Evaluate the Efficacy of Anti-Jak1 Inhibitors as Treatment for Patients With Aicardi-Goutières Syndrome

Multicenter Retrospective Observational Study to Evaluate the Efficacy of Anti-Jak1 Inhibitors as Treatment for Patients With Aicardi-Goutières Syndrome

Aicardi-Goutières Syndrome (AGS) is a hereditary multisystem autoinflammatory disorder that predominantly affects the central nervous system. It is characterized by severe neurological disability and chronic inflammation caused by the persistent overproduction of type I interferon. To date, nine causative genes of AGS have been identified, each of which can lead to classic AGS presentations, atypical forms, or other manifestations that do not meet the formal diagnostic criteria for AGS and are referred to as "AGS-related interferonopathies." Janus Kinase 1 (JAK1) inhibitors, including Baricitinib and Ruxolitinib, offer a promising therapeutic strategy for Aicardi-Goutières Syndrome (AGS) by directly targeting the central pathogenic pathway of the disease.

Patients treated with JAK1 inhibitors for AGS have shown significant improvement in systemic symptoms, though the effect on neurological symptoms and brain imaging remains unclear.

The aim of this project is to retrospectively analyze the efficacy, particularly on neurological symptoms and brain imaging, and the safety of JAK1 inhibitor treatment in AGS patients treated at Italian tertiary centers. Data will be collected before starting the therapy and during follow-up at 6, 12, 18, and 24 months, where available.

Preliminary data collection was carried out through a survey conducted by the AGS Italy group to assess the number of patients treated with JAK1 inhibitors.

Clinical, brain imaging, genetic, and laboratory data routinely recorded in nine different Italian centers as part of the standard clinical care of these patients will be retrospectively collected and analyzed.

In the second phase of the study, brain MRI data from AGS patients treated with JAK1 inhibitors will be compared to untreated AGS patients matched for age and genotype, in order to evaluate the potential therapeutic efficacy of JAK1 inhibitors on brain imaging compared to the natural clinical progression of the disease.

Through the analysis of the Italian experience, this study could lay the groundwork for drafting a potential consensus on the use of JAK1 inhibitors for the treatment of AGS patients.

Study Overview

• Status: Completed
• Conditions: Aicardi-Goutières Syndrome (AGS)
• Intervention / Treatment: Drug: JAK Inhibitor

• Study Type: Observational
• Enrollment (Actual): 24

Contacts and Locations

Study Locations

• Italy
  • Pisa, Italy, 56128
    • IRCCS Stella Maris Foundation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

A total of approximately 24 patients with Aicardi-Goutières Syndrome or AGS-related interferonopathies are expected to be enrolled, including 12 patients treated with different Janus Kinase 1/2 (JAK1/2) inhibitors, such as Baricitinib and Ruxolitinib, and 12 untreated patients, from the 9 Italian clinical centers involved in the study.

Description

Inclusion Criteria:

• Patients aged 0 to 25 years
• Patients who have been genetically diagnosed with Aicardi-Goutières Syndrome (AGS) or AGS-related interferonopathies For case cohort-Patients treated with Janus Kinase 1/2 (JAK1/2) inhibitors, such as Baricitinib or Ruxolitinib

Exclusion Criteria:

