French protocol for diagnosis and management of type 1 interferonopathies

Abstract

Type I interferonopathies are rare genetic diseases characterised by excessive production or signalling of type I interferons (IFN-I), which are key cytokines in the antiviral response. These conditions lead to inappropriate activation of IFN-I pathway, even in the absence of viral stimulation. Over thirty monogenic conditions have been identified, with Aicardi-Goutières syndrome being the most common. The genes involved often relate to the metabolism of intracellular nucleic acids, their detection and signalling pathways, contributing to excessive IFN-I production or signalling. Features usually appear early in life, often within the first year, but diagnosis can also occur in adulthood. It is important to investigate whether there is a family history of consanguinity or vertically transmitted conditions. Key diagnostic features include: (1) Neurological: pseudo-encephalitic phase, psychomotor development retardation or regression, static encephalopathy, spasticity, microcephaly, aseptic lymphocytic meningitis. (2) Radiological: cerebral calcifications, white matter signal abnormalities, cerebral atrophy. (3) Dermatological: chilblains, skin necrosis, skin lesions suggestive of systemic lupus erythematosus (SLE), vasculitis, livedo, panniculitis. (4) Ophthalmological: early-onset glaucoma. (5) Musculoskeletal: myalgia, myositis, joint deformity with calcification, joint subluxation. (6) Pulmonary and renal: interstitial lung disease, pulmonary fibrosis, alveolar haemorrhage, lupus nephritis. (7) Laboratory evidence: lymphopenia, elevated erythrocyte sedimentation rate with normal C-reactive protein, positive antinuclear antibodies. Type I interferonopathies can mimic more common conditions like viral foetopathy or systemic lupus erythematosus. The disease expressivity is variable, even within the same family, making a detailed family history essential. The hallmark of these diseases is increased IFN-I levels in peripheral blood and/or cerebrospinal fluid, a test available only in specialised laboratories. Based on clinical suspicion, patients should be referred to an expert centre. There is no curative treatment to date. Management is multidisciplinary, focusing on symptomatic treatment. In cases of systemic or dermatological involvement, immunosuppressive therapy may be considered, though it increases susceptibility to viral infections. Vaccinations should be updated, with live vaccines contraindicated during immunosuppression unless otherwise specified (Supplemental 2). Monitoring development, supporting disability, and coordinating with social and medical institutions are also crucial aspects of care.

Keywords: Aicardi-Goutières syndrome; COPA; Diagnosis; Diagnostic; Interféronopathies; Interférons de type I; Management; SAVI; Syndrome Aicardi-Goutières; Traitement; Type I interferonopathies; Type I interferons.