Response to upadacitinib in omalizumab refractory chronic spontaneous urticaria-Report of two patients

Chronic spontaneous urticaria (CSU) is defined as spontaneous wheals, angioedema, or both for ≥6 weeks without an identifiable trigger and remains refractory in up to 30–40% of patients despite guideline-directed escalation with high-dose second-generation antihistamines and omalizumab. Emerging insights into CSU pathobiology highlight persistent mast-cell activation, autoimmunity (Type I/IIb), and dysregulated cytokines, including interleukin (IL)-4, IL-13, IL-31, IL-6, and interferon-gamma, many of which converge through Janus kinase 1 (JAK1)-mediated signaling. Upadacitinib, a selective JAK1 inhibitor, therefore represents a rational therapeutic option for difficult-to-treat disease. We report two adults with severe, refractory CSU who failed maximal antihistamine therapy, omalizumab, and, in one case, cyclosporine. Both patients demonstrated rapid symptomatic improvement following initiation of upadacitinib 15 mg daily, achieving complete control (Urticaria activity score 7 = 0; Urticaria control test ≥15) by 12 weeks. It allowed tapering of antihistamines, and no significant adverse events were noted. These cases demonstrate the potential of selective JAK1 inhibition to address upstream immunologic mechanisms not targeted by antihistamines or biologics, supporting upadacitinib as a promising therapeutic option in refractory CSU. Larger controlled studies are warranted to further establish its efficacy and safety profile.