Abstract / Summary
Abstract Objectives With advances in genetic testing, monogenic lupus is increasingly recognized, yet disease-specific classification criteria are lacking. We compared all three classification criteria sets in the same monogenic lupus cohort and, for the first time, evaluated their performance across distinct genetic pathways. Methods This national multicenter study included 88 genetically confirmed monogenic lupus patients from 22 pediatric rheumatology centers across Türkiye. Fulfilment of the ACR-1997, SLICC-2012, and EULAR/ACR-2019 criteria and pathway-based differences in classification performance were assessed. Results Overall, 74% (n = 65) fulfilled ACR-1997, 70.5% (n = 62) SLICC-2012 and EULAR/ACR-2019 criteria, and 62.5% (n = 55) met all three, whereas 17% (n = 15) met none. Agreement was substantial (κ = 0.63–0.73), with no significant differences between criteria (p > 0.05). Classification performance differed significantly across genetic pathways (p < 0.05), with the highest fulfilment performances in complement deficiencies and the lowest in nucleic acid metabolism and type I interferon pathway defects. Most patients who did not fulfill any classification criteria had nucleic acid metabolism and clearance defects (13/15, 86.7%). Domain-level analyses showed that classification success was mainly driven by mucocutaneous, immunologic, and renal domains. Complement and immune-regulation defects showed a more classical lupus phenotype, with most fulfilling all three criteria (78.6%, 22/28 and 77.8%, 14/18), whereas the proportion was lower in type I interferon pathway and nucleic acid metabolism and clearance defects (33.3%, 2/6 and 47.2%, 17/36). No classification criteria was superior within genetic pathways. Conclusions One-third of genetically confirmed monogenic lupus patients remained unclassified, particularly those with interferon-related and nucleic acid metabolism defects, highlighting pathway-dependent limitations of current classification criteria.