#2-46E. Navigating DADA2: The Limits of ADA2 Activity and the Need for Genetic Confirmation (Arthritis Rheum, 2025)

When evaluating patients with challenging, early-onset vasculitis or unexplained strokes, how reliable is the plasma ADA2 enzyme assay for diagnosing Deficiency of ADA2 (DADA2)? DADA2 is a rare but critical monogenic autoinflammatory disease, often manifesting as polyarteritis nodosa, stroke, and bone marrow failure. Leveraging an international cohort of 200 DADA2 cases, this study aimed to characterize the diagnostic utility of the plasma ADA2 enzyme activity assay and investigate the implications of residual ADA2 activity. The most novel finding reveals that approximately 9% of genetically confirmed DADA2 cases possessed detectable residual ADA2 activity, sometimes overlapping with carrier levels. This residual activity was strongly associated with the vasculitis/inflammatory phenotype. This suggests that low, measurable ADA2 activity does not reliably exclude DADA2, underscoring the necessity of genetic evaluation for definitive diagnosis, especially in patients presenting with inflammatory features. However, a key consideration for critical appraisal is that the in vitro functional analysis supporting the genotype-phenotype correlation was based on an overexpression system in 293T cells, which do not naturally express ADA2, which may limit the generalizability of the mechanistic insights into synergistic protein disruption.

Citation: Jian Y, LeSon CE, Rimland CA, et al. Diagnostic implications and correlates of plasma ADA2 activity and ADA2 variants. Arthritis & Rheumatology. 2025. DOI: 10.1002/art.43412.

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