Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV the most clearly defined are generalized pustular pso pustular generalized are defined clearly most the orphanof among different, disease subtypes, which Pustular psoriasis isa clinically heterogeneous entity This isan open access article under the CC BY-NC license.www.medicaljournals.se/acta long-established clinical features with the more recently dermis and epidermis (2). The current review integrates tense afflux of neutrophils and in monocytes in an the by lesional level histological the at reflected responses, immune innate skin of deregulation major a involving mechanisms, pathogenic their of understanding the in advances major to due years 10 last the over interest of lot a attracted have phenotypes these Long-neglected, and, in some cases, psoriasis-related subphenotypes (2). or aseptic pustules, have been termed pustular psoriasis flammation with macroscopically visible, non-infectious all characterized by the presence of neutrophilic skin in clinical form of psoriasis, much rarer clinical phenotypes, ronmental triggers (1, 2). Aside from this most frequent P [email protected] her E-mail: France. 10, Vellefaux,FR-75475cedex Claude Parisavenue 1, Saint-Louis, Hôpital Dermatologie, de Service Bachelez, Hervé Corr: Acta DermVenereol 2020;100:adv00034. Accepted Nov 28;2019;EpubaheadofprintJan23,2020 psoriasis; palmoplantarpustulosis;interleukin-36. pustular generalized pustulosis; psoriasis; Key words: pustular sponse to most availableantipsoriaticdrugs. given the refractory nature of pustularpsoriasisinre arehighlynecessary which therapeutic approaches, led to the design andongoing development of tailored thethe understandingof diseasepathogenesis have IL36RN, genesof the3 different skininnateimmunesystem; in mutations of identification recent the by shown as netic background is thought to be mainly monogenic, however,riasis spectrum.Unlike theirge psoriasis, tablishing the rationale inthepso for theirinclusion may beassociated with plaquepsoriasislesions,es tically distinct from psoriasis vulgaris, thesesubtypes tinua of Hallopeau. Although phenotypically and gene and acrodermatitispalmoplantar psoriasis, con riasis, U1163, Institut Imagine, NeckerHospital,Paris,France Department of Dermatology, AP-HP Hôpital Saint-Louis, Université de Paris, Paris, and Laboratory of Genetics of Skin Diseases, UMR INSERM Hervé BACHELEZ Pustular Psoriasis:TheDawnofaNewEra of a multigenic, complex genetic background with envi mately 80% of cases, and resulting from the combination variant is by far the most prevalent, psoriasis representing approxi­ plaque or (PV) vulgaris psoriasis so-called Journal Compilation ©2020ActaDermato-Venereologica. includes different clinical phenotypes, of which the which of differentphenotypes, includes clinical soriasis is a chronic inflammatory disease entity that . These major advances in andAP1S3.ThesemajorCARD14 advances REVIEW ARTICLE ------aseptic pustules at an early stage, combined at some point cutaneous eruption an extensive skin rash covered with flare consists of the acute onset of a rapidly disseminating 0.0007%, in France and Japan, respectively (3, 4). Each ( or attacks with partial or complete remission in between characterized, in its typical forms, by intermittent flares is an orphan skin and multisystemic inflammatory disease GPP, the most severe of all the psoriatic disease variants, Clinical characteristicsanddiagnosticprocedures GENERALIZED PUSTULAR PSORIASIS and forotherskin-inflammatorydiseases. physiology in both inflammation, skin of mechanisms regarding insightful been also have psoriasis pustular of studies sense, this In models. mechanistic respective their in commonalities some by and patient, given a in coexistence frequent their by reflected is PV with overlap and intersection Their time. long a for debated skin disorders belong to the psoriasis spectrum has been form of psoriasis. The question of whether these pustular life-threatening potentially and severe disseminated, a (GPP), psoriasis pustular generalized (iii) and feet; or and/ hands the of areas acral involves predominantly which (ACH), Hallopeau of continua acrodermatitis (ii) (PPP); pustulosis palmoplantar called also (PPPP), psoriasis pustular palmoplantar by dominated psoriasis ( are: defined best the which of which havealreadydriventherapeuticinnovations. scenarios, physiopathological in importantly,advances more and, classification subtypes disease re-defined ih nelui-6 niios s h ms avne ex ample of therapeutic development. advanced most the as inhibitors interleukin-36 with psoriasis, pustular in inflammation of actors key targeting ces have initiated the design of biological drugs specifically called respectively system, immune