From Pustules to Pruritus: A Novel IL36RN Frameshift Variant Reveals a Triple Biologic Paradox and a Th17-To-Th2 Phenotypic Transition.

Pustular psoriasis (IL-36/Th17) and atopic dermatitis (Th2) are associated with different but partially overlapping inflammatory pathways. Sequential expression of these phenotypes in the same patient is uncommon. We describe a 64-year-old woman with longstanding psoriasis vulgaris, asthma, allergic rhinitis, and a family history of atopy who developed generalized pustular psoriasis after biologic treatments. Genetic testing identified a novel, previously unreported heterozygous IL36RN frameshift variant, c.319del (p.Leu107Serfs65). Over subsequent months, the pustular phenotype was replaced by chronic, intensely pruritic, xerotic, eczematous dermatitis fulfilling the Hanifin-Rajka criteria. Serial biopsies demonstrated mild spongiosis and an eosinophil-rich superficial perivascular infiltrate. Risankizumab and adalimumab were temporally associated with pustular exacerbations, whereas dupilumab was followed by worsening of the eczematous phenotype without recurrent pustulation. Methotrexate 15 mg weekly, which restrains both axes, together with topical treatment was associated with sustained near-complete clearance through Month 12. To our knowledge, this is the first report of a three-class biologic paradox in a single patient. Sequential single-pathway blockade in a genetically destabilized immune network may disinhibit alternative effector arms with cytokine shunting. Inborn errors of immunity should be considered in refractory inflammatory dermatoses-even in geriatric patients-and pathway-specific biologics used cautiously when the underlying immune architecture is monogenically perturbed.