Clinical research and real-world observational studies are essential for advancing the diagnosis and treatment of rare diseases, such as inborn errors of immunity/primary immune disorders (IEI/PID). To support efficient study planning, it is crucial to estimate patient numbers and identify centers caring for specific IEI/PID. The European Society for Immunodeficiencies has maintained a dedicated patient registry (ESID-R) for over 30 years, now containing data from 36,681 patients. In 2024, the ESID-R was migrated to a professional clinical trials operator to streamline and decentralize studies conducted by academic groups.
Unlike cross-sectional health-economic or epidemiologic datasets, the ESID-R provides longitudinal follow-up (age range 0–97 years; mean follow-up 7.2 years), capturing diagnostic pathways, treatments, organ involvement, and major events such as hematopoietic stem cell transplantation, gene therapy, malignancies, and death. Data are manually extracted from electronic health records into structured case report forms (CRFs). Alongside baseline level 1 data, approximately 10–15 concurrent sub-studies use level 2 (diagnosis- or country-specific) or level 3 (more detailed, protocol-based) CRFs for non-interventional studies.
Over its first three decades, the ESID-R supported more than 85 publications with a mean citation rate of 95. Recent studies include analyses of initial manifestations or malignancies in IEI/PID, natural history of SOCS1 or JAGN1 deficiency, cartilage hair hypoplasia and activated PI3K-delta syndrome, machine-learning–based diagnosis classification using the Immune Deficiency and Dysregulation Activity (IDDA) score, and real-world experience with JAK inhibitors. Ongoing projects include sub-registries on familial hemophagocytic lymphohistiocytosis and immune reconstitution in adenosine deaminase 1-deficient severe combined immune deficiency (ADA-SCID).
The ESID-R enables rapid sub-study feasibility assessments and represents a valuable platform for clinical research in very rare diseases. While challenges remain—particularly in motivating consistent data entry and addressing legal or technical barriers to sub-study integration—many obstacles have been resolved through the new technical framework and harmonized center agreements. Despite progress in some countries, automated data extraction or widespread consent waivers remain unlikely in the near term across >30 participating countries. Future directions include integrating artificial intelligence to enhance both data acquisition and analysis. To maximize impact while minimizing burden on clinicians, patient registries for IEI/PID across the globe should remain interoperable, collaborative, and nonredundant, enabling broad access for joint research initiatives.
