Current landscape of monogenic autoinflammatory actinopathies: A literature review

First author : P. Mertz

Review: Autoimmunity Reviews

Link to article: https://doi.org/10.1016/j.autrev.2024.103715

Autoinflammatory diseases (AID) are conditions leading to a hyperactivation of innate immunity without any underlying infection, and may be poly- (e.g. Still's disease) or monogenic. The number of monogenic AID is continuously expanding, with the discovery of novel pathologies and pathophysiological mechanisms, facilitated in part by easier access to pangenomic sequencing. Actinopathies with autoinflammatory manifestations represent a newly emerging subgroup of AID, associated with defects in the regulation of actin cytoskeleton dynamics. These diseases typically manifest in the neonatal period and variably combine a primary immunodeficiency of varying severity, cytopenia (particularly thrombocytopenia), autoinflammatory manifestations primarily affecting the skin and digestive system, as well as atopic and autoimmune features.

Diagnosis should be considered primarily when encountering an early-onset autoinflammatory skin and digestive disorder, along with a primary immunodeficiency and either thrombocytopenia or a bleeding tendency. Some of these diseases exhibit specific features, such as a risk of macrophage activation syndrome (MAS) or a predisposition to atopy or lymphoproliferation. The complete pathophysiology of these diseases is not yet fully understood, and further studies are required to elucidate the underlying mechanisms, which could guide therapeutic choices. In most cases, the severity of the conditions necessitates allogeneic marrow transplantation as a treatment option.

In this review, we discuss these novel diseases, providing a practical approach based on the main associated biological abnormalities and specific clinical characteristics, with a special focus on the newly described actinopathies DOCK11 and ARPC5 deficiency. Nonetheless, genetic testing remains essential for definitive diagnosis, and various differential diagnoses must be considered.

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Monogenic auto-inflammatory diseases associated with actinopathies: A review ofthe literature

P. Mertz a, V. Hentgenb, G. Boursier c, J. Delond, S. Georgin-Laviallee,∗,f

Link to article: https://doi.org/10.1016/j.revmed.2023.06.005

Abstract:

Auto-inflammatory diseases (AIDs) are diseases resulting from an inappropriate activation of innate immunity in the absence of any infection. The field of monogenic AIDs is constantly expanding, with the discovery of new pathologies and pathophysiological mechanisms thanks to pangenomic sequencing. Actinopathies withauto-inflammatorymanifestations are anew emerging group of AIDs, linked to defects in the regulation of the actin cytoskeleton dynamics. These diseases most often begin in the neonatal period and combine to varying degrees a more or less severe primary immune deficiency, cytopenias (especially thrombocytopenia), auto-inflammatory manifestations (especially cutaneous and digestive), atopic and auto-immune manifestations. The diagnosis is to be evoked essentially in front of a cutaneousdigestive auto-inflammation picture of early onset, associated with a primary immune deficiency and thrombocytopenia or a tendency to bleed. Some of these diseases have specificities, including a risk of macrophagic activation syndrome or a tendency to atopy or lymphoproliferation. We propose here a review of the literature on these new diseases, with a proposal for a practical approach according to the main associated biological abnormalities and some clinical particularities. However, the diagnosis remains genetic, and several differential diagnoses must be considered. The pathophysiology of these diseases is not yet fully elucidated, and studies are needed to better clarify the inherent mechanisms that can guide the choice of therapies. In most cases, the severity of the picture indicates allogeneic marrow transplantation.

© 2023 Publié par Elsevier Masson SAS au nom de Société Nationale Française de Médecine Interne (SNFMI).