Severe flare of generalized pustular psoriasis treated with spesolimab, an IL-36-directed monoclonal antibody

Abstract

Dear Editors,

Generalized pustular psoriasis (GPP) is a relatively rare and chronic autoinflammatory dermatologic condition with marked systemic involvement.¹ We present the first European patient, treated with spesolimab after official European Medicines Agency (EMA) approval for GPP. We describe a 34-year-old woman who reported redness and scaling of the lower limbs since September 2022 with subsequent spread over the trunk, upper limbs, and scalp. Two months later, the patient was hospitalized with disseminated nummular erythematosquamous plaques and pustules on the scalp, trunk, and extremities (Figure 1a). Palms and soles were erythematous, with lamellar desquamation, the tongue was plicated (Figure 1b). Lingua geographica was previously described in association with GPP.^{2, 3} The standard paraclinical findings were within reference ranges. A microbiological examination of pustules did not reveal any pathogenic microorganisms. The histopathological examination was consistent with a pustular psoriasis (Figure 1c). A systemic therapy with acitretin – a second-generation retinoid – (0.5 mg/kg BW) was initiated. Three weeks later, the rash generalized with erythroderma (Figure 2, 3), lakes of pus, and edema of the lower legs. At the end of November 2022, the patient was hospitalized with fever (38.5°C), anemia, leukocytosis (15.0×10⁹/l; normal range, 3.5–10.5×10⁹), hypoproteinemia (58g/l; 66–87 g/l) and elevated CRP (127 mg/l; 0–5 mg/l). Microbiological examination of pustules revealed a methicillin-resistant coagulase negative Staphylococcus (MR-CoNS). Acitretin therapy was then discontinued. Due to the deteriorating general health condition, a systemic therapy with methylprednisolone (1 mg/kg BW/day), clindamycin (3×600 mg/day), human albumin and antipyretics was initiated in combination with emollients and potassium permanganate baths. A week later, the hypoproteinemia was under control, CRP decreased (50 mg/l), the microbiological skin test became negative, and the body temperature normalized. However, the erythroderma and pustules persisted. On November 30, 2022, an oral therapy with cyclosporin A (CyA, 300 mg/day) was started. After two more weeks, the patient's condition deteriorated with fever (up to 38.9°C), and edema of the extremities, neck, and face. The Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) reached the highest score of 4 (5-grade numerical scale ranging from 0 [clear] to 4 [severe]).⁴

The patient was transferred to the intensive care unit with leukocytosis (17.9×10⁹/l), decreased hemoglobin (98 g/l), hypoproteinemia (52.0 g/l), hypoalbuminemia (30.3 g/l; 35–52 g/l) and elevated CRP (147 mg/l). Staphylococcus epidermidis was isolated from blood culture. A ten-day systemic therapy with vancomycin (2×1 g), methylprednisolone (1 mg/kg), famotidine (2×20 mg), human albumin (20 g/100 mL), Ringer solution (500 mL) and fondaparinux sodium (2.5 mg/0.5 mL) was administered.

On December 25, 2022, upon a negative hemoculture, the patient received an infusion with spesolimab (900 mg). Cyclosporine A was discontinued the same day, methylprednisolone was gradually tapered over a week. The patient rapidly improved, with no pustules visible 24 hours after the infusion (Figures 2, 3); a second dose of spesolimab was administered seven days later (Figures 2, 3). On January 5, 2023, the patient was discharged afebrile, without any pustule or edema, with mild persistent erythroderma. The standard paraclinical findings were within reference ranges (CRP: 3.7 g/l; protein: 61.5 g/l). The patient's condition was maintained with topical corticosteroids; three months later, a complete clearance was finally attained.

GPP is characterized by an acute eruption of macroscopically visible primary sterile pustules on erythematous base, not only limited to acral skin or psoriasis plaques, with a potentially life-threatening systemic inflammation. Systemic symptoms include fever, chills, malaise, and severe pain. Complications and morbidity from GPP may arise from secondary bacterial infection, sepsis, and renal, hepatic, or cardiorespiratory failure.¹ According to the ERASPEN criteria, GPP diagnosis should be suspected when the condition persists for more than three months or when it has relapsed at least once.⁵

Corticosteroid use and withdrawal is a known trigger for GPP flares; smoking, pregnancy, stress, infections, TNF-alpha inhibitors, and nonsteroidal anti-inflammatory drugs are other potential causes.^{6, 7}

Generalized pustular psoriasis is pathogenically different from plaque-type psoriasis and linked to a dysfunction of IL-36 signaling pathway.⁸ A dysregulation of this pathway seems essential to the development of GPP, wherein an uncontrolled expression and activation of IL-36 cytokines leads to the activation of clonal T-cell responses and neutrophil recruitment in the epidermis, with associated pustule formation.^{9, 10} In some GPP-affected patients, loss of-function mutations have been found in the IL36RN gene encoding an interleukin-36 receptor antagonist,¹¹ offering an interesting and new approach in the treatment of GPP.

Spesolimab – a humanized monoclonal antibody that blocks the IL-36 receptor – has shown promising outcomes in the treatment of GPP.¹² Spesolimab has recently been approved as monotherapy in the treatment of GPP flares, for instance by FDA and EMA.

Following spesolimab therapy, a rapid improvement of the skin and systemic inflammation was observed in a patient with life-threatening GPP flare. Longer follow-up is required for long-term efficacy evaluation of spesolimab in this setting.

Medical writing assistance was supported by Boehringer Ingelheim RCV GmbH & Co KG. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.

V.M. received honoraria from Boehringer Ingelheim for an advisory board as well as for lecturing services. P.V. received speaker honoraria from Boehringer Ingelheim. All other authors have no conflict of interest to declare.