skin the of genes 3 of any in mutations to related be haveto they shown vulgaris, been psoriasis from distinct Genetically pustules. aseptic of ce inflammatory diseases, which have in common the presen ofskin group a heterogeneous defines psoriasis Pustular SIGNIFICANCE Fig. 1). Estimated prevalences of GPP are 0.0002% and Pustular psoriasis consists of several clinical entities, IL36RN, Centenary theme section:PSORIASIS CARD14 Acta DermVenereol 2020;100: adv00034 and AP1S3 doi: 10.2340/00015555-3388 Tee eet advan recent These . i ) localized pustular localized ) - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV identified deficiencyofIL36receptorantagonist. pustules on an erythematous basis of the forearm of an adult patient with Theme issue:Psoriasis tures alternating with dilatations of the principal liver and biliary ducts, showing, in some patients, stric the of (MRI) imaging resonance magnetic from results inflammatory process. This hypothesis was reinforced by the by involvement liver/biliary aspecific of hypothesis mild to moderate cholestasis and/or cytolysis, raised the mainly attacks, GPP during abnormalities test liver of prevalence high reported 9–11).The (7, course disease flammatory cytokines), may occur at any stage during the aseptic shock (the last related to the massive release of in acute respiratory distress syndrome, and cardiovascular uveitis, osteoarthritis, as such GPP, of manifestations to the onset of ongoing GPP flare (7, 8). Extracutaneous liver test abnormalities, sometimes delayed with respect leukocytosis with neutrophilia, and a high prevalence of mainly C-reactive protein (CRP), peripheral blood hyper of raised serum concentrations of inflammatory proteins, consist typically abnormalities test Biological (6). unit complications requiring admission to the intensive care life-threatening even or fever high of presence the to diagnosis, out rule not does which symptoms, systemic any of absence the from ranging patient, given any in of severity of attacks varies widely between patients and with PV. GPP is an unpredictable disease; the spectrum associated GPP (iv) and subphenotype; clinical GPP annular the (iii) herpetiformis; impetigo named viously pregnancy,pre in GPP (ii) type; Zumbusch von acute the (i) presentation: clinical and course disease on both 6). Several subtypes of GPP have been defined depending polyarthralgia, are common, and arthritis may occur (5, extracutaneous manifestations, such as polymyalgia and fever up to 40°C, and general malaise with fatigue. of Other degree variable a as such symptoms, systemic with patient free of a in stage, later to a at scaling leading superficial with pustules, lake, pustular of confluent formation with covered is erythema diffuse A (A) Fig. 1. Skin lesions in patients with generalized pustular psoriasis. 88 H. Bachelez IL36RN or CARD14 mutation. (B) Disseminated, separated and/or - - - - appealing infectious safety profiles.safety infectious appealing of deciphering The with strategies therapeutic effective for need the sizing during GPP attacks with simultaneous infection, empha lenge of immune intervention with immunosuppressants 16). The role of these infectious triggers raises the chal 13, (9, system immune innate the of stimulation potent a with keeping in flare, GPP of onset and infection the between interval time short the is observation striking a and studies, several in raised been has triggers viral these (16). of (IL-36) role interleukin-36 The including pathogenesis, psoriasis in operating cytokines matory inflam of release the stimulate can and system, mune im innate the of agonists potent are acids nucleic viral subtypes of psoriasis, including GPP (16). Interestingly, ryngeal swabs in a small cohort of patients with different nasopha of analysis PCR-based multiplex by recently Infectious respiratory viral triggers have been identified Physiopathology andprognosis and foetus. mother both for situation life-threatening potentially serious, a as considered be should pregnancy in GPP viability.foetal of monitoring close requires pregnancy miscarriage, or foetal death (14, 15). Therefore, GPP in restriction, growth intrauterine to leading potentially nosis may be severe both for the mother and the foetus, now acknowledged as part of the GPP entity.are they Their but prog herpetiformis, impetigo termed also been pregnancy, usually early during the third trimester, have and pregnancy (5, 6, 13). Cases of GPP with onset during withdrawal, treatment corticosteroid stress, infections, triggering factors to be identified, the best known being allowed GPP of course flaring acutely intermittent, the background, genetic the Whatever (9). GPP of attacks between in persist lesions skin chronic which in