Pustular Psoriasis

Centenary theme section: PSORIASIS REVIEW ARTICLE DV Pustular Psoriasis: The Dawn of a New Era cta Hervé BACHELEZ Department of Dermatology, AP-HP Hôpital Saint-Louis, Université de Paris, Paris, and Laboratory of Genetics of Skin Diseases, UMR INSERM A U1163, Institut Imagine, Necker Hospital, Paris, France Pustular psoriasis is a clinically heterogeneous entity SIGNIFICANCE of different, orphan disease subtypes, among which the most clearly defined are generalized pustular pso- Pustular psoriasis defines a heterogeneous group of skin riasis, palmoplantar psoriasis, and acrodermatitis con- inflammatory diseases, which have in common the presen- tinua of Hallopeau. Although phenotypically and gene- ce of aseptic pustules. Genetically distinct from psoriasis tically distinct from psoriasis vulgaris, these subtypes vulgaris, they have been shown to be related to mutations enereologica may be associated with plaque psoriasis lesions, es- in any of 3 genes of the skin immune system, respectively V tablishing the rationale for their inclusion in the pso- called IL36RN, CARD14 and AP1S3. These recent advan- riasis spectrum. Unlike psoriasis, however, their ge- ces have initiated the design of biological drugs specifically netic background is thought to be mainly monogenic, targeting key actors of inflammation in pustular psoriasis, as shown by the recent identification of mutations in with interleukin-36 inhibitors as the most advanced ex- ermato- 3 different genes of the skin innate immune system; ample of therapeutic development. D IL36RN, CARD14 and AP1S3. These major advances in the understanding of the disease pathogenesis have cta led to the design and ongoing development of tailored re-defined disease subtypes classification and, more A therapeutic approaches, which are highly necessary importantly, advances in physiopathological scenarios, given the refractory nature of pustular psoriasis in re- which have already driven therapeutic innovations. sponse to most available antipsoriatic drugs. Pustular psoriasis consists of several clinical entities, of which the best defined are: i( ) localized pustular Key words: pustular psoriasis; pustulosis; generalized pustular psoriasis; palmoplantar pustulosis; interleukin-36. psoriasis dominated by palmoplantar pustular psoriasis DV (PPPP), also called palmoplantar pustulosis (PPP); (ii) Accepted Nov 28; 2019; Epub ahead of print Jan 23, 2020 acrodermatitis continua of Hallopeau (ACH), which cta Acta Derm Venereol 2020; 100: adv00034. predominantly involves acral areas of the hands and/ A or feet; and (iii) generalized pustular psoriasis (GPP), Corr: Hervé Bachelez, Service de Dermatologie, Hôpital Saint-Louis, 1, avenue Claude Vellefaux, FR-75475 Paris cedex 10, France. E-mail: her- a disseminated, severe and potentially life-threatening [email protected] form of psoriasis. The question of whether these pustular skin disorders belong to the psoriasis spectrum has been soriasis is a chronic inflammatory disease entity that debated for a long time. Their intersection and overlap Pincludes different clinical phenotypes, of which the with PV is reflected by their frequent coexistence in so-called psoriasis vulgaris (PV) or plaque psoriasis a given patient, and by some commonalities in their variant is by far the most prevalent, representing approxi- respective mechanistic models. In this sense, studies of mately 80% of cases, and resulting from the combination pustular psoriasis have also been insightful regarding of a multigenic, complex genetic background with envi- mechanisms of skin inflammation, both in physiology ronmental triggers (1, 2). Aside from this most frequent and for other skin-inflammatory diseases. clinical form of psoriasis, much rarer clinical phenotypes, all characterized by the presence of neutrophilic skin in- GENERALIZED PUSTULAR PSORIASIS flammation with macroscopically visible, non-infectious or aseptic pustules, have been termed pustular psoriasis Clinical characteristics and diagnostic procedures and, in some cases, psoriasis-related subphenotypes (2). GPP, the most severe of all the psoriatic disease variants, Long-neglected, these phenotypes have attracted a lot is an orphan skin and multisystemic inflammatory disease of interest over the last 10 years due to major advances characterized, in its typical forms, by intermittent flares in the understanding of their pathogenic mechanisms, or attacks with partial or complete remission in between involving a major deregulation of skin innate immune (Fig. 1). Estimated prevalences of GPP are 0.0002% and responses, reflected at the histological level by an in- 0.0007%, in France and Japan, respectively (3, 4). Each tense afflux of neutrophils and monocytes in the lesional flare consists of the acute onset