Pustular psoriasis L40.1

by Zumbusch, 1910

Sterile pustulosis on non-acral skin with or without psoriasis vulgaris, with or without systemic inflammation, which can occur peristently (> 3 months) or recurrently (> 1 episode) with an individually varying course (European Consensus Statement on phenotypes of pustular psoriasis).

Previously considered a rare, acquired, occasionally familial, severe, potentially life-threatening, maximum pustular variant of psoriasis characterized by a severe disturbance of general condition. In the meantime, it is seen as a clinical entity to be distinguished from psoriasis, although no uniform criteria have yet been established. It is clinically characterized by numerous, disseminated, sterile, white pustules on flat erythema, often also confluent into pus lakes.

The disease occurs in 3 subtypes:

1. Sporadic PPG without symptoms of psoriasis vulgaris
2. Sporadic PPG with symptoms of psoriasis vulgaris (30% of cases)
3. Family PPG

Rare; prevalence: 0.1-0.9/100,000 inhabitants. Highly concentrated in Japan (incidence: about 0.7/100,000 inhabitants).

Pustular psoriasis is a type of reaction that differs from psoriasis vulgaris and can occur with or without the precursor stage of psoriasis vulgaris. However, there are patients in whom both manifestations alternate. Also, psoriasis vulgaris may suddenly acquire a pustular component (psoriasis cum pustulatione).

Infections: Trigger factors of generalized pustular psoriasis are bacterial and also viral(Epstein-Barr virus infections) infections, medications (antihypertensives, terbinafine, chloroquine), pregnancy (see impetigo herpetiformis), or even sudden withdrawal of systemic glucocorticoid therapy. Rarely, a paradoxical reaction occurs during therapy with biologics (P Weisenseel 2016).

Genetics: In the rare cases of familial PPG, mutations of theinterleukin-36 receptor gene(IL-36RN), which encodes interleukin-36a, are causative. IL-36a is an antagonist of 3 proinflammatory interleukins of the IL-1 family (IL-36alpha, IL-36beta, IL-36gamma). Its dysfunction leads to a predominance of proinflammatory cytokines. Such mutations are also found in about 80% of sporadic cases without manifestations of psoriasis vulgaris. IL-36RN mutations are found in only 10% of PPG with psoriasis vulgaris.

Another mutation associated with pustular psoriasis generalisata involves the adaptor protein complex 1/ AP1S3 gene. This variant leads to destabilization and dysfunction of the "pattern recognition receptor" TLR-3(Toll-like receptor 3 ). Toll-like receptors are used for the recognition of so-called "Pathogen Associated Molecular Patterns" ( PAMPs).

Adults appearing after the 40th LJ. Rarely children.

The entire integument with preference of the trunk and extremities, also palmae and plantae, oral mucosa, mucous membranes of the upper respiratory tract and genital mucous membranes can be affected.

In the area of the oral mucosa, acute stomatitis with fine-lamellar, wipeable zircine or oval plaques (stomatitis geographica, stomatitis areata migrans) is found, in the tongue area findings which can be characterized as exfoliatio areata linguae.

Acute, "overnight" occurrence of extensive erythema and edema, accompanied by high fever and a severe feeling of illness, up to complete or incomplete erythroderma with countless white or yellow, sterile pustules, standing alone or also confluent to form pus lakes. The pustules burst within a short period of time, dry up, or leave behind flat weeping areas.

If left untreated, a relapsing course is typical, which may last for weeks or months. The relapse frequencies vary in length and can last for hours or days.

In the area of the oral mucosa, whitish or gray, veil-like, exfoliating plaques may be present.

Depending on the extent and severity of the lesions, a distinction is made between different degrees of severity of generalized pustular psoriasis:

either according to the Generalized Pustular Prosiasis Area and Severity Index (GPPASI), adapted from the PASI index. Depending on the severity, this index ranges from 0 (minimal involvement) to 72 (most severe involvement). Another index is the

Generalized Pustular Psoriasis Physician Global Assessment (GPPGA). This index evaluates the severity of the individual efflorescences erythema, scaling, pustules from severity 0 to 4, then the mean value is calculated.

BSG > 40 mm/hour; CRP > 50mg/l; leukocytosis mostly > 12,000/ul; neutrophilia often >80%; rarely hypoparathyroidism.

Superficial perivascular and interstitial lymphocytic and leukocytic dermatitis with epidermotropy and spongiform, subcorneal or highly intraepithelial pustules, see also Kogoj pustules.

• Subcorneal pustulose (Sneddon-Wilkinson)
• Pustulose, acute generalized exanthematic (AGEP)
• Toxic pustuloderm.

Bronchopneumonia, hepatic metabolic disorders, iron deficiency, renal insufficiency.

• The range of the clinical appearance is wide.
• PPG must be classified as a life-threatening disease.
• In the case of severe PPG, intensive care treatments in appropriately equipped therapy units apply.
• Discontinuation of possible provocative medication.
• Treatment of bacterial infections, focus search and remediation.
• General measures: isolation of the patient, protective clothing / mouthguards for medical/nursing staff, monitoring, sufficient volume supply, fluid balancing, heat supply, exact temperature control, supply of humidity in the room air, special bed for decubitus prophylaxis / positioning on Metalline foil, bladder catheter, documentation of the findings.

Notice! Check intravenous accesses regularly and change daily (high risk of contamination)!