cases are there but attacks, of onset the following weeks of matter a in happens attacks of remission spontaneous Typically,this forms. intermittent classical in least at flares, disease of pattern self-remitting spontaneously in morefrequentpsoriaticvariants(12). system is not exclusive to GPP, but may also be observed immune innate extracutaneous the of deregulation that with or without psoriatic arthritis, raising the hypothesis PV with those in and psoriasis, pustular localized with patients in reported been have cholangitis neutrophilic of cases recently, More (8). prognosis long-term its investigate to needed are studies follow-up additional although profile, evolutive medium-term and short- benign a have to seems and cholangitis, neutrophilic termed further was cholangitis, inflammatory of types spaces (6). This last entity, which shares features of other epithelium of biliary ducts and the portal and periportal innate immune cells, mainly neutrophils, infiltrating the showing biopsies liver of analysis histopathological by accessory biliary ducts, and was definitively ascertained One very specific evolutive feature of GPP is the is GPP of feature evolutive specific very One ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV with fresh evolutive pustules and erythemato-squamous lesions. (C) Typical lesions of ACH involving the toes, leading pustular psoriasis and to acrodermatitis continua of Hallopeau (ACH). (B) destruction Disseminated pustules of the soles leaveof dark-brown macular the lesions, coexisting nail apparatus. (A) Pustular lesions involving palmar areas of hands, with some degree of acropustular damage, reflecting the possible association between palmoplantar Fig. 2.Typicallesionsof palmoplantar pustular psoriasisin3differentpatients free of any mutation in autoimmune conditions, such as thyroiditis, although it is cholangitis (10). Occasionally PPPP may associate with neutrophilic with rarely, and, arthritis, disease, nail as such involvement, extracutaneous with associate may and cases, severe in life of quality patients’ impairs severely adulthood, PPPin of occurs onset usually The crusts, and at a later stage brown macular residual lesions. or scales yellow of form the in differentstages through aseptic pustular lesions following a chronic course, going as presents usually disease The 19). (18, smoking with link strong a with women, in predominates disease the Prevalence estimates of 0.01% have been reported, and (17). (Fig. 2 ) variant pustular localized common most the and variants, psoriasis pustular of common most the is (PPP), pustulosis PPPP,palmoplantar called also PALMOPLANTAR PUSTULAR PSORIASIS pustular psoriaticdiseasesareaddressedbelow. tion inGPP lesions(7). is not suitable, notably due to the absence of any indura where PV-specific Psoriasis Area Severity Index (PASI) disease a in tools, scoring reproducible specific, more for way the paving Japan, in launched been have flares GPP of severity the score to attempts symptoms-based and signs systemic and skin some Likewise, ledged. acknow is potential life-threatening its but available, crucial breakthroughwhichisaddressedbelow(13). a therapies, targeted of development the for rationale strong a established GPP, with patients of subset a in encoding a regulator of the IL-36 inflammatory pathway the of mutations mainly abnormalities, genetic causal of identification to due pathogenesis the Recent advances in the assessment of the severity of severity the of assessment the in advances Recent not are GPP of cohorts recent for rates Mortality gene IL36RN - - features and is usually easy. Characteristic histopatho easy.Characteristic usually is and features Diagnosis of pustular psoriasis relies mainly on clinical DIFFERENTIAL DIAGNOSES with ACH. and/or bone damage warrants early treatment of patients nail definitive of threat The (13). (DITRA) antagonist GPP flares in patients with deficiency of IL-36 receptor this rare, debilitating form has been reported PPPP,in between Like (22). 2C) (Fig. erosions bone underlying nail the of destruction sive involving extremities of the hands and feet, with progres lesions pustular by defined is subphenotype ACH The ACRODERMATITIS CONTINUA OF HALLOPEAU some patientswith ACH or, rarely, withGPP (13,16). subtypes, may associate with PV. It may also combine in PPPP is usually chronic and, of like other pattern pustular psoriatic evolutive the years, sometimes or months for last may that intervals disease-free with course tent established bybonescintigraphy(21). usually is diagnosis its and areas, manubrial and costal (1, 2). One major differentialGPPmajor of One diagnosis 2). (1, acute is composed of neutrophils, monocytes and T-lymphocytes infiltrate dermal marked with abscesses, neutrophilic logical findings include the formation of intraepidermal (16). This is characterized by painful swelling of sterno (synovitis, acne, pustulosis, hyperosteosis osteomyelitis) PPPP led to the definition of a syndrome called SAPHO axial spondyloarthritis feature observed in patients with higher than in the general population (20). One particular not known if the prevalence of clinical autoimmunity is While GPP typically follows a relapsing, intermit relapsing, a follows typically GPP While Pustular psoriasis:thedawnofanewera IL36RN, apparatus, with or without or with apparatus, CARD14 Theme issue:Psoriasis and

