JAK Inhibition in Aicardi-Goutières Syndrome: a Monocentric Multidisciplinary Real-World Approach Study

Abstract

The paradigm type I interferonopathy Aicardi-Goutières syndrome (AGS) is most typically characterized by severe neurological involvement. AGS is considered an immune-mediated disease, poorly responsive to conventional immunosuppression. Premised on a chronic enhancement of type I interferon signaling, JAK1/2 inhibition has been trialed in AGS, with clear improvements in cutaneous and systemic disease manifestations. Contrastingly, treatment efficacy at the level of the neurological system has been less conclusive. Here, we report our real-word approach study of JAK1/2 inhibition in 11 patients with AGS, providing extensive assessments of clinical and radiological status; interferon signaling, including in cerebrospinal fluid (CSF); and drug concentrations in blood and CSF. Over a median follow-up of 17 months, we observed a clear benefit of JAK1/2 inhibition on certain systemic features of AGS, and reproduced results reported using the AGS neurologic severity scale. In contrast, there was no change in other scales assessing neurological status; using the caregiver scale, only patient comfort, but no other domain of everyday-life care, was improved. Serious bacterial infections occurred in 4 out of the 11 patients. Overall, our data lead us to conclude that other approaches to treatment are urgently required for the neurologic features of AGS. We suggest that earlier diagnosis and adequate central nervous system penetration likely remain the major factors determining the efficacy of therapy in preventing irreversible brain damage, implying the importance of early and rapid genetic testing and the consideration of intrathecal drug delivery.

Keywords: Aicardi-Goutières syndrome (AGS); JAK inhibitors; interferon.

Fig. 1

Clinical and radiological response to treatment. A Evolution of the AGS developmental scale [14] in patients under JAK inhibition according to age and mutant genotype. Overall, a slight (mean, 1.2 points) but significant (p = 0.036, Kruskal-Wallis test) improvement on AGS severity scale was observed. B Brain magnetic resonance imaging (MRI) in 2 affected patients before and under treatment. The first patient (P2), 12 years old at treatment initiation, demonstrated global supra-tentorial atrophy on axial FLAIR (subpanel A) and T2 (subpanel B)–weighted images associated with calcifications of the globi pallidi on T2 star–weighted images (subpanel C, arrows). After 3 years of treatment, at age 15 years, atrophy had decreased (axial FLAIR (subpanel E), axial T2–weighted images (subpanel F)). On arterial spin labeling sequence (ASL) (subpanels D, H), cortical cerebral blood flow (CBF) increased between the ages of 12 and 15 years (CBF was measured at 53 ml/min/100 g per tissue in the temporal cortex at 12 years (subpanel D), increasing to 105 ml/min/100 g per tissue at 15 years old (subpanel H)). P6 demonstrated bilateral striatal anomalies (arrows) on axial FLAIR (subpanel I) and on axial T2–weighted images (subpanel K) at age 3.11 years. After 1.6 years of treatment, the appearance on the axial FLAIR–weighted (subpanel M) and axial T2–weighted (subpanel N) imaging showed nodular hyperintensity in the left thalamus (arrow). The diffusion-weighted images (subpanel O) showed an increased diffusion coefficient (subpanel P). On ASL (subpanels L, Q), CBF in the basal ganglia and cortex (about 40 ml/min/100 g tissue) (subpanels L and Q respectively) remained unchanged between the 2 periods

Fig. 2

Response of type I interferon biomarkers to treatment. Interferon scores assessed by qRT-PCR [20] or Nanostring [21] in the whole blood of patients (P1–P11) before and under treatment with a JAK inhibitor, either as composite data (A) or according to the JAK inhibitor used, i.e., ruxolitinib (Ruxo) or baricitinib (Bari) (B). Data are expressed as fold values of the normal interferon score (i.e., 2.466 and 2.724 for qRT-PCR and Nanostring Technologies respectively). Horizontal bars indicate median values and interquartile ranges. Comparison between the two groups was performed using Mann-Whitney test (****p < 0.0001). # indicates two samples taken during SARS-CoV-2 infection