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

INTRODUCTION

Chronic spontaneous urticaria (CSU) is defined in the 2022 EAACI/GA²LEN/EuroGuiDerm/APAAACI guideline as the spontaneous occurrence of wheals, angioedema, or both for ≥6 weeks in the absence of a specific external stimulus.^[1] Current guideline-directed management recommends a stepwise escalation beginning with standard-dose and subsequently updosing of second-generation H1-antihistamines (up to 4-fold), followed by omalizumab.^[2]

Although many patients respond to second-generation H1-antihistamines and omalizumab, an estimated 30–40% remain symptomatic. These non-responders frequently exhibit type IIb autoimmune CSU, associated with low immunoglobulin E (IgE) levels, IgG anti-FcεRI/anti-IgE autoantibodies, and positive basophil activation tests. Recent advances in CSU pathobiology highlight persistent mast-cell activation, autoimmunity (type I and IIb), and dysregulated cytokine networks, including interleukin (IL)-6, interferon-gamma (IFN-γ), and γ-chain cytokines as potential drivers of refractoriness.^[3]

These pathways converge predominantly through janus kinase inhibitor-1 (JAK1)-mediated signaling, suggesting that highly selective JAK1 inhibition may offer targeted modulation of upstream immunologic mechanisms not adequately addressed by existing therapies.^[4]

Within this scientific context, we examined the therapeutic role of upadacitinib in two patients with refractory CSU who had failed all guideline-recommended treatments.

CASE REPORT

Case 2

A 46-year-old man presented with an 18-month history of persistent, severe CSU characterized by daily widespread wheals and intense pruritus disturbing sleep [Figure 1].

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Figure 1: Erythematous wheals on the trunk.

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He did not experience angioedema. He had previously been treated with high-dose levocetirizine (20 mg twice daily) and bilastine (40 mg daily), along with hydroxyzine at night and montelukast. A 3-month course of cyclosporine at 3 mg/kg/day produced no meaningful clinical response. Omalizumab 300 mg every 4 weeks was administered for 4 months but failed to reduce symptom burden (UAS7 remained around 35–38). Before initiating upadacitinib, his baseline UAS7 was 38, and UCT was 7. Screening laboratories, including CBC, LFT, RFT, lipid profile, IGRA, and chest radiograph, were normal. ANA was weakly positive, but complements were normal. Serum IgE level was 53.5 IU/mL, and anti-TPO antibody was positive.

After appropriate counseling, he was started on upadacitinib 15 mg once daily while continuing antihistamines.

By the 8-week visit, he showed a marked reduction in symptoms (UAS7 = 10), allowing progressive tapering of antihistamines. At this point, because of sustained improvement, the dose of upadacitinib was reduced to 15 mg on alternate days. He resumed normal sleep and daily activities. No adverse events were reported throughout treatment. He is maintained on alternate-day upadacitinib with only as required antihistamines and continues to remain controlled.

DISCUSSION

Both our cases show significant improvement with upadacitinib. JAK1 is a key intracellular signaling node for multiple cytokines central to urticaria pathogenesis, including IL-4, IL-13, IL-31, thymic stromal lymphopoietin (TSLP), and interferons, which collectively drive mast-cell activation, IgE-mediated signaling, eosinophil recruitment, and the neuroimmune pathways responsible for pruritus. By selectively blocking JAK1, upadacitinib interrupts these inflammatory circuits while minimizing the off-target toxicities associated with broader JAK inhibition.^[5]