AP1S3

genes. 89 - - - -

Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Psoriasis to be more prevalent in PPPP and ACH (35). The major seem mutations hypomorphous AGEP,and while GPP preferentially associated with the most severe entities of leading to the absence of IL-36Ra protein expression are subtypes of pustular psoriasis (35). However, mutations cation of identical (29–32, 34). An interesting finding has been the identifi psoriasis pustular without PV with patients in detected causal no and PPPP, with much lower prevalences have been observed in patients mutations, ranging from approximately 5% to territories have reported various prevalences of geographical various from cohorts of studies scale rent far,GPPSo in (34). diffecells of TH17 activation and expansion the trigger to shown been also has pathway IL1 and IL23 (33). Dysregulated activation of the IL-36 veral inflammatory mediators including CXCL8, TNFα, by keratinocytes, macrophages and dendritic cells, of se tion factor NFκB (13). from subsequent uncontrolled activation of the transcrip and receptor, their with IL36γ and IL36β IL36α, nists from unrepressed interactions of the IL36 pathway ago resulting responses inflammatory increased to leading encoded protein, the IL36 receptor its antagonist (IL36Ra), of impairments functional and structural major to the age of disease onset (32). Mutations of patients with GPP without plaque psoriasis, and influence 26–32). These (13, worldwide territories geographical different from patients in GPP of cases familial or sporadic in found immune responses. Indeed, innate systemic and skin of intensity the of limitation regulator of the IL-36 pathway, which is involved in the mutations of the loss-of-function heterozygous, composite or mozygous has been robustly established by the identification of ho model, unlike most cases of PV. This monogenic model lian familial cases, raised the hypothesis of a monogenic GPP,especially disorders, Mende of existence the and The extreme severity of these inflammatory pustular skin MECHANISMS GENETICS ANDIMMUNOPATHOGENIC entities (25). lenges the current view of AGEP and GPP being separate chal GPP/DITRA, with patients in identified ones the in mutations of AGEP with patients in detection recent The 24). (23, others among drugs, anti-inflammatory non-steroidal as such classes, other also but amoxicillin, and pristinamycin drugs, notably by anti-infectious chemotherapy, such as by caused GPP,is from differentiatewhich to but sible the clinical signs and symptoms of which may be impos (AGEP), eruption pustular generalized exanthematous 90 H. Bachelez IL36RN mutations are more prevalent in IL36RN gene, which encodes a negative IL36RN mutations across the different This This results in the massive release , sometimes identical to identical sometimes IL36RN, IL36RN mutation has been has mutation IL36RN mutations have been IL36RN lead 70%, while IL36RN ------member of the Adaptor Protein 1 (AP1) family,(AP1) contri 1 the Protein of Adaptor member a protein, the of alterations functional and structural to pes of pustular psoriasis, mainly GPP and ACH, leading heterozygously mutated in patients with different subty subunit sigma 3 (AP1S3) gene has been also found to be pilaris (40–43). The Adaptor Related Protein Complex 1 rubra pityriasis with patients some in and PV of forms dominant autosomal in involved primarily be to shown been has activation, NFκB of regulator positive a 10, Bcl with interacts which of protein the keratinocytes in ting recruitment domain, member 14), a gene expressed suggesting that the IL23/IL17 pathway is not the major the not is pathway IL23/IL17 the that suggesting level, population the at placebo over superiority levant re clinically showed drug neither However, 50). (49, respectively IL17AIL23p19, of and inhibitors targeted conducted in PPPP with secukinumab and guselkumab, been have trials clinical 3 phase placebo-controlled recently,randomized, More (46–48). methotrexate and is weak or very weak evidence, respectively, for acitretin has the highest level of evidence for efficacy, while there PPPP,therapy.In