• Patients over the age of 25 years
• Patients who have not been genetically diagnosed with Aicardi-Goutières Syndrome (AGS) or AGS-related interferonopathies.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patients with AAGS or AGS-related interferonopathies treated with Anti-Jak1/2; Study group: Patients aged 0 to 25 years; Genetic diagnosis of Aicardi-Goutières Syndrome or AGS-related interferonopathies; Treatment with Janus Kinase 1/2 (JAK1/2) inhibitors, including Baricitinib and Ruxolitinib	Drug: JAK Inhibitor; The retrospective analysis will examine the effects of Janus Kinase 1/2 (JAK1/2) inhibitors, such as Baricitinib and Ruxolitinib, on neurological symptoms and brain MRI.
Patients with AGS or AGS-related interferonopathies not treated with Anti-Jak1/2; Control group: Patients aged 0 to 25 years matched with the study cases; Genetic diagnosis of Aicardi-Goutières Syndrome or AGS-related interferonopathies with genotype matched to the study cases; Not treated with Janus Kinase 1/2 (JAK1/2) inhibitors, such as Baricitinib and Ruxolitinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy of JAK-1/2 inhibitor therapy on Clinical criteria (AGS scale)	Evaluate the efficacy of JAK-1/2 inhibitor therapy through clinical criteria (AGS scale) in all patients with Aicardi-Goutières Syndrome or AGS-related interferonopathies, highlighting potential differences in efficacy between the different genotypes. The Aicardi-Goutières Syndrome (AGS) Severity Scale is a clinical tool used to assess the severity of neurological impairment in individuals with AGS. The scale ranges from 0 to 11, with higher scores indicating better neurological function.	After 6, 12, 18, and 24 months of treatment, if the data is available.
Efficacy of JAK-1/2 inhibitor therapy on laboratory parameter (IFN signature)	Evaluate the efficacy of JAK-1/2 inhibitor therapy through IFN signature (IFN score) on blood in all patients with Aicardi-Goutières Syndrome or AGS-related interferonopathies, highlighting potential differences in efficacy between the different genotypes. The IFN Score is typically expressed as a fold change relative to healthy controls or as a normalized relative value, measuring the expression of interferon-stimulated genes (ISGs). In patients with pathological activation of the interferon pathway, the IFN Score ranges from 0 to >10-15, indicating significant ISG upregulation. While the pathological cut-off varies across studies, an IFN Score >2-3 is often considered indicative of abnormal interferon pathway activation.	After 6, 12, 18, and 24 months of treatment, if the data is available.
Efficacy of JAK-1/2 inhibitor therapy on instrumental parameters (brain MRI)	Evaluate the efficacy of JAK-1/2 inhibitor therapy through brain MRI (Improved/Unchanged/Worsening) in all patients with Aicardi-Goutières Syndrome or AGS-related interferonopathies, highlighting potential differences in efficacy between the different genotypes.	After 6, 12, 18, and 24 months of treatment, if the data is available.
Evaluate the side effects of JAK-1/2 inhibitor	Evaluate the side effects of JAK-1/2 inhibitor therapy in patients with Aicardi-Goutières Syndrome or AGS-related interferonopathies.	After 6, 12, 18, and 24 months of treatment, if the data is available.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Consensus on indication of JAK-1/2 Inhibitor Therapy for Aicardi-Goutières Syndrome and Related Interferonopathies on Clinical criteria (AGS scale)	Develop a possible consensus within the AGS Italia network on AGS scale criteria that define the indication for starting JAK-1/2 inhibitor therapy in Aicardi-Goutières Syndrome or AGS-related interferonopathies. The Aicardi-Goutières Syndrome (AGS) Severity Scale is a clinical tool used to assess the severity of neurological impairment in individuals with AGS. The scale ranges from 0 to 11, with higher scores indicating better neurological function.	Until study completion, an average of 2 year.
Consensus on indication of JAK-1/2 Inhibitor Therapy for Aicardi-Goutières Syndrome and Related Interferonopathies on genetic criteria (type of Genetic mutation)	Develop a possible consensus within the AGS Italia network on Genetic mutation that define the indication for starting JAK-1/2 inhibitor therapy in Aicardi-Goutières Syndrome or AGS-related interferonopathies. At now nine causative genes for Aicardi-Goutières Syndrome (AGS) are known: TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, IFIH1, LSM11, and RNU7-1, all involved in nucleic acid metabolism and the interferon pathway.	Until study completion, an average of 2 year.
