts as a potent ties have also been used, including triamcinolone with wet inducer of neutrophil recruitment [1]. Brodalumab, an IL-17 body wraps and photochemotherapy using psoralen plus receptor antagonist approved in Taiwan and Thailand for Table 2  Biologic systemic therapies for generalized pustular psoriasis Drug Efficacy and onset of action General safety considerations TNFα-blocking agents [55] Infliximab Infliximab is reported to have a rapid onset of action (1–3 days) based on Increased risk of serious infections [81] assessment of pustule clearance; however, the efficacy measures were not Increased risk of lymphoma and other malignancies [60] defined [30] May induce GPP flares [7] Adalimumab In a national, multicenter, retrospective study conducted among patients with Immunogenicity may limit its efficacy [33] GPP (N = 11) at a French university hospital, patients were treated with the TNFα inhibitors etanercept, infliximab, and adalimumab. For those treated with adalimumab, remission was achieved by two of three patients, and time to remission was 7–28 days. The efficacy of TNFα-blocking agents was based on the number of pustules and recurrence of GPP flares [55] In a study that included 10 Japanese patients with GPP, adalimumab treatment was effective and well tolerated for up to 52 weeks [67] Etanercept Case studies demonstrated successful treatment of patients with GPP using etanercept [57, 59, 61, 68] IL-17 inhibitors [21, 22, 26] Treatment Options and Goals for Generalized Pustular Psoriasis Brodalumab In an open‐label, multicenter, long‐term, phase III study of 12 Japanese The most commonly reported AE was nasopharyngitis (33.3%). Five serious patients with GPP or erythrodermic psoriasis, brodalumab treatment was AEs occurred during the study; however, none were considered treatment- effective; by Week 12 of treatment, 83.3% of the patients were in related [26]. Arthralgia, headache, and fatigue were the most common AEs clinical remission or experienced improvement in GPP symptoms, and by associated with brodalumab [82] Week 52, 91.7% were in clinical remission or experienced improvement in GPP symptoms. Efficacy was defined using PASI, CGI, and Psoriasis Symptom Scale scores [26] Ixekizumab In a phase III study that included five patients with GPP, ixekizumab treat- Ixekizumab is generally safe and effective in patients with GPP. The most ment resulted in achievement of the study endpoints in 4/5 patients (80%). frequently reported TEAEs associated with ixekizumab include nasopharyn- The clinical measures used were PASI, itch numeric rating scale, and gitis, eczema, injection-site reaction, and seborrheic dermatitis [22, 53] Dermatology Life Quality Index [22, 53] Secukinumab In a phase III, multicenter, open-label trial, treatment with secukinumab Secukinumab is well tolerated with no unexpected safety signals. Nasopharyn- resulted in improved CGI score in 83.3% of patients. Moreover, the area of gitis, urticaria, diabetes mellitus, and arthralgia were the most frequent AEs erythema with pustules improved as early as Week 1 and resolved by reported [21] Week 16 in most patients. The improvements were maintained throughout 52 weeks based on PASI, CGI, and JDA severity index scores [21] IL-23 inhibitors [23] Guselkumab Results from a phase III, multicenter, open-label study involving 10 patients The TEAEs reported overall were nasopharyngitis (6/21, 28.6%), with GPP showed guselkumab treatment resulted in rapid onset of action, gastroenteritis, nausea, arthralgia, and alopecia (2/21, 9.5% each) [23] with response observed within 1 week of treatment. The efficacy was assessed using CGI, PASI, and JDA severity index scores The median per- centage improvement in PASI was 86.8% and the treatment success based on the JDA severity index was 100% [23] S57 Table 2  (continued) S58 Drug Efficacy and onset of action General safety considerations IL-23 and IL-12 inhibitors [50] Ustekinumab In a case series of four patients with GPP, ustekinumab treatment induced Ustekinumab is well tolerated without any known complications or severe sustained remission in all patients. This response was independent of infections [50] IL36RN mutations and was consolidated by combination with low doses of the retinoid acitretin [70] In a case study of one patient, ustekinumab induced rapid resolution of symptoms within 4 weeks of treatment and the patient remained in remission for 2.5 years on a maintenance dose of ustekinumab 45 mg every 12 weeks [50] IL-1 inhibitors [45, 48, 49] Canakinumab In a case report, 1-year treatment with canakinumab suppressed GPP symptoms and was well tolerated [49] Gevokizumab In a case study of two patients with GPP, gevokizumab resulted in a 79% No notable AEs were related to gevokizumab, although one patient developed and 65% reduction in GPPASI scores at Weeks 4 and 12, respectively, with an abscess in a hematoma