cyclosporine systemic requires often psoriasis pustular area, surface body involved limited are still used in mild forms of pustular skin phototherapies disease with or combined, or agents single as used derivatives, D vitamin and/or steroids topical although scientific evidence regarding treatment efficacy. Indeed, frequency in many cases of GPP,flaring unpredictable explain the with low level disease of the of course cious capri the and psoriasis pustular of prevalence low The MEDICINE THERAPEUTICS: TOWARDS PRECISION approaches. therapeutic personalized to contribute greatly to likely is and psoriasis, pustular of map genetic current the genes, especially in GPP, will other undoubtedly complement of identification Further (32). far so identified genes 3 the of 2 in damaging be to reported mutations by characterized pattern a e.g. features, “digenic” have patients some that notable is it Likewise, 45). 44, (42, buting to deregulation of skin innate immune responses so far are deregulation oftheIL-36pathwayinPV lesions(39). shown have studies PV,several with patients in found of mutations causal although striking lesions of joints and bones (13, 37, 38). Finally, of presence the by (DIRA) antagonist receptor IL-1 of deficiency described previously the from differs which DITRA, called entity new a of definition the to led and without ambiguity the autoinflammatory nature of GPP, the breakthrough in the identification of causal mutations of gain-of-function mutations of The 2 other genes associated with pustular psoriasis pustular with associated genes other 2 The gene has been instrumental in establishing in instrumental been has gene IL36RN CARD14 and AP1S3. Likewise, heterozygous CARD14 (caspase activa have not been not have IL36RN - - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Pharmaceuticals andUCB. Sun Pfizer, Novartis, Mylan, Pharma, Leo Janssen, Eli-Lilly, Celgene, Boehringer-Ingelheim, Biocad, Amgen, Almirall, vie, HB had paid activities as advisor, speaker or consultant for Abb ACKNOWLEDGEMENTS description ofGPP byvonZumbusch (58). strategies, approximately 100 years after the pioneering therapeutic specific of development the as well as ties, enabling the better nosological classification of subenti between medical experts and scientists is encouraging in collaboration increasing the However, heterogeneity. inflammatory skin diseases, with both clinical and genetic Pustular psoriasis is a very challenging spectrum of auto CONCLUSION targeted strategy. new this of safety and efficacy the of picture accurate more a provide will studies 3 and 2 phase Ongoing only 3 of whom were carrying patients, 7 in results encouraging very showed GPP, single intravenous dose, proof-of-concept study in acute receptor monoclonal antibody, which, administered as a most advanced development investigates an anti-IL-36 IL-36 pathway in GPP and PPPP is not surprising. The the of inhibitors specific of development emerging the toinflammatory syndromesoftheskin(36). Therefore, of pathogenic pathways across different monogenic au in patients with DIRA, emphasizing the fine specificity fronted with the outstanding efficacy of IL-1 inhibitors con be should cases These 56). (55, responses partial and transient often most reporting DITRA, without or GPPwith of series case a in only reported been has antagonist, receptor IL-1 the of form recombinant the anakinra, of efficacy the Furthermore, 54). (53, effect trolled studies to assess the magnitude of their efficacy GPP in Japan, these interventions lack randomized con logics, such as IL17 inhibitors, have been approved for promoted for severe acute flares, and although some bio steroids, cyclosporine, acitretin and apheresis have been considered with caution. Therefore, although high-dose beshould trials, prospective open-labelled or spective, retro of setting the in interventions drug biological or flare. Thus positive responses reported with conventional taneously self-remitting evolutive pattern of acute GPP the previously exposed challenges, but also to the spon cases, includingwith ACH (51,52). isolated in responses encouraging on based antagonist, receptor IL-1 the of form recombinant the anakinra, of vanced programme investigating the efficacy and safety ad family,most IL-1 the the of cytokines of inhibitors clinical trials are currently being conducted in PPPP with pathogenic axis in pustular disease (49, 50). Randomized There is even less available evidence in GPP,in evidence available less even is toThere due IL36RN mutations (57). ------22. 21. 10. 20. 15. 19. 17. 14. 23. 18. 16. 13. 12. 11. REFERENCES 7. 6. 3. 9. 5. 2. 8. 4. 1. Puig L, Barco D, Vilarrasa E, Alomar A. Treatment of acro Treatmentof A. 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