Abstract
To the Editor,
We read with interest the systematic review and meta-analysis by Cevallos-Cueva et al evaluating Bruton’s tyrosine kinase (BTK) inhibitors in chronic spontaneous urticaria (CSU). 1 While the study addresses an important therapeutic gap, several methodological limitations merit further consideration.
First, the inclusion of heterogeneous BTK inhibitors with distinct pharmacologic profiles and dosing regimens (including multiple dose arms within individual trials) challenges the assumption of a class effect. This concern is particularly relevant given the dominance of remibrutinib trials in the pooled dataset.
Second, an important limitation arises from the inclusion of early-phase studies such as the fenebrutinib randomized trial. 2 This study was characterized by a small sample size (n = 93), adaptive design with early termination after interim analysis, and short treatment duration (8 weeks), all of which are known to inflate effect estimates and limit generalizability. Moreover, substantial dose heterogeneity was present, with only higher doses demonstrating consistent efficacy, raising concerns about pooling across dosing strata. Notably, baseline imbalances in disease severity across treatment arms and wide confidence intervals further underscore the imprecision of the findings. Additionally, safety signals—including reversible transaminase elevations—were observed, suggesting that conclusions regarding safety may be premature.
Third, restricting follow-up to 4 to 12 weeks is difficult to justify in a chronic condition such as CSU and may bias conclusions toward early treatment effects. The rationale for excluding longer-term outcomes is unclear, particularly given the availability of evidence extending to 24 weeks. 3 Incorporating such data is essential to adequately assess treatment durability and clinical relevance.
Fourth, the robustness of the pooled efficacy estimates is questionable. Although the authors acknowledge that the trial sequential analysis did not cross monitoring boundaries despite reaching the required information size—indicating that the evidence remains inconclusive and vulnerable to random error—this limitation is not adequately reflected in their interpretation. The emphasis on efficacy in the conclusions appears disproportionate to the underlying statistical uncertainty, raising concern for overestimation of treatment effects.
Finally, the designation of “high certainty” evidence using GRADE appears overly optimistic, given imprecision, heterogeneity, short follow-up duration, potential publication bias, and reliance on early-phase trials—all of which would typically warrant downgrading the certainty of evidence.
In conclusion, although BTK inhibitors represent a promising therapeutic approach for antihistamine-refractory CSU, the current evidence base remains preliminary. Larger, adequately powered, head-to-head trials with longer follow-up are required before firm conclusions regarding efficacy, safety, and clinical positioning can be drawn.