secondary to an injury [48] some improvements in quality-of-life instruments [48] Anakinra In a 45-year-old patient who presented with a GPP flare following a GI tract infection that was resistant to adalimumab, treatment with anakinra sup- pressed the formation of new pustules by Day 9 and normalized the CRP level and leukocyte count [45] Future treatment options IL-36 receptor inhibitors [19, 51] Spesolimab (BI 655130) In the phase I, proof-of-concept trial, a single, intravenous dose of Drug-related AEs were observed in 57.1% of patients; all AEs were mild or 10 mg/kg spesolimab resulted in rapid (within 1 week) skin and pustule moderate [19] clearance that was sustained up to Week 20 [19]. In Effisayil™ 1, a 12-week, double-blind, randomized, placebo-controlled, phase II study in patients with a GPP flare, 53 patients were randomized 2:1 to receive a single 900 mg intravenous dose of spesolimab or placebo [52]. A GPPGA pustula- tion subscore of 0 at Week 1 was achieved by 19/35 patients (54.3%) receiv- ing spesolimab versus 1/18 (5.6%) of those receiving placebo, and a GPPGA score of 0/1 at Week 1 was achieved by 15/35 patients (42.9%) receiving spesolimab versus 2/18 (11.1%) of those receiving placebo [52]. At Week 4, 16/35 patients (45.7%) receiving spesolimab achieved 75% improvement in GPPASI versus 2/18 (11.1%) of those receiving placebo [52] Imsidolimab (ANB019) Currently being developed for the treatment of GPP [44] AE adverse event, CGI Clinical Global Impression, CRP C-reactive protein, JDA Japanese Dermatological Association, GI gastrointestinal, GPP generalized pustular psoriasis, GPPASI Gen- eralized Pustular Psoriasis Area and Severity Index, GPPGA Generalized Pustular Psoriasis Physician Global Assessment, IL interleukin, PASI Psoriasis Area and Severity Index, TEAEs treat- ment-emergent adverse events, TNF tumor necrosis factor J. Krueger et al. Treatment Options and Goals for Generalized Pustular Psoriasis S59 the treatment of GPP, has demonstrated efficacy in small IL36RN mutation status [70], but no specific disease meas- clinical trials [26]. In an open‐label, multicenter, long‐term, ures were mentioned. phase III study of 12 Japanese patients with GPP or erythrodermic psoriasis, 83.3% of the patients treated with 2.2.4 IL‑1β and IL‑1R Inhibitors brodalumab achieved clinical remission or improved clinical status by Week 12 of treatment. By Week 52, 91.7% were in Canakinumab, a monoclonal antibody that targets IL-1β, has clinical remission or had improved clinical status. Similar shown efficacy in a patient who experienced hypersensitivity trends were also observed in the PASI and Psoriasis Symp- to the IL-1R antagonist anakinra. Canakinumab treatment tom Scale scores [26]. resulted in relief of the patient’s symptoms based on com- Secukinumab, a monoclonal antibody that targets IL- plete skin clearance and prevention of future recurrence of 17A, has demonstrated efficacy in a phase III study of 12 systemic symptoms [49]. In addition, absolute eosinophil patients with GPP in Japan. Secukinumab monotherapy and count and liver tests were normalized [49]. Gevokizumab, co-therapy resulted in 9/12 patients (75%) achieving a Clini- another monoclonal antibody that blocks the activation of cal Global Impression (CGI) score of ‘very much improved’ IL-1β receptors, has shown encouraging results in an open- at Week 12, and 7/12 patients (58.3%) achieving this at label, expanded-access study in two patients with severe, Week 52 [21]. PASI 75 was achieved by 8/12 patients recalcitrant GPP. Two patients treated with gevokizumab had (72.7%) at approximately Weeks 3–4, which reached a respective 79% and 65% reduction in Generalized Pustular the maximum at approximately Week 16 (10/12 patients Psoriasis Area and Severity Index scores at Week 4 and 12, [83.3%]) and was sustained until Week 52 [21]. with some improvements in quality-of-life instruments [48]. Ixekizumab, an IL-17A antagonist, has demonstrated effi- Anakinra is an IL-1R antagonist that has the potential to be cacy in patients with GPP in three phase III, open-label, mul- an effective treatment for GPP. In a case report of a 45-year- ticenter studies, which included Japanese patients with GPP old patient who presented with a GPP flare following a gas- as a subset [22]. Of the five patients with GPP who were trointestinal tract infection that was resistant to adalimumab, included in the study, four achieved a PASI 75 response, treatment with anakinra suppressed the formation of new and two had completely clear skin by Week 12; the response pustules by Day 9 and normalized the C-reactive protein was maintained for the 52-week treatment period [22]. In the level and leukocyte count [45]. Although these reports dem- 3-year long-term follow-up study, all five patients with GPP onstrate encouraging results, large, prospective, randomized had a Global Improvement Score of resolved or improved clinical trials in patients with GPP are needed to confirm the from Week 12 onwards. In addition, all patients experienced broad efficacy and safety of IL-1-targeted therapies for the improvement in PASI scores [69]. The mean PASI score treatment of GPP flares. was 12.8 at baseline and 1.8 and 1.6 at Weeks 52 and 244, respectively [69]. 