BTK in CSU Pathogenesis: Recent Updates
Bruton's tyrosine kinase (BTK) has emerged as a critical intracellular signaling node in CSU pathogenesis, linking both autoallergic (type I) and autoimmune (type IIb) mechanisms through its role in FcεRI and B-cell receptor signaling pathways. 1
Core Pathogenic Role of BTK
BTK functions as a cornerstone signaling molecule downstream of multiple receptors central to CSU:
FcεRI signaling: BTK is essential for signal transduction after IgE cross-linking on mast cells and basophils, regardless of whether the trigger is IgE autoantibodies (autoallergic CSU) or IgG autoantibodies targeting FcεRI or bound IgE (autoimmune CSU) 1, 2
B-cell receptor signaling: BTK drives autoreactive B-cell generation and autoantibody production, perpetuating the autoimmune cycle in CSU 1
Myeloid cell activation: BTK participates in signaling through Fc receptors, toll-like receptors, and chemokine receptors on mast cells and other myeloid cells 3
Why BTK Matters Clinically
The convergence of multiple CSU pathways through BTK makes it an attractive therapeutic target:
Both autoallergic and autoimmune CSU mechanisms involve FcεRI cross-linking and BTK-dependent downstream signaling—meaning BTK inhibition can theoretically address both endotypes simultaneously. 1, 2 This is particularly relevant because these mechanisms may co-occur in the same patient 1.
Patients with autoimmune (type IIb) CSU—characterized by higher disease severity, autoimmune comorbidities, low total IgE levels, and reduced omalizumab responsiveness 2—represent a population where BTK inhibition may offer particular benefit given the IgG-mediated mechanism.
Clinical Translation
Phase 2 trials with BTK inhibitors (remibrutinib and fenebrutinib) demonstrated rapid and sustained improvements in CSU disease activity 1. Remibrutinib has now completed phase 3 trials and received FDA approval in 2025 4, 5, representing the first oral BTK inhibitor approved for antihistamine-refractory CSU.
The therapeutic advantage of BTK inhibitors lies in targeting an intracellular signaling pathway rather than a single extracellular molecule, potentially offering efficacy across different CSU phenotypes 6.
Mechanistic Nuances
Beyond classical autoantibody pathways, emerging evidence suggests BTK may also be relevant to non-IgE-dependent mechanisms in CSU, including:
- MRGPRX2-mediated mast cell activation
- Neuroimmune interactions
- Coagulation and complement cascade activation
- Persistent low-grade inflammation 2
However, the extent to which BTK inhibition affects these alternative pathways remains under investigation.
Important Caveats
First-generation BTK inhibitors (like ibrutinib) had unfavorable safety profiles including cardiotoxicity, hypertension, hemorrhage, and rash, limiting their use in non-malignant conditions 1, 3. Second-generation inhibitors (remibrutinib, fenebrutinib, rilzabrutinib, TAS5315) demonstrate improved selectivity and safety 1, 7, though long-term safety data are still accumulating 6.
The variable efficacy of BTK inhibitors across different autoimmune diseases (disappointing in rheumatoid arthritis and lupus, more positive in multiple sclerosis and CSU) 3 suggests disease-specific factors influence therapeutic response—likely reflecting differences in pathway dependence and cellular sensitivity to BTK inhibition.