Digital Features for this article can be found at https://doi.org/10.6084/m9.figshare.16823503. |
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 biologic therapies for the treatment of patients with GPP is limited and mainly based on case studies and small, open-label, single-arm studies. |
Advances in our understanding of the pathogenesis of GPP have led to the development of targeted therapies, such as interleukin-36 receptor inhibitors, which have shown promising efficacy and acceptable safety in early-phase clinical trials. |
1 Introduction
2 Current Treatment Options for Patients with GPP
Drug | Mechanism of action | Efficacy and onset of action | General safety considerations |
---|---|---|---|
Methotrexate | The exact mechanism is unknown. It is proposed to suppress DNA synthesis and induce apoptosis of keratinocytes [1] | Efficacy in GPP has been demonstrated in several retrospective studies and case reports. Clearance of skin lesions could be achieved within 3–5 months [29] | Contraindicated during pregnancy [29] May cause hepatotoxicity and hematotoxicity [29] |
Cyclosporine | Pregnancy category C [1] | ||
Retinoids | Normalizes keratinization and epidermal cell proliferation and may suppress the production of proinflammatory cytokines, including TNFα, IL-1, and IL-6 [78] | The efficacy of acitretin has been demonstrated in case reports and retrospective studies. A retrospective study demonstrated that acitretin disrupted the formation of new pustules within 3 days, and skin lesion remission was observed within 5–7 days [35] In a retrospective study conducted in 1350 patients with GPP from a national Japanese registry, orally administered etretinate exhibited higher efficacy rates than cyclosporine, methotrexate, or corticosteroids; however, the efficacy measures were not defined [20] | Teratogenic; contraindicated in pregnancy [1] |
MMF | Immunosuppressive agent that acts through inhibition of de novo purine synthesis [79] | The most commonly reported AEs associated with MMF are GI-related, including nausea, vomiting, diarrhea, abdominal cramps, constipation, soft stools, and frequent stools [79] | |
Hydroxyurea | Antimetabolite that is considered an effective treatment for chronic psoriasis [80] | The evidence that supports the use of hydroxyurea is limited. In a prospective, non-randomized study that included 80 patients with chronic plaque psoriasis and GPP with more than 20% body surface area involvement and psoriatic erythroderma, a good treatment response (up to 50% reduction in PASI score) was reported in 59/76 patients (77.6%) [40] | All patients showed lesional pigmentation [40] |
Apremilast | Inhibits phosphodiesterase-4 in immune cells, leading to decreased levels of proinflammatory cytokines and chemokines [41] | In a case report, improvement of plaque psoriasis and GPP was noted after 2–3 weeks of treatment. Complete clearance of plaque psoriasis and GPP was noted 6 weeks after starting apremilast, with sustained remission of psoriatic plaques and pustular flares for 9 months at the time of this writing [41] | Mild-to-moderate AEs have been reported, including diarrhea, nausea, headache, and nasopharyngitis [41] |
2.1 Non-Biologic Systemic Therapies
2.1.1 Methotrexate
2.1.2 Calcineurin Inhibitors
2.1.3 Retinoids
2.1.4 Other Non-Biologic Agents
2.2 Biologic Systemic Therapies
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 assessment of pustule clearance; however, the efficacy measures were not defined [30] | Increased risk of serious infections [81] Increased risk of lymphoma and other malignancies [60] May induce GPP flares [7] Immunogenicity may limit its efficacy [33] |
Adalimumab | In a national, multicenter, retrospective study conducted among patients with 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 | ||
Brodalumab | In an open‐label, multicenter, long‐term, phase III study of 12 Japanese patients with GPP or erythrodermic psoriasis, brodalumab treatment was effective; by Week 12 of treatment, 83.3% of the patients were in clinical remission or experienced improvement in GPP symptoms, and by 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 | ||
Secukinumab | In a phase III, multicenter, open-label trial, treatment with secukinumab resulted in improved CGI score in 83.3% of patients. Moreover, the area of erythema with pustules improved as early as Week 1 and resolved by Week 16 in most patients. The improvements were maintained throughout 52 weeks based on PASI, CGI, and JDA severity index scores [21] | Secukinumab is well tolerated with no unexpected safety signals. Nasopharyngitis, urticaria, diabetes mellitus, and arthralgia were the most frequent AEs reported [21] |
IL-23 inhibitors [23] | ||
Guselkumab | Results from a phase III, multicenter, open-label study involving 10 patients with GPP showed guselkumab treatment resulted in rapid onset of action, with response observed within 1 week of treatment. The efficacy was assessed using CGI, PASI, and JDA severity index scores The median percentage improvement in PASI was 86.8% and the treatment success based on the JDA severity index was 100% [23] | The TEAEs reported overall were nasopharyngitis (6/21, 28.6%), gastroenteritis, nausea, arthralgia, and alopecia (2/21, 9.5% each) [23] |
IL-23 and IL-12 inhibitors [50] | ||
Ustekinumab | In a case series of four patients with GPP, ustekinumab treatment induced sustained remission in all patients. This response was independent of 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] | Ustekinumab is well tolerated without any known complications or severe infections [50] |
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% and 65% reduction in GPPASI scores at Weeks 4 and 12, respectively, with some improvements in quality-of-life instruments [48] | No notable AEs were related to gevokizumab, although one patient developed an abscess in a hematoma secondary to an injury [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 suppressed the formation of new pustules by Day 9 and normalized the CRP level and leukocyte count [45] | |
Future treatment options | ||
Spesolimab (BI 655130) | In the phase I, proof-of-concept trial, a single, intravenous dose of 10 mg/kg spesolimab resulted in rapid (within 1 week) skin and pustule 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 pustulation subscore of 0 at Week 1 was achieved by 19/35 patients (54.3%) receiving 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] | Drug-related AEs were observed in 57.1% of patients; all AEs were mild or moderate [19] |
Imsidolimab (ANB019) | Currently being developed for the treatment of GPP [44] |