3 Future Treatment Options 2.2.3 IL‑23 and IL‑23/IL‑12 Inhibitors 3.1 IL‑36 Pathway Inhibitors Guselkumab, a monoclonal IL-23 inhibitor, was found to be effective in patients with GPP. In a phase III, multicenter, Understanding the central role of the IL-36 pathway in open-label study in Japan involving 10 patients with GPP, the pathogenesis of GPP has paved the way for the devel- treatment success (defined as a CGI score of ‘very much opment of novel targeted anti-IL-36 therapies for the improved’, ‘much improved’, or ‘minimally improved’) was treatment of patients with the disease. Spesolimab (BI observed with guselkumab within 1 week in five patients 655130), a selective, humanized antibody against the (50%) with GPP [23]. In this study, guselkumab 50 mg was IL-36 receptor that blocks its activation and suppresses administrated subcutaneously at Weeks 0 and 4, and every downstream proinflammatory signaling, has demonstrated 8 weeks thereafter until Week 52. At Week 52, treatment efficacy in a phase I, proof-of-concept trial. A single success was achieved by all eight patients who completed intravenous dose of spesolimab 10 mg/kg was associated the study [23]. with rapid (within 1 week) clearance of skin and pustules Risankizumab, which targets the p19 subunit of IL-23, is up to Week 20. In seven patients presenting with a GPP another monoclonal antibody that is approved in Japan for flare, spesolimab was associated with rapid and sustained the treatment of patients with GPP [56]. In addition, usteki- improvements in clinical symptoms. A Generalized Pus- numab, a monoclonal antibody targeted against IL-23 and tular Psoriasis Physician Global Assessment (GPPGA) IL-12, has been reported to be effective in a case series of score of 0 or 1 was achieved within 1 week of treatment four patients with treatment-refractory GPP regardless of by five patients (71.4%) and maintained up to Week 20. Rapid improvements in the signs and symptoms of GPP S60 J. Krueger et al. Fig. 2  Treatment goals in patients with GPP. GPP is a systemic disease with manifestations that affect several organs. Treatment goals should focus on improving skin-related symptoms and systemic inflammation. GPP generalized pustular psoriasis after treatment with spesolimab were achieved according GPP were recently reported [72]. Based on these data, a to patient-reported outcomes [19]. Spesolimab was effec- phase III trial, GEMINI-1, will be conducted, in which 45 tive regardless of IL36RN mutation status, which indicates patients with GPP flares will be enrolled to receive a single that the IL-36 pathway is critical to the pathogenesis of dose of 750 mg intravenous imsidolimab, 300 mg intra- GPP irrespective of a patient’s genetic background [19]. venous imsidolimab, or placebo. The primary endpoint of These findings were confirmed by the results of the this trial is the proportion of patients achieving clear or Effisayil™ 1 study, a 12-week, double-blind, randomized, almost clear skin as determined by a GPPGA score of 0 or placebo-controlled, phase II study in patients with a GPP 1 at Week 4 [51]. Patients will subsequently be enrolled flare. A total of 53 patients were randomized 2:1 to receive in the GEMINI-2 trial to receive monthly doses of 200 a single 900 mg intravenous dose of spesolimab or placebo mg subcutaneous imsidolimab or placebo based on their [52]. A GPPGA pustulation subscore of 0 at Week 1 was response to treatment in the GEMINI-1 trial [51]. Simi- achieved by 19/35 patients (54.3%) receiving spesolimab larly, A-552, a small molecule antagonist of IL-36γ, was versus 1/18 (5.6%) of those receiving placebo (one-sided recently identified using high-throughput screening and is p = 0.0004) [52]. These results were sustained through- being evaluated for the treatment of plaque psoriasis and out the 12-week study. Spesolimab had a tolerable safety potentially other inflammatory skin diseases [73]. profile, and most adverse events were mild to moderate and comparable to those in the placebo arm [52]. Spesoli- mab is currently being evaluated for the prevention of GPP 4 Establishing Treatment Goals in GPP flares in Effisayil™ 2, a phase IIb, dose-finding study [71]. Several other anti-IL-36 therapies are currently under Treatment goals in GPP are not well defined due to the rarity development. Imsidolimab (ANB019) is a monoclo- of the disease, its heterogeneous symptoms, and the lack of nal antibody targeted against the IL-36 receptor that is consistent treatment guidelines and therapeutic monitoring currently being