How is DADA2 Treated?

Phenotype-Based Treatment — Disease phenotype is an important consideration for the treatment of DADA2. Tumor necrosis factor alpha (TNFa) inhibition is associated with lower risk of stroke and decreased inflammatory manifestations in patients with vasculitis but does not appear to be effective in patients with immunodeficiency or bone marrow failure.

Vasculitis and Systemic Inflammation — For patients with DADA2 who have vasculitis and/or systemic inflammation, experts suggest treatment with TNF inhibitors (TNFi) is the treatment of choice. Clinical improvement has been reported with the use of etanercept, adalimumab, infliximab, and golimumab, as well as biosimilars. Observational data show that the use of TNF inhibitors is associated with a significantly lower risk for additional strokes and decreased inflammatory burden of the disease. Currently continue treatment with TNF inhibitors indefinitely. At least one death has occurred due to gastrointestinal hemorrhage several months after discontinuation of TNF inhibitors.

The efficacy of TNF inhibition is illustrated in these examples:

• In a series from the United States, 15 patients with DADA2 and a history of strokes were begun on TNF inhibitor therapy with etanercept (0.8 to 1.2 mg per kg body weight, maximum of 50 mg weekly), adalimumab (40 mg every one to two weeks), infliximab (4 to 5 mg/kg every six weeks), or golimumab (50 mg weekly). In the 2077 patient-months before initiation of treatment, patients had 55 strokes. In 733 patient-months on therapy, no further strokes were observed.
• In a series from the United Kingdom, 27 patients received anti-TNF treatment for a median of 32 months. The median event rate of central nervous system (CNS) and non-CNS ischemic events before anti-TNF treatment was 2.37 per 100 patient-months compared with 0.00 per 100 patient-months posttreatment. General improvement of systemic vasculitis was reflected by a reduction in Pediatric Vasculitis Activity Score (PVAS), with a median score of 20/63 pretreatment versus 2/63 posttreatment.

Glucocorticoids, disease-modifying antirheumatic drugs, and other biologic agents such as tocilizumab (monoclonal interleukin [IL] 6 receptor antagonist) may partially ameliorate systemic inflammation, but these agents are less effective in preventing strokes. Anticoagulation in DADA2 patients with strokes is not given because of concerns that it may precipitate or worsen hemorrhagic stroke.

Asymptomatic or No Vasculitis — Whether patients discovered to have DADA2 but who have not yet had a stroke or other symptoms of vasculitis (e.g., discovered by screening of family members) should be treated with TNF inhibitors remains a difficult dilemma. It is suggested that treating all such patients, even if asymptomatic, because of the potentially devastating and even life-threatening consequences of a first stroke.

Symptomatic Carriers — Some persons present with features of DADA2 but are found to have only a single deleterious ADA2 mutation and an intermediate level of ADA2 enzymatic activity. Periodic fever, oral ulcers, skin rash, arthritis, and systemic inflammation have been reported in these symptomatic carriers. Optimal management of heterozygous ADA2 deficiency is uncertain due to the lack of systematic studies. The decision may be influenced by the severity of symptoms in relatives with the same pathogenic mutation as well as the preference of the patient/caregivers. In these cases, experts seek to balance the active disease features and risk of future disease-related clinical events with the risk and cost of indefinite immunosuppression.

Bone Marrow Failure and Immunodeficiency — For patients with DADA2 who have treatment refractory bone marrow failure, we suggest hematopoietic cell transplantation (HCT) rather than TNF inhibitors and supportive care. TNF inhibitors are generally ineffective for severe hematologic manifestation of DADA2 but may ameliorate concurrent features of inflammation in some patients with bone marrow failure. In addition, the use of TNF inhibitors in patients with bone marrow failure syndrome and/or immunodeficiency may further increase the risk for infection. Intravenous immune globulin, granulocyte colony-stimulating factor (GCSF), glucocorticoids, and other immunosuppressive agents also have proven largely ineffective for severe hematologic manifestations. Fresh-frozen plasma contains ADA2, but sustained treatment is not feasible given the short half-life of the protein. Restoration of ADA2 production by HCT is potentially curative for patients, and reduced-intensity conditioning appears to be effective. In a cohort of 14 patients that underwent HCT, all patients were alive and well, hematologic, and inflammatory features of the disease all showed significant improvement, and no new vascular events were reported during a median follow-up of 18 months. In a series of 30 DADA2 patients, HCT corrected the hematologic phenotype in all patients, although one patient died from infection, six required a second HCT due to graft failure, and six patients developed graft-versus-host disease by one year after transplant. Gene therapy and enzyme replacement therapy are promising options that are undergoing preclinical evaluation.

DADA2 patients with immune deficiency as documented by low IgG levels and failure of provocative testing are placed on gamma globulin, either intravenous or subcutaneous.

See link below to review a landmark publication on May 31, 2023, in the medical journal, JAMA Network Open Access. The DADA2 Foundation and three DADA2 patients and 35 physicians from 18 countries made this amazing publication happen. A special thanks to Pui Lee, M.D., Ph.D., a pediatric rheumatologist at Boston Children's Hospital for his work on this important journal article.