<i>Artemisia annua</i> Sublingual Immunotherapy Is Efficacious and Well Tolerated in Patients With Season Allergic Rhinitis: A Prospective, Open‐Label, Multicenter Phase <scp>IV</scp> Trial

BACKGROUND: Artemisia pollen is a major allergen of seasonal allergic rhinitis (SAR) in northern China. Although Artemisia annua sublingual immunotherapy (SLIT) has been approved for treating SAR, large-scale and long-term evidence regarding its efficacy, durability, safety, and immunological mechanisms remains limited. METHODS: This prospective, open-label, multicenter phase IV clinical trial was conducted across eight centers in northern China. Adults with A. annua-induced SAR received SLIT for two consecutive pollen seasons (Y1, Y2), followed by 1-year post-treatment observation (Y3). The primary endpoint was the combined symptom and medication score (CSMS) during the peak pollen period (PPP). Secondary endpoints included individual nasal and ocular symptoms, medication use, and safety outcomes. Exploratory analyses assessed immunoglobulin profiles in serum and nasal secretions and serum inflammatory protein profiles using Olink proteomics. RESULTS: Among 316 patients included in the full analysis set, CSMS decreased significantly from last autumn (Y0, 4.03 ± 0.75) to the Y1 PPP (1.74 ± 0.92, p < 0.0001) and Y2 PPP (1.25 ± 0.74, p < 0.0001) during treatment, and remained stable during the Y3 PPP (1.34 ± 0.93, p = 0.7864) with no significant rebound in symptoms or medication use. SLIT also significantly reduced nasal and ocular symptoms and increased the proportion of medication-free days during the PPP. Serum total IgE showed a transient increase in Y1 and returned to baseline by Y2, while sIgA and sIgG4 increased in both serum and nasal secretions, with an early and significant rise in the sIgA/sIgE ratio in the nasal secretions in Y1. Proteomic analysis identified dynamic regulation of inflammation-related proteins, including downregulation of CCL3, IL-8, OSM, and ST1A1 during long-term treatment. A. annua SLIT was well tolerated, with most adverse events being mild and self-limiting. CONCLUSIONS: Artemisia annua SLIT is a safe and effective treatment for A. annua-induced SAR. Two years of SLIT achieved durable symptom control with reduced medication use, accompanied by immunological signatures of enhanced local immune tolerance and attenuated chronic inflammation.