Dear Editor,

We appreciate the opportunity to reply to the letter to the editor from Dr. Kirchner pertaining to our publication [1] in which we have computed background incidence rates of autoimmune diseases in European healthcare data sources as part of the IMI-ADVANCE project [2].

The author of the letter to the editor criticized the methodology that was applied in our background incidence rates study and highlighted possible misidentification of a vaccine safety signal. Following this, it is of importance that we reiterate the context in which this study has been conducted and we provide additional clarity on data interpretation and contextualization for vaccine safety signal assessment.

Our background incidence rate study demonstrated that the ADVANCE system can identify specific autoimmune events, generate rapid estimation of rates, and detect age-specific patterns. In our manuscript, we emphasized the heterogeneity of the various data sources that were used and attempted to demonstrate that the type of care that is captured in the data sources (general practitioners versus record-linkage data sources) should be cautiously considered when data are used, for instance, in observed-to-expected analysis. The heterogeneity across European healthcare data sources has been further assessed in ACCESS [3], a project funded by the European Medicines Agency leveraging expertise in the European Pharmacoepidemiology and Pharmacovigilance research network, and the VAC4EU, in which we highlighted the importance of the nature of the events and the setting in which it is diagnosed. We demonstrated that data sources containing exclusively general practitioner data may not be suitable to identify events requiring immediate care at hospital level.

Regarding background incidence rate of acute disseminated encephalomyelitis (ADEM), the author of the letter pointed out that rates from our ADVANCE study are largely above rates from other published sources. Although we acknowledge the numerical differences, we would like to stress the importance of the clinical definitions that were used across the listed studies in Table 1 of the letter to the editor. Study design, the use of different medical codes, narrow or broad clinical definitions, and the implementation of a case validation process through medical chart review impact the generated evidence. Among the nine studies listed in Table 1 below, seven applied a case ascertainment process, which makes more robust the validation of the outcome under assessment. Regarding the two studies from Willame et al. (2021 [4] and 2023 [3]), the major difference resides in the applied clinical definitions. The Willame et al. 2021 [4] paper used a broad clinical definition (ICD-10: G35-G37.9; G04; G04.3; G04.9; G36.9) compared with the Willame et al. 2023 [3] paper (ICD-10 narrowed to: G04.00; G04.01; G04.02), which led to higher incidence rates in the ADVANCE background rate study.

Table 1 Heterogeneity in clinical definitions for ADEM across nine studies
Full size table

The author of the letter mentioned that, in the minutes of the PRAC meeting held on 5–8 July 2021 concerning the Pfizer/BioNTech COVID-19 mRNA-vaccine BNT 162b2 [12], the PRAC recommended to use background incidence rates from the ACCESS study [3] to evaluate a potential safety signal for ADEM, but the author of letter stated that ACCESS data were not available. This statement is incorrect as the ACCESS data including broad and narrow clinical definitions were made immediately available to the scientific community in February 2021 on the ENCePP website (https://www.encepp.eu/phact_links.shtml), far before the PRAC request. Updated background incidence rates were also made publicly available on the VAC4EU dashboard (https://vac4eu.org) and Zenodo platform (https://www.zenodo.org/record/5255870#.ZA7sTuyZP0o).

The ADVANCE background rate study paved the way for further improvements to generate background incidence rates through a benefit–risk system at the European level, which has been made successful with ACCESS. Variations in background incidence rates are often observed across different sources owing to differences in data sources, years of the study conduct, study populations, and clinical case definitions. In vaccine safety signal assessment, it is our recommendation to consider several sources of data for background incidence rates depending on availability of age-stratified data and the validity of study outcomes.