Spesolimab (Spevigo®): A Comprehensive Monograph on the First-in-Class Interleukin-36 Receptor Antagonist for Generalized Pustular Psoriasis

Section 1: Introduction to Spesolimab (Spevigo®)

1.1 The Clinical Challenge of Generalized Pustular Psoriasis (GPP)

Generalized Pustular Psoriasis (GPP) is a rare, severe, and chronic autoinflammatory skin disease that is both genetically and clinically distinct from the more common plaque psoriasis.[1] The condition is characterized by the sudden and widespread eruption of painful, sterile pustules that form on an erythematous base, often covering large areas of the body.[3] These flares are frequently accompanied by systemic inflammation, manifesting as fever, chills, intense pruritus, debilitating fatigue, myalgia, and joint pain.[3] The immunopathology of GPP is primarily driven by the dysregulation and hyperactivity of the interleukin-36 (IL-36) signaling pathway, a key component of the innate immune system.[6]

The clinical burden of GPP is profound. Flares are unpredictable and can be life-threatening, with the potential for severe complications including sepsis, hypocalcemia, cardiovascular failure, and multi-organ failure if left untreated.[2] This places an immense physical and emotional toll on patients and a significant burden on healthcare systems, often requiring hospitalization for management.[1] Prior to the advent of targeted therapies, the therapeutic landscape for GPP was fraught with challenges. There were no globally approved treatments developed specifically for GPP, forcing clinicians to rely on off-label use of systemic agents such as retinoids, cyclosporine, and methotrexate.[5] The evidence supporting these traditional therapies was limited, primarily derived from small case series and retrospective studies, and their use often resulted in unsatisfactory or only partial control of the disease, coupled with significant toxicity profiles.[11] This created a critical and long