developed for several skin indications, strategies. Clinically relevant treatment goals for GPP flares including GPP. Positive results of a single-arm, open- involve the cessation of pustulation and the resolution of ery- label, phase II trial of imsidolimab in eight patients with thema and edema. Several treatment goals can be proposed Treatment Options and Goals for Generalized Pustular Psoriasis S61 based on the recent advances in our understanding of disease 5 Conclusions pathogenesis and the development of novel, effective biolog- ics (Fig. 2). Proposed treatment goals can be divided into International treatment guidelines for patients with GPP immediate and long term. are lacking and most available treatments are used off-label based on efficacy in plaque psoriasis or limited evidence 4.1 Immediate Treatment Goals derived from case reports and small, uncontrolled, open- label, single-arm trials in GPP. Recent advances in our The main immediate therapeutic goals during a GPP flare understanding and treatment of GPP offer several opportu- are to improve skin symptoms and reduce the burden of sys- nities to improve patient care. Moreover, there is a lack of temic manifestations to prevent potential complications [56]. consensus regarding the definition of treatment success or Rapid control of skin symptoms, within a week of treatment, failure and the optimal time to switch patients to an alter- is a feasible treatment goal based on the results of spesoli- native treatment. With the emergence of new and effective mab clinical trials [19]. Short-term treatment goals should therapeutic interventions, patient care will continue to evolve also focus on the prevention of further complications such towards improving therapeutic outcomes and quality of life. as neutrophilic cholangitis, uveitis, acute respiratory dis- tress syndrome, cardiovascular aseptic shock, heart failure, Acknowledgements All authors meet the criteria for authorship as rec- prerenal kidney failure, and severe infections. ommended by the International Committee of Medical Journal Editors (ICMJE) and made the decision to submit the manuscript for publica- tion. The authors did not receive payment related to the development 4.2 Long‑Term Treatment Goals of the manuscript. Agreements between Boehringer Ingelheim and the authors included the confidentiality of the study data. Yasser Heakal, In the long-term management of GPP, treatment goals PhD, of OPEN Health Communications (London, UK) provided medi- cal writing, editorial and/or formatting support, which was contracted should focus on the prevention of new flares or disease and funded by Boehringer Ingelheim. Boehringer Ingelheim was given worsening and the treatment of GPP comorbidities such as the opportunity to review the manuscript for medical and scientific hypertension, diabetes mellitus, hyperlipidemia, ischemic accuracy as well as intellectual property considerations. heart disease, osteoarthritis, and cholangitis, with the ulti- mate goal of improving patients’ quality of life [15, 74]. Declarations Specific long-term treatment goals are not well defined in clinical trials; however, the results of a recent survey of Disclosure statement This article has been published as part of a jour- nal supplement wholly funded by Boehringer Ingelheim. Corrona Registry dermatologists indicated that in > 80% of patients, symptoms still persist in between flares, and Funding Medical writing support was funded by Boehringer many treatments are not effective at preventing flares [75]. ­Ingelheim. These findings highlight the need for rigorous real-world studies to further evaluate current and emerging GPP treat- Conflicts of interest James Krueger has received grants from and been ment options and define feasible long-term goals to improve an investigator for Boehringer Ingelheim; received personal fees from AbbVie, Baxter, Biogen Idec, Delenex Therapeutics, Kineta, Sanofi, patients’ quality of life. Serono, and XenoPort; and received grants from Amgen, Bristol My- ers Squibb, Dermira, Innovaderm Research, Janssen, Kadmon, Kyowa 4.3 Other Treatment Goals Kirin, Eli Lilly, Merck, Novartis, Parexel, and Pfizer. Lluís Puig has received grants/research support or participated in clinical trials (paid to institution) from AbbVie, Almirall, Amgen, Boehringer Ingelheim, During pregnancy, GPP flares should be treated promptly Celgene, Janssen, LEO Pharma, Lilly, Novartis, Pfizer, Regeneron, to prevent any further complications that may impact the Roche, Sanofi, and UCB; received honoraria or consultation fees from well-being of the mother and fetus [76]. In addition, treat- AbbVie, Almirall, Amgen, Baxalta, Biogen, Boehringer Ingelheim, ment goals of infantile and juvenile pustular psoriasis should Bristol Myers Squibb, Celgene, Fresenius-Kabi, Janssen, JS BIOCAD, LEO Pharma, Lilly, Mylan, Novartis, Pfizer, Regeneron, Roche, San- focus