How do I diagnose and treat a child or young adult with unexplained small‑ or medium‑vessel vasculitis, early skin lesions, strokes and cytopenias—should I test for adenosine deaminase 2 deficiency and start anti‑tumor necrosis factor therapy?

Adenosine Deaminase 2 Deficiency (DADA2) in Vasculitis

Direct Answer

Yes, you should test for DADA2 in any child or young adult presenting with unexplained small- or medium-vessel vasculitis, early skin lesions, strokes, and cytopenias, and if confirmed, initiate anti-TNF therapy immediately as first-line treatment. 1

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When to Suspect DADA2

Consider DADA2 testing in patients presenting with:

• Early-onset (often childhood) polyarteritis nodosa-like vasculitis with recurrent strokes and skin changes 1
• Recurrent strokes (ischemic and/or hemorrhagic) in children or young adults without other clear etiology 2, 3
• Livedo reticularis or livedo racemosa as early skin manifestations 2, 4
• Cytopenias, including pure red cell aplasia, immune thrombocytopenia, or neutropenia 2, 4
• Early-onset fevers and rashes even without positive family history 2
• Hypogammaglobulinemia or recurrent infections suggesting immunodeficiency 4

The American Heart Association notes that cerebral vasculitis should be considered in children with stroke accompanied by unexplained skin lesions, multifocal neurological events, or cytopenias 1

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Diagnostic Approach

Confirm DADA2 Diagnosis

Test for DADA2 through:

• ADA2 enzyme activity assay (functional testing showing reduced enzyme activity) 3, 5
• ADA2 gene sequencing to identify biallelic mutations 2, 5

Over 100 disease-causing mutations have been identified affecting catalytic activity, protein dimerization, and secretion 2, 6

Baseline Evaluation

Once DADA2 is suspected, perform:

• Brain MRI (abnormal in >90% of CNS vasculitis cases) to assess for stroke and vascular abnormalities 7
• Vascular imaging (MRA, CTA, or conventional angiography) to evaluate medium-vessel involvement 1
• Complete blood count to assess for cytopenias 2
• Immunoglobulin levels to evaluate for humoral immunodeficiency 4
• Inflammatory markers (ESR, CRP), though these may be normal or only minimally elevated 1
• Skin biopsy if accessible lesions present to confirm vasculitis histologically 1

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Treatment Algorithm

First-Line Therapy: TNF Inhibitors

The American College of Rheumatology/Vasculitis Foundation strongly recommends TNF inhibitors over glucocorticoids alone for patients with confirmed DADA2. 1

• TNF inhibitors are highly effective in controlling inflammation and preserving vascular integrity, particularly preventing strokes 1, 2
• This represents a strong recommendation (not conditional) based on the compelling signal of benefit in preventing devastating outcomes like recurrent strokes 1
• TNF inhibitors work for vasculitic-predominant manifestations and respond extremely well compared to conventional immunosuppression 3

Why TNF Inhibitors Over Conventional Therapy

• Conventional immunosuppression (including cyclophosphamide) has been largely ineffective in treating the relapsing-remitting nature of DADA2 3
• Outside of high-dose glucocorticoids, standard immunosuppressive agents do not adequately prevent strokes 1
• TNF inhibitors specifically address the pathophysiology of DADA2, which involves imbalanced monocyte differentiation toward proinflammatory M1 macrophages 2

Alternative Treatment Considerations

Hematopoietic stem cell transplantation (HSCT):

• Consider for patients with severe hematological manifestations (pure red cell aplasia, bone marrow failure) 2, 3
• HSCT can normalize enzyme activity and resolve vasculitic, hematologic, and immunologic manifestations 3, 5
• Be aware that treatment-related adverse effects are not uncommon 3

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Critical Pitfalls to Avoid

Do Not Delay TNF Inhibitor Therapy

• Early detection and treatment prevents devastating clinical outcomes, especially recurrent strokes that can cause permanent neurological damage 3, 5
• Do not wait for biopsy confirmation if clinical suspicion is high and enzyme testing is pending 1

Do Not Use Standard PAN Treatment Protocols

• Unlike classic polyarteritis nodosa, DADA2 does not respond adequately to cyclophosphamide and glucocorticoids alone 1, 3
• The ACR guideline specifically distinguishes DADA2 from idiopathic PAN in treatment recommendations 1

Recognize Phenotypic Heterogeneity

• Disease presentation is highly variable, even among family members with identical mutations 4, 6
• Some patients may remain asymptomatic through adulthood, while others present with life-threatening manifestations in early childhood 4
• Evidence of systemic inflammation and vasculopathy is not uniformly present 4

Monitor for Hematologic Complications

• If pure red cell aplasia is present, provide red blood cell transfusions as supportive care while awaiting response to TNF inhibitors 8
• Avoid erythropoiesis-stimulating agents (ESAs) as they can cause antibody-mediated pure red cell aplasia in DADA2 8

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Multidisciplinary Coordination

• Manage patients with DADA2 in collaboration with centers of expertise given the rarity and complexity of the disease 7, 5
• Coordinate care between rheumatology, neurology, hematology, and immunology specialists 5
• Balance the high morbidity and mortality of untreated disease against risks of immunosuppressive therapy 7

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Prognosis and Long-Term Management

• With early TNF inhibitor therapy, prognosis is significantly improved with prevention of recurrent strokes and control of vasculitis 1, 3
• Continue monitoring for disease activity and treatment response with regular clinical assessments 5
• DADA2 is estimated to affect more than 35,000 cases worldwide, making it among the more common monogenic autoinflammatory diseases 5