The drug has already demonstrated strong efficacy and acceptable safety across several immune-mediated dermatological disorders such as atopic dermatitis, prurigo nodularis, and chronic eczematous diseases, positioning it as a promising candidate for severe, treatment-refractory CSU.^[5] The clinical improvement observed with upadacitinib in our refractory CSU patients is consistent with its profile as a highly selective JAK1 inhibitor, a property demonstrated across biochemical, engineered cellular, and in vivo models. Upadacitinib shows >40–100-fold selectivity for JAK1 over JAK2, JAK3, and tyrosine kinase 2, enabling preferential inhibition of JAK1-dependent cytokine pathways, including IL-6/signal transducer and activator of transcription (STAT3), IFN-γ/STAT1, IL-2/STAT5, and oncostatin M (OS-M) signaling that are increasingly implicated in sustaining mast-cell activation, autoreactivity, and chronic inflammatory amplification in severe urticaria.^[6]

Importantly, this high degree of JAK1 specificity means that upadacitinib minimally interferes with pathways mediated by JAK2 and JAK3. Since JAK2 is required for erythropoietin signaling and red-cell production, and JAK3 regulates γ-chain cytokines critical for NK-cell survival, broader JAK inhibition often leads to anemia or natural killer-cell depletion. Upadacitinib largely spares these pathways, allowing effective suppression of key inflammatory cytokines without significant hematologic or immunologic toxicity.^[6] This precise, pathway-selective modulation provides a strong mechanistic rationale for its benefit in severe, treatment-refractory CSU, where upstream cytokine dysregulation may persist despite antihistamines and biologic agents.

Recent evidence further strengthens the rationale for JAK-1 inhibition in difficult-to-treat urticaria. Magen et al.^[7] reported a case of severe refractory CSU with concomitant rheumatoid arthritis that achieved complete and sustained remission on upadacitinib after failure of antihistamines and high-dose omalizumab.

The case report by Wu et al.^[8] on acute severe urticaria patient showed no improvement in wheals, edema, or throat obstruction, with progression to fever, worsening swelling, and rising inflammatory markers, despite high-dose glucocorticoid therapy. Only after initiation of upadacitinib 30 mg/day did the patient demonstrate rapid symptom reversal, with near-complete clearance of edema and wheals by day 6 of therapy, and normalization of UAS7 from 36 to 5 by discharge.

A 2025 case series from Canada^[9] reported that six patients with severe, dupilumab-refractory CSU achieved marked improvement (UAS ≤5 within 3 months) on upadacitinib, despite previously failing high-dose antihistamines and omalizumab.

The case report from Almaghrabi et al.^[10] describes a 39-year-old woman with biopsy-confirmed urticarial vasculitis who suffered for years from painful wheals lasting more than 24 hours, accompanied by arthralgia, myalgia, fatigue, and episodic swelling despite exhaustive therapy with corticosteroids, colchicine, dapsone, cyclosporine, mycophenolate mofetil, rituximab, and omalizumab. Initiation of upadacitinib 30 mg daily led to a striking clinical reversal, with near-complete resolution of cutaneous and systemic symptoms within 1 month and no reported adverse events. Although ultraviolet is more severe and structurally different from CSU, both conditions share mast-cell activation and cytokine-driven pathways, making the therapeutic response highly relevant to refractory urticaria.

The observed efficacy suggests that JAK1-mediated cytokine signaling may sustain urticarial activity when IgE-targeted and immunosuppressive therapies fail, reinforcing the rationale for evaluating upadacitinib in difficult-to-treat CSU. While our observations highlight the potential utility of upadacitinib as an effective rescue therapy in recalcitrant CSU, it is important to recognize that this represents an initial step in establishing its role in disease management. The transition from an experimental or rescue approach to a standard therapeutic option necessitates robust evidence from large-scale, randomized, placebo-controlled trials. Furthermore, long-term safety considerations and the sustainability of remission following treatment discontinuation remain key unanswered questions that merit focused investigation.

CONCLUSION

Both cases demonstrated complete control of treatment-refractory CSU with upadacitinib. JAK-1 inhibition targets IL-4, IL-13, IL-31, TSLP, IL-6, and IFN-γ pathways, addressing mechanisms unmet by omalizumab or cyclosporine. Larger controlled trials are needed to further evaluate this emerging treatment modality.