on preventing recurrences, which have been reported doz, Samsung-Bioepis, Sanofi, and UCB; and participated in compa- to occur annually [3]. Furthermore, treatment of geriatric ny-sponsored speaker’s bureau for Celgene, Janssen, Lilly, Novartis, patients with GPP may pose substantial challenges due to and Pfizer. Diamant Thaçi has served as a consultant, advisory board comorbidities and potential exposure to medications that member, and/or investigator for Pfizer, AbbVie, Almirall, Amgen, Beiersdorf, Bristol Myers Squibb, Boehringer Ingelheim, Dainippon could trigger flares. Sumitomo Pharma, Eli Lilly, Galapagos, GlaxoSmithKline, Janssen- The identification of patient-desired treatment goals is Cilag, LEO Pharma, Maruho, Medac, MorphoSys, Novartis, Regen- needed to improve patients’ quality of life and alleviate the eron, Samsung, Sandoz, Sanofi, Sun Pharma, and UCB. emotional burden caused by the psychological or physical Availability of data and material Not applicable. pain associated with a GPP diagnosis (these are discussed in greater detail in Chapter 7 [https://doi.org/10.1007/s40257- Code availability Not applicable. 021-00663-y] of this supplement). S62 J. Krueger et al. Author contributions The sponsor of the supplement and all authors Japanese patients with generalized pustular psoriasis. Hum Mutat. identified and discussed the concept for each chapter and the supple- 2013;34(1):176–83. ment as a whole; further development of each review article was at 12. Sugiura K, Takemoto A, Yamaguchi M, Takahashi H, Shoda Y, the direction of the authors, who provided guidance to OPEN Health Mitsuma T, et al. The majority of generalized pustular psoriasis Communications on the content of the article, critically revised the without psoriasis vulgaris is caused by deficiency of interleukin-36 work, and approved the content for publication. receptor antagonist. J Invest Dermatol. 2013;133(11):2514–21. 13. Wang TS, Chiu HY, Hong JB, Chan CC, Lin SJ, Tsai TF. Cor- Ethics approval Not applicable. relation of IL36RN mutation with different clinical features of pustular psoriasis in Chinese patients. Arch Dermatol Res. Consent to participate Not applicable. 2016;308(1):55–63. 14. Tauber M, Bal E, Pei XY, Madrange M, Khelil A, Sahel H, et al. Consent for publication Not applicable. IL36RN mutations affect protein expression and function: a basis for genotype-phenotype correlation in pustular diseases. J Invest Dermatol. 2016;136(9):1811–9. Open Access This article is licensed under a Creative Commons Attri- 15. Bachelez H. Pustular psoriasis: the dawn of a new era. Acta Derm bution-NonCommercial 4.0 International License, which permits any Venereol. 2020;100(3):adv00034. non-commercial use, sharing, adaptation, distribution and reproduction 16. Arakawa A, Vollmer S, Besgen P, Galinski A, Summer B, in any medium or format, as long as you give appropriate credit to the Kawakami Y, et al. Unopposed IL-36 activity promotes clonal original author(s) and the source, provide a link to the Creative Com- CD4(+) T-cell responses with IL-17A production in generalized mons licence, and indicate if changes were made. The images or other pustular psoriasis. J Invest Dermatol. 2018;138(6):1338–47. third party material in this article are included in the article's Creative 17. Buhl AL, Wenzel J. Interleukin-36 in infectious and inflammatory Commons licence, unless indicated otherwise in a credit line to the skin diseases. Front Immunol. 2019;10:1162. material. If material is not included in the article's Creative Commons 18. Zhou J, Luo Q, Cheng Y, Wen X, Liu J. An update on genetic licence and your intended use is not permitted by statutory regula- basis of generalized pustular psoriasis (review). Int J Mol Med. tion or exceeds the permitted use, you will need to obtain permission 2021;47(6):118. directly from the copyright holder. To view a copy of this licence, visit 19. Bachelez H, Choon SE, Marrakchi S, Burden AD, Tsai TF, http://​creat​iveco​mmons.​org/​licen​ses/​by-​nc/4.​0/. 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. 20. Fujita H, Terui T, Hayama K, Akiyama M, Ikeda S, Mabuchi T, et al. Japanese guidelines for the management and treatment of References generalized pustular psoriasis: the new pathogenesis and treatment of GPP. J Dermatol. 2018;45(11):1235–70. 1. Gooderham MJ, Van Voorhees AS, Lebwohl MG. An update 21. Imafuku S, Honma M, Okubo Y, Komine M, Ohtsuki M, Morita on generalized pustular psoriasis. Expert Rev Clin Immunol. A, et al. Efficacy and safety of secukinumab in patients with gener- 2019;15(9):907–19. alized pustular psoriasis: a 52-week analysis from phase III open- 2. Navarini AA, Burden AD, Capon F, Mrowietz U, Puig L, Koks label multicenter Japanese study. J Dermatol. 2016;43(9):1011–7. S, et al. European consensus statement on phenotypes of pustular 22. Saeki H, Nakagawa H, Nakajo K, Ishii T, Morisaki Y, Aoki T, psoriasis. J Eur Acad Dermatol Venereol. 