Background/Purpose: Deficiency of adenosine deaminase 2 (DADA2) is a rare autosomal recessive autoinflammatory disorder first identified in 2014. Four major disease phenotypes have been described: vasculitic, hematologic, immunodeficient, asymptomatic. The mainstay treatment is TNF inhibitors (TNFi), especially in patients with the vasculitic phenotype. The prevalence of its various clinical and laboratory manifestations has not been previously reported in a meta-analysis.We aimed to calculate the prevalence of the following clinical and laboratory manifestations: cutaneous involvement, polyarteritis nodosa (PAN)-like presentation, stroke (ischemic or hemorrhagic), ocular involvement, cytopenias, recurrent infections, hemophagocytic lymphohistiocytosis (HLH), fever and hepatosplenomegaly.

Methods: We searched PubMed and EMBASE for cohorts of patients with DADA2. In order to be considered eligible for our inclusion criteria, studies should have met the following criteria: (1) DADA2 diagnosis confirmed with genetic analysis, (2) reporting of clinical manifestations in both children and adults.

Results: Ten studies, 9 retrospective and 1 prospective, published between 2016 and 2025 provided data on 225 patients with DADA2. Cutaneous findings were the most common clinical manifestations with a prevalence of 80.82% (95% CI: 72.03-88.45%), while biopsy confirmed PAN was present in 28.94% (95% CI: 15.04-44.93%) of patients. Ischemic stroke was the manifestation with the lowest heterogeneity among included studies and yielded a prevalence of 38.66% (95% CI: 31.26-46.29%), while the prevalence of hemorrhagic stroke was lower at 9.86% (95% CI: 3.97-17.46%). Other common manifestations included fever 61.99% (95% CI: 48.72-74.49%), cytopenias 38.47% (95% CI: 23.60-54.40%), recurrent infections 35.72% (95% CI: 9.00-67.75%), hepatosplenomegaly 30.80% (95% CI: 16.63-46.82%), ocular involvement 13.85% (95% CI: 8.02-20.71%) and HLH 6.92% (95% CI: 1.69-14.50%). Finally, the majority (n=127, 56.4%) received TNFi; etanercept (79 patients) and adalimumab (31 patients) were the most commonly used.

Conclusion: In this meta-analysis of 225 patients with DADA2, cutaneous involvement, fever and ischemic stroke were the most common manifestations. Closer monitoring for cytopenia is needed to reduce the risk of recurrent infections. Both outcomes occurred in one third of patients included in this study. More than half of patients are receiving TNFi, leading to prolongation of life-expectancy. Therefore, adult rheumatologists are expected to encounter patients with DADA2 more frequently and increased awareness of the disease and its manifestations is warranted for optimized patient care.

Figure 1.

Pooled Prevalence of Clinical Manifestations Among Patients with DADA2.

Table 1.

Baseline characteristics and treatment options.

AZA: azathioprine, CYC: cyclophosphamide, IL1i: Interleukin 1 inhibitor, MMF: mycophenolate mofetil, MTX: methotrexate, RTX: rituximab, TNFi: tumor necrosis alpha factor inhibitor

Figure 2.

Pooled Prevalence of Ischemic Stroke with 95% Confidence Intervals. ES: Effect Size (Prevalence)

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/prevalence-of-clinical-and-laboratory-manifestations-of-patients-with-deficiency-of-adenosine-deaminase-2-dada2-a-systematic-review-and-meta-analysis/