Consensus on indication of JAK-1/2 Inhibitor Therapy for Aicardi-Goutières Syndrome and Related Interferonopathies on laboratory parameter (IFN signature)	Develop a possible consensus within the AGS Italia network on laboratory parameter (IFN signature) that define the indication for starting JAK-1/2 inhibitor therapy in Aicardi-Goutières Syndrome or AGS-related interferonopathies. The IFN Score is typically expressed as a fold change relative to healthy controls or as a normalized relative value, measuring the expression of interferon-stimulated genes (ISGs). In patients with pathological activation of the interferon pathway, the IFN Score ranges from 0 to >10-15, indicating significant ISG upregulation. While the pathological cut-off varies across studies, an IFN Score >2-3 is often considered indicative of abnormal interferon pathway activation.	Until study completion, an average of 2 year.
Consensus on Monitoring laboratory parameter (IFN signature) for JAK-1/2 Inhibitor Therapy in Aicardi-Goutières Syndrome and Related Interferonopathies	Develop a possible consensus within the AGS Italia network on laboratory parameter (IFN signature) to be monitored during JAK-1/2 inhibitor therapy to assess the potential continuation or discontinuation due to lack of efficacy. The IFN Score is typically expressed as a fold change relative to healthy controls or as a normalized relative value, measuring the expression of interferon-stimulated genes (ISGs). In patients with pathological activation of the interferon pathway, the IFN Score ranges from 0 to >10-15, indicating significant ISG upregulation. While the pathological cut-off varies across studies, an IFN Score >2-3 is often considered indicative of abnormal interferon pathway activation.	Until study completion, an average of 2 year.
Consensus on Monitoring Clinical criteria (AGS scale) for JAK-1/2 Inhibitor Therapy in Aicardi-Goutières Syndrome and Related Interferonopathies	Develop a possible consensus within the AGS Italia network on Clinical criteria (AGS scale) to be monitored during JAK-1/2 inhibitor therapy to assess the potential continuation or discontinuation due to lack of efficacy. The Aicardi-Goutières Syndrome (AGS) Severity Scale is a clinical tool used to assess the severity of neurological impairment in individuals with AGS. The scale ranges from 0 to 11, with higher scores indicating better neurological function.	Until study completion, an average of 2 year.
Consensus on instrumental parameters (brain MRI) for JAK-1/2 Inhibitor Therapy in Aicardi-Goutières Syndrome and Related Interferonopathies	Develop a possible consensus within the AGS Italia network on brain MRI to be monitored during JAK-1/2 inhibitor therapy to assess the potential continuation or discontinuation due to lack of efficacy. Evaluate based on the progression of brain MRI to determine whether it improves, remains stable, or worsens.	Until study completion, an average of 2 year.

Collaborators and Investigators

• Sponsor: IRCCS Fondazione Stella Maris

Study record dates

Study Major Dates

• Study Start (Actual): April 7, 2024
• Primary Completion (Actual): December 18, 2024
• Study Completion (Actual): December 18, 2024

Study Registration Dates

• First Submitted: March 5, 2025
• First Submitted That Met QC Criteria: March 20, 2025
• First Posted (Actual): March 27, 2025

Study Record Updates

• Last Update Posted (Actual): March 27, 2025
• Last Update Submitted That Met QC Criteria: March 20, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Ruxolitinib; Baricitinib; Anti-Jak1/2; AGS-related interferonopathies
• Additional Relevant MeSH Terms: Nervous System Diseases; Pathologic Processes; Autoimmune Diseases; Immune System Diseases; Disease; Congenital Abnormalities; Syndrome; Autoimmune Diseases of the Nervous System; Nervous System Malformations; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Janus Kinase Inhibitors
• Other Study ID Numbers: AGS-AntiJak1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: A common format (Case Report Form, CRF) for all the centers involved in the study will be used to record data for each enrolled patient. In addition, all data related to the study have been and will be shared through a mailing list.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No