2017;31(11):1792–9. et al. Efficacy and safety of ixekizumab treatment for Japanese 3. Benjegerdes KE, Hyde K, Kivelevitch D, Mansouri B. Pustular patients with moderate to severe plaque psoriasis, erythroder- psoriasis: pathophysiology and current treatment perspectives. mic psoriasis and generalized pustular psoriasis: results from a Psoriasis (Auckl). 2016;6:131–44. 52-week, open-label, phase 3 study (UNCOVER-J). J Dermatol. 4. Zelickson BD, Muller SA. Generalized pustular psoriasis. A 2017;44(4):355–62. review of 63 cases. Arch Dermatol. 1991;127(9):1339–45. 23. Sano S, Kubo H, Morishima H, Goto R, Zheng R, Nakagawa 5. Takedai T, Yamamoto I, Tokeshi J. Acute generalized pustular H. Guselkumab, a human interleukin-23 monoclonal antibody in psoriasis presenting with erythroderma associated with shock and Japanese patients with generalized pustular psoriasis and erythro- acute renal failure. Hawaii Med J. 2003;62(12):278–81. dermic psoriasis: efficacy and safety analyses of a 52-week, phase 6. Choon SE, Lai NM, Mohammad NA, Nanu NM, Tey KE, Chew 3, multicenter, open-label study. J Dermatol. 2018;45(5):529–39. SF. Clinical profile, morbidity, and outcome of adult-onset gen- 24. UCB. ­CIMZIA® (certolizumab pegol) now available for patients eralized pustular psoriasis: analysis of 102 cases seen in a tertiary in Japan living with multiple psoriatic diseases. Available at: hospital in Johor, Malaysia. Int J Dermatol. 2014;53(6):676–84. https://​www.​ucb.​com/​stori​es-​media/​Press-​Relea​ses/​artic​le/​CIM- 7. Brunasso AM, Laimer M, Massone C. Paradoxical reactions to ZIA-c​ ertol​ izuma​ b-p​ egol-n​ ow-A ​ vaila​ ble-f​ or-P ​ atien​ ts-i​ n-J​ apan-l​ iv- targeted biological treatments: a way to treat and trigger? Acta ing-​with-​Multi​ple-​Psori​atic-​Disea​ses. Accessed Aug 2021. Derm Venereol. 2010;90(2):183–5. 25. Wilsmann-Theis D, Schnell LM, Ralser-Isselstein V, Bieber T, 8. Baker H, Ryan TJ. Generalized pustular psoriasis. A clini- Schon MP, Huffmeier U, et al. Successful treatment with interleu- cal and epidemiological study of 104 cases. Br J Dermatol. kin-17A antagonists of generalized pustular psoriasis in patients 1968;80(12):771–93. without IL36RN mutations. J Dermatol. 2018;45(7):850–4. 9. Marrakchi S, Guigue P, Renshaw BR, Puel A, Pei XY, Fraitag S, 26. Yamasaki K, Nakagawa H, Kubo Y, Ootaki K, Japanese Broda- et al. Interleukin-36-receptor antagonist deficiency and general- lumab Study G. Efficacy and safety of brodalumab in patients ized pustular psoriasis. N Engl J Med. 2011;365(7):620–8. with generalized pustular psoriasis and psoriatic erythroderma: 10. Onoufriadis A, Simpson MA, Pink AE, Di Meglio P, Smith CH, results from a 52-week, open-label study. Br J Dermatol. Pullabhatla V, et al. Mutations in IL36RN/IL1F5 are associated 2017;176(3):741–51. with the severe episodic inflammatory skin disease known as gen- 27. Pharmaceuticals and Medical Devices Agency, Japan. Report on eralized pustular psoriasis. Am J Hum Genet. 2011;89(3):432–7. the deliberation of results. Tremfya subcutaneous injection 100 11. Farooq M, Nakai H, Fujimoto A, Fujikawa H, Matsuyama A, mg syringe (guselkumab). Available at: https://​www.​pmda.​go.​jp/​ Kariya N, et al. Mutation analysis of the IL36RN gene in 14 files/​00023​4741.​pdf. Accessed Aug 2021. Treatment Options and Goals for Generalized Pustular Psoriasis S63 28. Robinson A, Van Voorhees AS, Hsu S, Korman NJ, Lebwohl palmoplantar pustulosis and in acrodermatitis continua of Hal- MG, Bebo BF Jr, et al. Treatment of pustular psoriasis: from the lopeau. J Eur Acad Dermatol Venereol. 2020;34(10):2330–8. Medical Board of the National Psoriasis Foundation. J Am Acad 47. Johnston A, Xing X, Wolterink L, Barnes DH, Yin Z, Reingold Dermatol. 2012;67(2):279–88. L, et al. IL-1 and IL-36 are dominant cytokines in generalized 29. Haustein UF, Rytter M. Methotrexate in psoriasis: 26 years’ expe- pustular psoriasis. J Allergy Clin Immunol. 2017;140(1):109–20. rience with low-dose long-term treatment. J Eur Acad Dermatol 48. Mansouri B, Richards L, Menter A. Treatment of two patients Venereol. 2000;14(5):382–8. with generalized pustular psoriasis with the interleukin-1beta 30. Zhou LL, Georgakopoulos JR, Ighani A, Yeung J. Systemic mono- inhibitor gevokizumab. Br J Dermatol. 2015;173(1):239–41. therapy treatments for generalized pustular psoriasis: a systematic 49. Skendros P, Papagoras C, Lefaki I, Giatromanolaki A, Kotsianidis review. J Cutan Med Surg. 2018;22(6):591–601. I, Speletas M, et al. Successful response in a case of severe pus- 31. David M, Hodak E, Lowe NJ. Adverse effects of retinoids. Med tular psoriasis after interleukin-1beta inhibition. Br J Dermatol. Toxicol Adverse Drug Exp. 1988;3(4):273–88. 2017;176(1):212–5. 