Treatment and Outcome in Deficiency of Adenosine Deaminase 2: A Literature Review

Abstract

Objectives: Deficiency of adenosine deaminase 2 (DADA2) is a rare disease with varying phenotypes and disease outcomes. We evaluated the treatment of DADA2 and explored the factors associated with disease outcome. Methods: A systemic literature review of DADA2 was conducted. Cases were included if they had documented detailed genotypes, phenotypes, treatment protocols, and outcomes. Patients were categorized as having uncontrolled and controlled disease. Factors associated with disease outcome were analyzed using logistic regression models. Results: The study population comprised 242 DADA2 patients with data on treatment protocols and responses, of whom 17 required no treatment. Tumor necrosis factor a inhibitors (TNFi) were effective in 78.6% (103/131). Hematological abnormalities and increased acute phase reactants are independently associated with the effectiveness of TNFi (OR, 0.21 [95%CI, 0.07-0.661; P=.007] and 9.62 [95%CI, 2.31-40.00; P=.002, respectively). Among the 225 patients requiring active treatment, 157 (69.8%) had controlled disease and 68 (30.2%) uncontrolled disease. Neither age of disease onset nor genotype was associated with disease outcome. Increased acute phase reactant values, constitutional symptoms, neurological symptoms, and treatment with TNFi were independently associated with disease control, while recurrent infections and severe vascular events were the main causes of mortality (10/21 and 6/21, respectively). Conclusion: In patients requiring treatment, symptoms of systemic inflammation and vasculitis and treatment with TNFi are associated with disease control. Recurrent infections and severe vascular events should be treated intensively, as they are the main causes of death. Hematological abnormalities should be monitored, as they decrease the effectiveness of TNFi.

A case report on deficiency of adenosine deaminase 2 with relapse–remission course and analysis of genotype–phenotype correlation

“…Furthermore, the use of TNFis is significantly associated with disease control in systemic inflammation and vasculitic manifestations. However, TNFis are ineffective in correcting hematology, and patients with refractory hematologic abnormalities have to resort to hematopoietic stem cell transplantation (Hashem, Kumar, et al, 2017; Zhang et al, 2021).…”

Allogeneic Hematopoietic Cell Transplantation for Patients With Deficiency of Adenosine Deaminase 2 (DADA2): Approaches, Obstacles and Special Considerations

“…At present time, more than 240 patients have been reported in the literature (10,11,(29)(30)(31). The onset of disease is usually in childhood but adult-onset has also been described with the oldest patients reported at 59 years of age (27,31,32).…”

ADA2 regulates inflammation and hematopoietic stem cell emergence via the A2bR pathway in zebrafish

“…The precise biological function of ADA2 and the pathogenetic mechanisms causing such a wide range of phenotypes are unclear. As a result, current treatments alleviate hematological symptoms of DADA2, such as G-CSF, or reduce inflammation like anti-TNF agents, but they fail to offer a definitive cure 5,[9][10][11][12] . Allogeneic hematopoietic stem cell transplantation stands as the only therapeutic option capable of completely and definitively correcting both the inflammatory and hematological phenotypes of DADA2 in patients [13][14][15][16][17] .…”