of a rapidly disseminating dvances in dermatology and venereology dermis and epidermis (2). The current review integrates cutaneous eruption an extensive skin rash covered with A long-established clinical features with the more recently aseptic pustules at an early stage, combined at some point This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta doi: 10.2340/00015555-3388 Journal Compilation © 2020 Acta Dermato-Venereologica. Acta Derm Venereol 2020; 100: adv00034 88 H. Bachelez accessory biliary ducts, and was definitively ascertained by histopathological analysis of liver biopsies showing innate immune cells, mainly neutrophils, infiltrating the DV epithelium of biliary ducts and the portal and periportal spaces (6). This last entity, which shares features of other cta types of inflammatory cholangitis, was further termed A neutrophilic cholangitis, and seems to have a benign short- and medium-term evolutive profile, although additional follow-up studies are needed to investigate its long-term prognosis (8). More recently, cases of neutrophilic cholangitis have been reported in patients with localized pustular psoriasis, and in those with PV with or without psoriatic arthritis, raising the hypothesis that deregulation of the extracutaneous innate immune system is not exclusive to GPP, but may also be observed enereologica in more frequent psoriatic variants (12). V One very specific evolutive feature of GPP is the spontaneously self-remitting pattern of disease flares, Fig. 1. Skin lesions in patients with generalized pustular psoriasis. (A) A diffuse erythema is covered with confluent pustules, leading to at least in classical intermittent forms. Typically, this formation of pustular lake, with superficial scaling at a later stage, in a spontaneous remission of attacks happens in a matter ermato- patient free of IL36RN or CARD14 mutation. (B) Disseminated, separated of weeks following the onset of attacks, but there are pustules on an erythematous basis of the forearm of an adult patient with D identified deficiency of IL36 receptor antagonist. cases in which chronic skin lesions persist in between attacks of GPP (9). Whatever the genetic background, cta the intermittent, acutely flaring course of GPP allowed A with systemic symptoms, such as a variable degree of fever up to 40°C, and general malaise with fatigue. Other triggering factors to be identified, the best known being extracutaneous manifestations, such as polymyalgia and infections, stress, corticosteroid treatment withdrawal, polyarthralgia, are common, and arthritis may occur (5, and pregnancy (5, 6, 13). Cases of GPP with onset during 6). Several subtypes of GPP have been defined depending pregnancy, usually early during the third trimester, have both on disease course and clinical presentation: (i) the been also termed impetigo herpetiformis, but they are DV acute von Zumbusch type; (ii) GPP in pregnancy, pre- now acknowledged as part of the GPP entity. Their prog- viously named impetigo herpetiformis; (iii) the annular nosis may be severe both for the mother and the foetus, cta GPP clinical subphenotype; and (iv) GPP associated potentially leading to intrauterine growth restriction, A with PV. GPP is an unpredictable disease; the spectrum miscarriage, or foetal death (14, 15). Therefore, GPP in of severity of attacks varies widely between patients and pregnancy requires close monitoring of foetal viability. in any given patient, ranging from the absence of any GPP in pregnancy should be considered as a serious, systemic symptoms, which does not rule out diagnosis, potentially life-threatening situation for both mother to the presence of high fever or even life-threatening and foetus. complications requiring admission to the intensive care unit (6). Biological test abnormalities typically consist Physiopathology and prognosis of raised serum concentrations of inflammatory proteins, Infectious respiratory viral triggers have been identified mainly C-reactive protein (CRP), peripheral blood hyper- recently by multiplex PCR-based analysis of nasopha- leukocytosis with neutrophilia, and a high prevalence of ryngeal swabs in a small cohort of patients with different liver test abnormalities, sometimes delayed with respect subtypes of psoriasis, including GPP (16). Interestingly, to the onset of ongoing GPP flare (7, 8). Extracutaneous viral nucleic acids are potent agonists of the innate im- manifestations of GPP, such as osteoarthritis, uveitis, mune system, and can stimulate the release of inflam- acute respiratory distress syndrome, and cardiovascular matory cytokines operating in psoriasis pathogenesis, aseptic shock (the last related to the massive release of in- including interleukin-36 (IL-36) (16). The

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