32. Yan K, Xu W, Huang Y, Zhang Z, Huang Q, Xin KZ, et al. Metho- 50. Storan ER, O’Gorman SM, Markham T. Generalized pustu- trexate restores the function of peripheral blood regulatory T cells lar psoriasis treated with ustekinumab. Clin Exp Dermatol. in psoriasis vulgaris via the CD73/AMPK/mTOR pathway. Br J 2016;41(6):689–90. Dermatol. 2018;179(4):896–905. 51. AnaptyBio. Imsidolimab. Available at: https://​www.​anapt​ysbio.​ 33. Kawakami H, Maeda T, Abe N, Matsumoto Y, Mitsuhashi Y, com/​pipel​ine/​imsid​olimab/. Accessed 11 Aug 2021. Tsuboi R, et al. Efficacy of adalimumab and methotrexate com- 52. Bachelez H CS, Marrakchi S, Burden AD, Tsai TF, Morita A, bination therapy on generalized pustular psoriasis patients unre- et al. Effisayil 1: a multicenter, randomized, double-blind, pla- sponsive to infliximab monotherapy due to anti-infliximab anti- cebo-controlled study to evaluate the efficacy, safety, and toler- body development. J Dermatol. 2015;42(1):94–5. ability of spesolimab in patients with a generalized pustular psori- 34. Kang S, Li XY, Voorhees JJ. Pharmacology and molecular action asis flare. The World Psoriasis and Psoriatic Arthritis Conference. of retinoids and vitamin D in skin. J Investig Dermatol Symp Proc. Stockholm; 30 June–3 July 2021. p. 35129. 1996;1(1):15–21. 53. Saeki H, Nakagawa H, Ishii T, Morisaki Y, Aoki T, Berclaz PY, 35. Chen P, Li C, Xue R, Chen H, Tian X, Zeng K, et al. Efficacy and et al. Efficacy and safety of open-label ixekizumab treatment in safety of acitretin monotherapy in children with pustular psoriasis: Japanese patients with moderate-to-severe plaque psoriasis, eryth- results from 15 cases and a literature review. J Dermatol Treat. rodermic psoriasis and generalized pustular psoriasis. J Eur Acad 2018;29(4):353–63. Dermatol Venereol. 2015;29(6):1148–55. 36. Otley CC, Stasko T, Tope WD, Lebwohl M. Chemoprevention 54. Tsai YC, Tsai TF. Anti-interleukin and interleukin therapies for of nonmelanoma skin cancer with systemic retinoids: practi- psoriasis: current evidence and clinical usefulness. Ther Adv cal dosing and management of adverse effects. Dermatol Surg. Musculoskelet Dis. 2017;9(11):277–94. 2006;32(4):562–8. 55. Viguier M, Aubin F, Delaporte E, Pages C, Paul C, Beylot-Barry 37. Lee CS, Li K. A review of acitretin for the treatment of psoriasis. M, et al. Efficacy and safety of tumor necrosis factor inhibi- Expert Opin Drug Saf. 2009;8(6):769–79. tors in acute generalized pustular psoriasis. Arch Dermatol. 38. Yang H, Tan Q, Chen GH, Chen JS, Fu Z, Ren FL, et al. Plasma 2012;148(12):1423–5. retinol as a predictive biomarker of disease activity and response 56. Wang WM, Jin HZ. Biologics in the treatment of pustular psoria- to acitretin monotherapy in children with generalized pustular sis. Expert Opin Drug Saf. 2020;19(8):969–80. psoriasis. J Eur Acad Dermatol Venereol. 2020;34(6):e270–2. 57. Cuperus E, Koevoets R, van der Smagt JJ, Toonstra J, de Graaf 39. Ji YZ, Geng L, Ma XH, Wu Y, Zhou HB, Li B, et al. Severe gen- M, Frenkel J, et al. Juvenile interleukin-36 receptor antagonist eralized pustular psoriasis treated with mycophenolate mofetil. J deficiency (DITRA) with c.80T>C (p.Leu27Pro) mutation suc- Dermatol. 2011;38(6):603–5. cessfully treated with etanercept and acitretin. JAAD Case Rep. 40. Das S, Das S. Hydroxyurea—an experience in the management 2018;4(2):192–5. of psoriasis. J Pak Assoc Dermatol. 2013;23(4):401–6. 58. Esposito M, Mazzotta A, Saraceno R, Schipani C, Chimenti S. 41. Jeon C, Nakamura M, Sekhon S, Yan D, Wu JJ, Liao W, et al. Influence and variation of the body mass index in patients treated Generalized pustular psoriasis treated with apremilast in a with etanercept for plaque-type psoriasis. Int J Immunopathol patient with multiple medical comorbidities. JAAD Case Rep. Pharmacol. 2009;22(1):219–25. 2017;3(6):495–7. 59. Fialova J, Vojackova N, Vanousova D, Hercogova J. Juvenile gen- 42. Kromer C, Loewe E, Schaarschmidt ML, Pinter A, Gerdes S, eralized pustular psoriasis treated with etanercept. Dermatol Ther. Herr R, et al. Drug survival in the treatment of generalized pus- 2014;27(2):105–8. tular psoriasis: a retrospective multicenter study. Dermatol Ther. 60. Fiorentino D, Ho V, Lebwohl MG, Leite L, Hopkins L, Galindo 2021;34(2):e14814. C, et al. Risk of malignancy with systemic psoriasis treatment 43. Zachariae H, Kragballe K, Herlin T. Colchicine in generalized in the Psoriasis Longitudinal Assessment Registry. J Am Acad pustular psoriasis: clinical response and antibody-dependent Dermatol. 2017;77(5):845-54 e5. cytotoxicity by monocytes and neutrophils. Arch Dermatol Res. 61. Kamarashev J, Lor P, Forster A, Heinzerling L, Burg G, Nestle 1982;274(3–4):327–33. FO. Generalised pustular psoriasis induced by cyclosporin a with- 44. ClinicalTrials.gov. A study to evaluate the efficacy and safety of drawal responding to the tumour necrosis factor alpha inhibitor ANB019 in subjects with generalized pustular psoriasis (GPP). etanercept. Dermatology. 2002;205(2):213–6. Available at: https://​clini​caltr​ials.