Background/Purpose: The deficiency of adenosine deaminase type 2 (DADA2) is an autosomal recessive disease resulting from biallelic mutations in CECR1. Patients commonly present with vascular and inflammatory manifestations including livedo racemosa, fevers, ischemic strokes, anemia and polyarteritis nodosa (PAN). Neurologic events can occur even when acute phase reactants are normal. Therapeutic options have included anti-thrombotic agents as well as anti-inflammatory agents without adequate disease suppression. Hematopoietic stem cell transplant has been reported to be a successful therapeutic option but has associated risks. Previous reports have demonstrated perivascular tumor necrosis factor (TNF) in DADA2, and suggest that TNF inhibitors ameliorate DADA2-associated PAN. We therefore aimed to assess whether anti-TNF agents would reduce the number of strokes in DADA2.

Methods: Patients with DADA2 and a history of ischemic stroke seen at the NIH between June 2013 and May 2016 were included in this cohort. Patients were initiated on anti-TNF therapy with etanercept, adalimumab or golimumab, and were monitored by follow-up visits to the NIH every six to twelve months. The primary outcome was the number of strokes after initiation of an anti-TNF agent compared to the number of strokes before anti-TNF treatment. Secondary outcomes included progression of other DADA2 related clinical manifestations, change in acute phase reactants, and hematologic markers.

Results: Out of 22 DADA2 patients followed at the NIH, 15 had a history of ischemic stroke. Before anti-TNF initiation, the 15 patients in the stroke cohort had 55 strokes over 1173 patient months (model based recurrence rate 0.043) compared to 0 strokes over 373 patient months occurring post-initiation of anti-TNF (recurrence rate 0). The P value for testing equal recurrence rate is 1.68 x 10^-8. A matched follow up time analysis using 328 patient months both prospectively and retrospectively has an estimated probability of 1 (15/15) for the strokes occurring before anti-TNF treatment as opposed to after, with a 95% Blyth-Still-Casella exact confidence interval of (0.7873, 1) (P =5.1×10^-5). This refutes the null hypothesis that anti-TNF therapy will not have an effect on stroke frequency and that the probability of stroke pre-anti-TNF initiation is 0.5. Laboratory studies showed statistically significant improvements in ESR, CRP, hematocrit, hemoglobin, platelets, leukocytes and serum iron.

Conclusion: These results show that anti-TNF treatment is highly effective in reducing the risk of stroke and improving laboratory parameters in DADA2. Although not directly addressed here, it may be advisable to initiate anti-TNF at the time of diagnosis of DADA2 even in the face of normal acute phase reactants.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-deficiency-of-adenosine-deaminase-type-2-dada2-results-of-anti-tnf-treatment-in-a-cohort-of-patients-with-a-history-of-stroke/