Generalized pustular psoriasis – a model disease for specific targeted immunotherapy, systematic review

Abstract

Generalized pustular psoriasis (GPP) is a rare, multisystemic skin disease characterized by recurrent episodes of pustulation. GPP can be life-threatening and is often difficult to treat. In the era of precision medicine in dermatology, GPP stands exemplary for both challenges and chances-while new treatments offer great hope, there is urgent need for better definition and stratification of this severe and heterogeneous disease. Our objective was to systematically review the literature for evidence of efficacy of targeted immunotherapy and their mode of action in the context of clinical phenotype, classification and pathogenesis of adult GPP. Classifying GPP is challenging since clinical criteria for description and diagnosis are not consistent between expert centres. We therefore defined diagnostic feasibility of the reviewed cases by assessing four criteria: compatible clinical history, typical dermatological features and/or diagnostic histopathology, consistent clinical pictures and the DITRA status. Pathogenesis of GPP is mediated by pathways that partly overlap plaque type psoriasis, with a more pronounced activity of the innate immune system. Both IL-1 and IL-36 but also IL-17 play a major role in disease formation. We ascertained a total of 101 published cases according to our predefined criteria and identified TNF-α, IL-12/23, IL-17 and IL-1β as targets for immunotherapy for the treatment of GPP. Of those cases, 61% showed complete response and 27% partial response to targeted immunotherapy. Only 12% experienced weak or no response. These data indicate that specific immunotherapy can be used to effectively treat GPP, with most evidence existing for anti-IL-17 agents.

An update on generalized pustular psoriasis

“…As GPP often presents in individuals with existing/history of plaque psoriasis (reported in more than 65% of GPP cases [11,26]), GPP has been categorized as a variant of plaque psoriasis. However, recent clinical, histological, and genetic evidence suggests that GPP is a distinct clinical entity and requires a separate diagnosis [2,7,[27][28][29][30].…”

“…IL-17 is one of the main cytokines produced by T-helper (Th) 17/Th1 cells, which have a key role in the pathogenesis of plaque psoriasis. IL-17A is a potent inducer of tissue inflammation and neutrophil recruitment [48], and is assumed to have a role in GPP pathogenesis [30]. Although activation of Th17/Th1 signaling is common to both GPP and plaque psoriasis, expression levels of Th17-/Th1-related cytokines (such as IL-17A, IL-22, IL-23p19, IFNγ, and IL-18) were observed to be significantly increased in plaque psoriasis lesions compared with GPP lesions [29].…”

“…Oral retinoids are contraindicated in women who are pregnant or who may become pregnant [76]. A recent systematic review that identified 101 published adult cases of patients with GPP (predominantly acute GPP/ von Zumbusch type) who had received targeted immunotherapy reported that the most common treatment agents applied before or concomitantly with targeted immunotherapy were cyclosporine and retinoids (including acitretin, etretinate, isotretinoin, and bexarotene; however, it should be noted that only acitretin is currently approved by the FDA for systemic use in psoriasis) [30], followed by methotrexate and systemic corticosteroids. Case reports of GPP treatment using other agents, such as the antineutrophil agent dapsone (five cases treated) [54] and the small molecule (phosphodiesterase-4 inhibitor) apremilast (one case treated) [81], have also been published.…”

“…Not recommended for long-term use due to potential for hypertension & renal dysfunction [17,77] Anti-TNF-α Adalimumab [59]; etanercept [57]; infliximab [56] • Antagonist of TNF-α, a cytokine that is upregulated in GPP lesions [29] • Infliximab reported to have a rapid onset of action (pustule clearance 1-3 days) [30] • Increased risk of serious infections (including tuberculosis, bacterial sepsis, invasive fungal infections, & infection by invasive opportunistic pathogens) [56,57,59] • Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with these agents [56,57,59] Anti-IL-1/IL- Increased risk of infections [60,61] • Injection site reactions [60,61] • Decreased neutrophil count has been reported with anakinra [60] Anti-IL-17…”

A focus on rare and undiagnosed skin diseases

“…The current collection of papers rounds off a series of closely related rare diseases/genodermatosis articles that have recently been published in the journal (see, for example, Kárpáti et al, Zingkou et al, Saigusa et al, Taniguchi et al and Boehner et al) documenting that these rare and often undiagnosed, but no less clinically important skin diseases offer fascinating new insights into basic biological principles, for which these dermatoses can serve as natural human models. Uncovering these principles carries the highest likelihood that more effective clinical management strategies can be offered to affected patients in the future.…”