​gov/​ct2/​show/​NCT03​619902. 62. Yost J, Gudjonsson JE. The role of TNF inhibitors in psoriasis Accessed 11 Aug 2021. therapy: new implications for associated comorbidities. F1000 45. Huffmeier U, Watzold M, Mohr J, Schon MP, Mossner R. Suc- Med Rep. 2009;1:30. cessful therapy with anakinra in a patient with generalized 63. Routhouska SB, Sheth PB, Korman NJ. Long-term management pustular psoriasis carrying IL36RN mutations. Br J Dermatol. of generalized pustular psoriasis with infliximab: case series. J 2014;170(1):202–4. Cutan Med Surg. 2008;12(4):184–8. 46. Husson B, Barbe C, Hegazy S, Seneschal J, Aubin F, Mahe E, 64. Poulalhon N, Begon E, Lebbe C, Liote F, Lahfa M, Bengoufa et al. Efficacy and safety of TNF blockers and of ustekinumab in D, et al. A follow-up study in 28 patients treated with inflixi- mab for severe recalcitrant psoriasis: evidence for efficacy and S64 J. Krueger et al. high incidence of biological autoimmunity. Br J Dermatol. as a novel therapeutic approach for plaque psoriasis. Sci Rep. 2007;156(2):329–36. 2019;9(1):9089. 65. Adachi A, Komine M, Hirano T, Tsuda H, Karakawa M, Murata 74. Miyachi H, Konishi T, Kumazawa R, Matsui H, Shimizu S, Fush- S, et al. Case of generalized pustular psoriasis exacerbated dur- imi K, et al. Treatments and outcomes of generalized pustular pso- ing pregnancy, successfully treated with infliximab. J Dermatol. riasis: a cohort of 1516 patients in a nationwide inpatient database 2016;43(12):1439–40. in Japan. J Am Acad Dermatol. 2021. https://​doi.​org/​10.​1016/j.​ 66. Trent JT, Kerdel FA. Successful treatment of Von Zum- jaad.​2021.​06.​008 (Epub 8 Jun 2021). busch pustular psoriasis with infliximab. J Cutan Med Surg. 75. Strober B, Kotowsky N, Medeiros R, Mackey RH, Harrold LR, 2004;8(4):224–8. Valdecantos WC, et al. Unmet medical needs in the treatment 67. Morita A, Yamazaki F, Matsuyama T, Takahashi K, Arai S, Asa- and management of generalized pustular psoriasis flares: evidence hina A, et al. Adalimumab treatment in Japanese patients with from a survey of corrona registry dermatologists. Dermatol Ther generalized pustular psoriasis: results of an open-label phase 3 (Heidelb). 2021;11(2):529–41. study. J Dermatol. 2018;45(12):1371–80. 76. Trivedi MK, Vaughn AR, Murase JE. Pustular psoriasis 68. Esposito M, Mazzotta A, Casciello C, Chimenti S. Etanercept at of pregnancy: current perspectives. Int J Womens Health. different dosages in the treatment of generalized pustular psoria- 2018;10:109–15. sis: a case series. Dermatology. 2008;216(4):355–60. 77. Ho S, Clipstone N, Timmermann L, Northrop J, Graef I, Fioren- 69. Okubo Y, Mabuchi T, Iwatsuki K, Elmaraghy H, Torisu-Itakura tino D, et al. The mechanism of action of cyclosporin A and H, Morisaki Y, et al. Long-term efficacy and safety of ixeki- FK506. Clin Immunol Immunopathol. 1996;80(3 Pt 2):S40–5. zumab in Japanese patients with erythrodermic or general- 78. Umezawa Y, Ozawa A, Kawasima T, Shimizu H, Terui T, Tagami ized pustular psoriasis: subgroup analyses of an open-label, H, et al. Therapeutic guidelines for the treatment of generalized phase 3 study (UNCOVER-J). J Eur Acad Dermatol Venereol. pustular psoriasis (GPP) based on a proposed classification of 2019;33(2):325–32. disease severity. Arch Dermatol Res. 2003;295(Suppl 1):S43-54. 70. Arakawa A, Ruzicka T, Prinz JC. Therapeutic efficacy of inter- 79. Park H. The emergence of mycophenolate mofetilin dermatology: leukin 12/interleukin 23 blockade in generalized pustular pso- from its roots in the world of organ transplantation to its versatile riasis regardless of IL36RN mutation status. JAMA Dermatol. role in the dermatology treatment room. J Clin Aesthet Dermatol. 2016;152(7):825–8. 2011;4(1):18–27. 71. ClinicalTrials.gov. A study to test whether BI 655130 (spesoli- 80. Lee ES, Heller MM, Kamangar F, Park K, Liao W, Koo J. Hydrox- mab) prevents flare-ups in patients with generalized pustular pso- yurea for the treatment of psoriasis including in HIV-infected indi- riasis. Available at: https://​clini​caltr ​ials.​gov/​ct2/​show/​NCT04​ viduals: a review. Psoriasis Forum. 2011;17(3):180–7. 399837. Accessed 11 Aug 2021. 81. Penso L, Dray-Spira R, Weill A, Pina Vegas L, Zureik M, Sbidian 72. Gudjonsson J RA, Barker J, Pink A, Reynolds N, Griffiths C, et al. E. Association between biologics use and risk of serious infection Imsidolimab, an anti-IL-36 receptor monoclonal antibody, in the in patients with psoriasis. JAMA Dermatol. 2021;157(9):1056–65. treatment of generalized pustular psoriasis: results from a phase 82. Lebwohl M, Strober B, Menter A, Gordon K, Weglowska J, Puig 2 trial. 30th EADV Congress; 29 September–2 October 2021. L, et al. Phase 3 studies comparing brodalumab with ustekinumab 73. Todorovic V, Su Z, Putman CB, Kakavas SJ, Salte KM, in psoriasis. N Engl J Med. 2015;373(14):1318–28. McDonald HA, et al. Small molecule IL-36 gamma antagonist