Comparative Efficacy of Subcutaneous and Sublingual Allergen Immunotherapy for Grass Pollen-Induced Allergic Rhinoconjunctivitis: Pairwise and Adjusted Indirect Treatment Comparison of Standardized ALK Products

Background: Allergen immunotherapy (AIT) is the only disease-modifying treatment for grass pollen-induced allergic rhinoconjunctivitis (ARC). Three delivery routes-subcutaneous (SCIT), sublingual drops (SLIT-D), and sublingual tablets (SLIT-T)-lack head-to-head comparative evidence. Objective: To compare three ALK-Abelló grass pollen AIT modalities using pairwise meta-analyses and adjusted indirect treatment comparisons restricted to a single manufacturer. Methods: We searched PubMed, Embase, and CENTRAL for double-blind, placebo-controlled RCTs evaluating ALK grass pollen AIT. Primary outcomes were symptom scores (SS) and medication scores (MS), analyzed as standardized mean differences (SMD, Hedges' g). Indirect comparisons used the Bucher method. A prespecified sensitivity analysis excluded two biased studies (Dolz 1996, Feliziani 1995). GRADE assessed certainty of evidence. Studies span three eras: SCIT (1991-2006), SLIT-D (1995-2009), SLIT-T (2006-2017). Results: Fifteen RCTs (5 SCIT, 3 SLIT-D, 7 SLIT-T; 3,546 patients) were included. SCIT and SLIT-T showed significant efficacy versus placebo; SLIT-D showed a non-significant trend. SCIT had the largest effects (SS: SMD = -1.07; MS: SMD = -1.35) but substantial heterogeneity (I2 = 89-91%), driven by the outlier Dolz 1996 (g = -6.59). SLIT-T showed consistent effects (SS/MS: SMD = -0.24; p < 0.001). In the sensitivity analysis, SCIT heterogeneity disappeared (I2 = 0%), effect sizes converged, and SCIT-vs-SLIT-T comparisons became non-significant. GRADE certainty: moderate for SLIT-T; low-to-very-low for others. Conclusions: Excluding high-risk-of-bias studies, SCIT and SLIT-T show broadly similar efficacy. SLIT-T provides the most robust evidence base. SLIT-D did not reach statistical significance in either analysis. Treatment selection should integrate efficacy, patient preferences, and practical considerations via shared decision-making.