Background/Purpose:  The deficiency of adenosindeaminase 2 (DADA2) is a recently described autosomal recessive autoinflammatory disease, caused by mutations of CECR1 and characterized by early onset vasculopathy with livedoid skin associated to systemic inflammation. In some patients, the disease is mild and skin-limited, in others is severe, with multi-organ involvement including ischemic or hemorrhagic strokes. In some DADA2 patients a mild immunodeficiency was detected involving adaptive immunity. TNF inhibitors are very efficacious. Recently, an upregulation of type I interferon-stimulated gene transcripts, so called interferon signature, was described also in two DADA2 patients. We describe the clinical course of a 4 patients with CECR1 mutations and we assess the role of interferon type I signature as marker of disease’s activity

Methods:  Molecular analysis of CECR1 was performed using next generation sequencing and confirmed by sanger sequencing. Blood was collected into PAXgene tubes and expression levels of IFI-27 IFI-44L IFIT-1, ISG-15, RSAD-2 and SIGLEC- determined. The IFN score was derived as described (1). The mean interferon score of the controls plus two SD was calculated: 1.62 and scores higher than this value were considered positive

Results:  Four Caucasian patients (2 brothers males and 2 unrelated females) were identified carrying CECR1 mutations (compound eterozygous Leu249Pro/Pro344Leu in the two brothers, compound heterozygosity T360A/R49Gfs*4 deletion in one and homozygous Y453C mutation in one). Mean age was 12.2 ± 2.0 years. Three of the described patients presented with clinical features consistent with the phenotype of DADA2 already reported including recurrent fever, livedo reticularis, persistent elevation of inflammatory markers, arthralgia/ arthritis. Unusual/undescribed manifestation included in 1 patient: early onset gastrointestinal involvement with a biopsy consistent with unspecific inflammation, posterior reversible encephalopathy with seizures, deafness and malignant hypertension. The latter is due to nephrogenic hypertension secondary to kidney infarction. His younger brother showed a very mild phenotype characterized by a single episode of prolonged fever with abdominal pain and arthralgia. He is the 1 patient showing hypogammaglobulinemia. All patients showed a complete normalization of clinical and laboratory findings with no recurrences after treatment with etanercept (follow-up ranging from 8 months to 20 months). The interferon score before treatment was elevated in 3 (ranging from 3.6 to 10.4) out of 4 patients (except for the younger brother), and rapidly normalized after treatment

Conclusion:  Our data confirm the highly variability of DADA2 regarding age of onset, severity and organ involvement, even within families and, for unknown reasons, among patients with the same mutations. Furthermore, these data suggest that type I interferon score could be used in DADA2 patients as a useful biomarker of disease’s activity. The relation between type I IFN hyperactivity, deficiency of ADA2 and response to TNF inhibition remain elusive References: (1) Rice GI et al. Lancet Neurol. 2013 Dec;12(12):1159-6

« Back to 2016 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/variable-clinical-phenotypes-and-relation-of-interferon-signature-with-disease-activity-in-ada-2-deficiency/