Abstract
The deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessively inherited disease that has undergone extensive phenotypic expansion since being first described in patients with fevers, recurrent strokes, livedo racemosa, and polyarteritis nodosa in 2014. It is now recognized that patients may develop multisystem disease that spans multiple medical subspecialties. Here, we describe the findings from a large single center longitudinal cohort of 60 patients, the broad phenotypic presentation, as well as highlight the cohort’s experience with hematopoietic cell transplantation and COVID-19. Disease manifestations could be separated into three major phenotypes: inflammatory/vascular, immune dysregulatory, and hematologic, however, most patients presented with significant overlap between these three phenotype groups. The cardinal features of the inflammatory/vascular group included cutaneous manifestations and stroke. Evidence of immune dysregulation was commonly observed, including hypogammaglobulinemia, absent to low class-switched memory B cells, and inadequate response to vaccination. Despite these findings, infectious complications were exceedingly rare in this cohort. Hematologic findings including pure red cell aplasia (PRCA), immune-mediated neutropenia, and pancytopenia were observed in half of patients. We significantly extended our experience using anti-TNF agents, with no strokes observed in 2026 patient months on TNF inhibitors. Meanwhile, hematologic and immune features had a more varied response to anti-TNF therapy. Six patients received a total of 10 allogeneic hematopoietic cell transplant (HCT) procedures, with secondary graft failure necessitating repeat HCTs in three patients, as well as unplanned donor cell infusions to avoid graft rejection. All transplanted patients had been on anti-TNF agents prior to HCT and received varying degrees of reduced-intensity or non-myeloablative conditioning. All transplanted patients are still alive and have discontinued anti-TNF therapy. The long-term follow up afforded by this large single-center study underscores the clinical heterogeneity of DADA2 and the potential for phenotypes to evolve in any individual patient.
Highlights
The deficiency of adenosine deaminase 2 (DADA2) was initially described as a syndrome of small and medium-sized vessel vasculitis/vasculopathy manifesting as recurrent episodes of fever, early-onset lacunar strokes, and cutaneous involvement including livedo racemosa, Raynaud’s phenomenon, and polyarteritis nodosa
In this paper we describe the findings of a large single center longitudinal cohort and expand the phenotypic presentation of the patients to include evidence for lymphocyte driven immunemediated neutropenia, as well as describe the spectrum of presentations of peripheral vasculopathy
We report the results of hematopoietic cell transplant (HCT) in 6 patients from this cohort
Summary
The deficiency of adenosine deaminase 2 (DADA2) was initially described as a syndrome of small and medium-sized vessel vasculitis/vasculopathy manifesting as recurrent episodes of fever, early-onset lacunar strokes, and cutaneous involvement including livedo racemosa, Raynaud’s phenomenon, and polyarteritis nodosa. The function of ADA2 is poorly characterized, studies in a zebrafish model suggest that ADA2 has a role in the development of hematopoietic cells and maintenance of vascular integrity, which may explain some of the manifestations that have been observed in both the bone marrow and vasculature [1]. Deficiency of ADA2 has been associated with polarization of myeloid cells towards M1 (pro-inflammatory) relative to M2 (antiinflammatory) macrophages. These tissue resident M1 macrophages can produce proinflammatory cytokines and cause a hyperinflammatory environment that is damaging to blood vessels and may contribute to the propensity of affected individuals to develop strokes. ADA2 has been reported to function as a sensor for extracellular purine nucleosides and lack of ADA2 can trigger a type I interferon (IFN) cellular response [7]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
