Disease Mechanisms, Emerging Therapies, and Reducing Corticosteroid Reliance in CSU
Experts examine CSU endotypes and their implications for treatment selection and preview the emerging therapeutic pipeline including barzolvolimab and novel mast cell–depleting strategies.
Chronic spontaneous urticaria is increasingly understood as a heterogeneous condition driven by distinct immunological endotypes rather than a single unified pathophysiological mechanism. At least 2 major subtypes have been described: type I, characterized by IgE-mediated mast cell activation through the high-affinity IgE receptor (FcεRI), and type IIb, in which IgG autoantibodies directly activate mast cells via FcεRI or other receptors in an IgE-independent manner. This mechanistic complexity helps explain the variable response to omalizumab and informs the rationale for agents with broader or alternative mechanisms. Remibrutinib acts at the BTK convergence point downstream of both IgE-mediated and non-IgE-mediated mast cell activation pathways, giving it theoretical breadth across endotypes; dupilumab's inhibition of IL-4Rα targets the type 2 inflammatory milieu at a different level, potentially relevant in patients whose disease is amplified by type 2 cytokine activity. As the field accumulates head-to-head data and real-world experience with all 3 agents, endotype-informed treatment sequencing may become increasingly feasible.
The CSU pipeline is active. Barzolvolimab, an anti-KIT monoclonal antibody under investigation by Celldex, targets the mast cell directly via the stem cell factor receptor — an approach with theoretical advantages across endotypes, since eliminating the effector cell renders the upstream activating mechanism clinically irrelevant. Data presented at a recent major allergy meeting included safety and long-term efficacy results for barzolvolimab, as well as new remibrutinib data in chronic inducible urticaria and a preliminary signal for high-dose remibrutinib (75 mg twice daily) in the prevention of food-induced anaphylaxis. If mast cell–depleting strategies achieve approval, they may fundamentally alter the treatment algorithm by addressing the shared final effector pathway irrespective of immunological subtype. Remibrutinib's emerging signals in conditions beyond CSU further suggest that BTK inhibition may have broader utility across mast cell–driven disease.
In this final video segment, Nicole Chase, MD, and Jason Hawkes, MD, address the persistent problem of systemic corticosteroid use in CSU, a pattern both characterize as clinically concerning despite the availability of effective, targeted, steroid-sparing agents. While short-term corticosteroid bridges have a defined role in acute severe exacerbations, repeated courses and chronic low-dose oral prednisone expose patients to well-characterized toxicities, such as metabolic dysfunction, adrenal suppression, osteoporosis, and infection risk, that are disproportionate to the disease burden of CSU, which carries no risk of end-organ damage or mortality. Hawkes draws a pointed risk-framing comparison: clinicians who express concern about remibrutinib's approximately 4% rate of mild bruising and petechiae should weigh that against the hemorrhagic, metabolic, and immunosuppressive risks of even short-term corticosteroid exposure. The availability of fast-acting targeted therapies — particularly remibrutinib — substantially reduces the clinical scenarios in which corticosteroids are genuinely the best available option, and clinicians should systematically revisit steroid-dependent patients to initiate discussions about transition to guideline-concordant care.