Applysulfadiazine-silver cream(e.g. Flammazine) thinly to affected areas (erosions). Wound debridement, detach necrotic skin sections; puncture and open blisters sterilely. Gauze mesh on erosive wound areas if necessary with antibiotic additive (e.g. bactigrass). Oral hygiene with astringent liquids (e.g. rp. 255 , Hexoral Lsg.). Eye hygiene several times a day with disinfecting and astringent eye drops (e.g. Solan eye drops). In addition, apply eye ointment containing dexpanthenol in a thick layer. Loosen adhesions with stick swab.

Treat pustular skin briefly with potent glucocorticoid such as 0.1% betamethasone rp. 029 or 0.05% clobetasol cream rp. 054 . In groins and axillae, 0.5% hydrocortisone zinc cream rp. 127 . After resolution of pustular relapse activity, transition to bland local therapy with hydrophilic ointments (e.g., Ungt. emulsif. aq.).

• First approved targeted therapy is spesolimab (^Spevigo®) for GPP relapses. Among them rapid remission of skin and systemic symptoms: already after 8 days 50% of patients pustule-free, 71% at week 12. Dosage: in relapse 900 mg as infusion over a period of 90 minutes. In case of persistence 2nd dose at identical level.
  Another IL-36R antibody (imsidolimab) shows promising study results.
• Currently, there are no performance guidelines for therapy. It is recommended to use conventional immunosuppressants (ciclosporin, methotrexate, corticosteroids) or retinoids in the acute phase, if necessary in combination with phototherapy (PUVA, narrow band UVB), or to start the initiation with biologicals like anti-TNF-alpha, anti-IL-17 or anti-IL-12/IL-23/IL-23p19, depending on the situation of the patient and the experience of the practitioner.
• In severe courses, fully balanced parenteral nutrition in the first days. Scheme with daily application of colloidal solution (1 ml/kg bw x affected KO), electrolyte solution (physiological saline 1 ml/kg bw x affected KO).
• Antibiosis according to antibiogram.
• If stable, transition to high-calorie liquid diet (e.g., Meritene). Later diet with passaged food; no spices, no fruit acids.
• Treatment options for psoriasis vulgaris are often adopted: acitretin, ciclosporin, methotrexate, short-term steroids, also UV irradiation, see above.

• Successes with acitretin (Neotigason) 0.5-1.0 mg/kg bw/day p.o. have been reported (note: the therapeutic principle has not been sufficiently proven!). After the initiation phase, reduction to lowest possible maintenance dose according to clinic. In case of therapy failure methotrexate (e.g. MTX) or fumaric acid ester (Fumaderm). Priority is given to methotrexate 15 - 25 mg/week i.v. because of faster onset of action!

  Alternative: If necessary, a combination of methotrexate and fumaric acid esters is possible. After interception of the acute episode, therapy can be continued with fumaric acid esters alone, if necessary.

• Successes with infliximab (off-label use!) are described in individual case reports. See also Psoriasis vulgaris

  . Infliximab is already included in the guidelines of the British Association of Dermatology for this indication! However, since a rapid and reliable response to therapy is mandatory, infliximab is currently to be regarded as the "assured" therapy of first choice.

• Experimental and alternative: An application of interleukin-1 inhibitors (Gevokizumab) led in single cases (2 Pat.) to a prompt response within a 4-week period!
• Concomitant sedating antihistamine such as promethazine 75-100 mg/day p.o. (e.g. Atosil Drg.) or dimetindene 2 times/day 4 mg i.v. (e.g. Fenistil).

Comment: Internal glucocorticoids may be contraindicated from the etiologic understanding of the disease. However, they are quite effective in a very acute initial period, both externally and internally (200-250mg prednisolone i.v.) and are suitable to bridge an acute initial phase!

See illustration above

1. Cassandra M et al (2003) Childhood pustular psoriasis elicited by the streptococcal antigen: a case report and review of the literature. Pediatr Dermatol 20: 506-510
2. Hussain S et al (2015) IL36RN mutations define a severe autoinflammatoryphenotype of generalized pustular psoriasis. J Allergy Clin Immunol 135:1067-1070
3. Jiyad Z et al (2014) Generalized pustular psoriasis associated with Epstein-Barr virus. Clin Exp Dermatol 40:146-148
4. Kim HS et al (2014) Two cases of generalized pustular psoriasis: successful treatment with infliximab. Ann Dermatol 26:787-788
5. Mansouri B et al (2014) Treatment of two patients with generalized pustular psoriasis with the interleukin-1β inhibitor gevokizumab. Br J Dermatol 173: 239-241.
6. Setta-Kaffetzi N ET AL: (2014) AP1S3 mutations are associated with pustular psoriasis and impaired Toll-like receptor 3 trafficking. Am J Hum Genet 94:790-797.
7. Shiratori T et al (2015) IL36RN gene analysis of two Japanese patients with generalized pustular psoriasis. Int J Dermatol 54:e60-62.
8. Sugiura K et al (2013) The majority of generalized pustular psoriasis without psoriasis vulgaris is caused by deficiency of interleukin-36 receptor antagonist. J Invest Dermatol 133:2514-2521
9. Tholen S et al (1987) Oral mucosal changes in pustular psoriasis generalisata. Dermatologist 38: 419-421
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11. Weißenseel P et al (2016) Pustular psoriasis. Dermatologist 67: 445-453
12. Von Zumbusch LR (1910) Psoriasis and pustular exanthema. Arch Dermatol Syphilol (Berlin) 99: 335-346.
13. Reich K et al (2022) Generalized pustular psoriasis: overview of the status quo and results of a panel discussion. J Dtsch Dermatol Ges. 20:753-771.
14. Navarini AA, et al. (2017) ERASPEN Network. European consensus statement on phenotypes of pustular psoriasis. J Eur Acad Dermatol Venereol. 31: 1792-1799.