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

Abstract

Allergen immunotherapy (AIT) is the only disease-modifying treatment for grass pollen-induced allergic rhinoconjunctivitis. Three delivery routes-subcutaneous (SCIT), sublingual drops (SLIT-D), and sublingual tablets (SLIT-T)-lack head-to-head comparative evidence. To compare 3 ALK-Abelló grass pollen AIT modalities using pairwise meta-analyses and adjusted indirect treatment comparisons restricted to a single manufacturer. We searched PubMed, Embase, and Cochrane Central Register of Controlled Trials for double-blind, placebo-controlled randomized controlled trials (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 2 biased studies (Dolz 1996, Feliziani 1995). Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessed certainty of evidence. Studies span 3 eras: SCIT (1991-2006), SLIT-D (1995-2009), SLIT-T (2006-2017). Fifteen RCTs (5 SCIT, 3 SLIT-D, 7 SLIT-T; 3546 patients) were included. SCIT and SLIT-T showed significant efficacy versus placebo; SLIT-D showed a nonsignificant 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 < .001). In the sensitivity analysis, SCIT heterogeneity disappeared (I² = 0%), effect sizes converged, and SCIT versus SLIT-T comparisons became nonsignificant. GRADE certainty was moderate for SLIT-T and low to very low for others. 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.