What does elevated Immunoglobulin G (IgG) and Immunoglobulin A (IgA) with normal Immunoglobulin M (IgM) indicate in a Deficiency of Adenosine Deaminase 2 (DADA2) pediatric patient?

From the Guidelines

In a pediatric patient with DADA2, elevated IgG and IgA levels with normal IgM indicate an inflammatory immune dysregulation pattern consistent with this rare autoinflammatory disorder, suggesting the need for treatment with tumor necrosis factor inhibitors, such as etanercept or adalimumab, to prevent serious complications like strokes and vasculopathy. This immunoglobulin profile suggests chronic immune activation and inflammation, which are hallmarks of DADA2, as described in the 2021 American College of Rheumatology/Vasculitis Foundation guideline for the management of polyarteritis nodosa 1. The condition results from mutations in the ADA2 gene, leading to deficient adenosine deaminase 2 enzyme activity, causing vascular inflammation, immune dysregulation, and often hypogammaglobulinemia, though some patients paradoxically develop hypergammaglobulinemia as seen in this profile.

Key aspects of DADA2 include:

• Recurrent strokes and skin changes
• Diagnosis using ADA2 sequencing or ADA2 functional assays
• Treatment with tumor necrosis factor inhibitors, such as etanercept or adalimumab, which have been shown to prevent strokes 1
• Regular immunoglobulin monitoring every 3-6 months, along with inflammatory markers like CRP and ESR
• Potential need for hematological support for associated cytopenias

The use of tumor necrosis factor inhibitors is strongly recommended over glucocorticoids alone for patients with clinical manifestations of DADA2, as stated in the guideline 1. Early treatment is crucial to prevent serious complications like strokes, vasculopathy, and end-organ damage that characterize this condition.

From the Research

Immunoglobulin Levels in DADA2 Pediatric Patients

• High IgG and IgA levels with normal IgM in a DADA2 pediatric patient may indicate a severe immune defect or a chronic inflammatory disease 2.
• DADA2 is a recessively inherited autoinflammatory disorder characterized by systemic vasculitis, early-onset stroke, bone marrow failure, and/or immunodeficiency 3, 4.
• Elevated IgA levels are often associated with severe immune defects, chronic rheumatic diseases, or inflammatory bowel disease in pediatric patients 2.
• The combination of high IgG and IgA levels with normal IgM may suggest an imbalance in the immune response, which is common in DADA2 patients due to the deficiency of adenosine deaminase 2 (ADA2) enzyme 3, 4.

Clinical Implications

• High IgG and IgA levels with normal IgM in DADA2 pediatric patients may require further evaluation and management to prevent complications such as systemic vasculitis, stroke, or bone marrow failure 4.
• Treatment with TNF inhibitors has been shown to be effective in reducing inflammation and improving outcomes in DADA2 patients 3.
• Immunoglobulin levels should be monitored regularly in DADA2 patients to assess disease activity and response to treatment 4.