Janus Kinase (JAK) Inhibition in Aicardi–Goutières Syndrome (AGS)

Overview

The Aicardi-Goutieres Syndrome Advocacy Association (AGSAA), AGS experts, and AGS families overwhelmingly recommend the use of a class of drugs called “JAK inhibitors” to ameliorate the consequences of AGS disease activity. The mostly widely used and studied JAK inhibitor, baricitinib (brand name Olumiant), was originally developed for the treatment of rheumatoid arthritis and repurposed to treat AGS and other related conditions. This is called “off-label” use, a common practice in rare conditions. Depending on your location and the availability of these medicines, you might use ruxolitinib (brand name Jakafi), tofacitinib (brand name Xeljanz), or other “jakinibs” to the same effect; although we still recommend baricitinib for the safety, dosing, and efficacy information available to our disorder. AGS children and adults take this small, easily dissolvable pill multiple times a day at much higher doses than adults with rheumatoid arthritis to relieve inflammation caused by AGS. Studies have shown that AGS children of all ages and degrees of neurologic severity have the potential to benefit from baricitinib, including both improvements in their quality of life as well as the acquisition of developmental skills/milestones. Treatment with baricitinib requires a long term commitment, and its benefits may not be readily apparent. The primary goal of treatment is to offer protection against brain damage; no change is a good thing. However, many parents report an immediate improvement in irritability, sleep, and secondary symptoms (e.g. skin issues). JAK inhibition remains complex, requires careful monitoring for changes and events related to significant immunosuppression, and typically involves a multi-disciplinary approach. Nevertheless, AGS is a complex and serious disease that requires aggressive approaches.

Rationale

The Leukodystrophy Center of Excellence at the Children’s Hospital of Philadelphia (CHOP) has performed the most extensive research available with the Janus kinase inhibitor baricitinib. In an open label study that included 35 children on study for at least 12 months, the authors concluded that barcitinib can be of benefit to those living with AGS, regardless of their current condition.

The measurement of neurologic improvement is complex, but our data suggest improvement in neurologic function, even in patients with severe and long-standing disease.

Vanderver A, Adang L, Gavazzi F, et al. Janus Kinase Inhibition in the Aicardi-Goutières Syndrome. N Engl J Med. 2020;383(10):986-989. doi:10.1056/NEJMc2001362.

Consequently, the American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR) convened a task force a consisting of rheumatologists, neurologists, an immunologist, geneticists, patient advocates, and an allied health care professional formulated research questions for a systematic literature review. Then, based on literature, Delphi questionnaires, and consensus methodology, the ACR and EULAR developed “points to consider” to guide patient management. Collectively, the authority on AGS and other interferonopathies concluded the following points and recommend the use of JAK inhibitors.

Chronic systemic and organ-specific inflammation is present in patients with CANDLE/PRAAS, SAVI, and AGS. When untreated, chronic inflammation results in progressive organ damage, early morbidity, and increased mortality.

[…] The goal of treatment of autoinflammatory type I interferonopathies is to prevent and/or decrease systemic and organ inflammation, thereby improving the quality of life.

[…] For improving CANDLE/PRAAS, SAVI, and AGS symptoms, Janus kinase (JAK) inhibitors are beneficial.

Cetin Gedik K, Lamot L, Romano M, et al. The 2021 European Alliance of Associations for Rheumatology/American College of Rheumatology points to consider for diagnosis and management of autoinflammatory type i interferonopathies: CANDLE/PRAAS, SAVI, and AGS. Arthritis Rheumatol. Published online March 21, 2022. doi:10.1002/art.42087

At our 2022 AGS Family Symposium, Dr. Laura Adang discussed the benefits of barcitinib that were observed during their trial. Neurological benefits of baricitinib were demonstrated through a retrospective natural history study and the development of the AGS Scale.

References

• Vanderver A, Adang L, Gavazzi F, et al. Janus Kinase Inhibition in the Aicardi-Goutières Syndrome. N Engl J Med. 2020;383(10):986-989. doi:10.1056/NEJMc2001362

• Cetin Gedik K, Lamot L, Romano M, et al. The 2021 European Alliance of Associations for Rheumatology/American College of Rheumatology points to consider for diagnosis and management of autoinflammatory type i interferonopathies: CANDLE/PRAAS, SAVI, and AGS. Arthritis Rheumatol. Published online March 21, 2022. doi:10.1002/art.42087

• Sanchez GAM, Reinhardt A, Ramsey S, et al. JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies. J Clin Invest. 2018;128(7):3041-3052. doi:10.1172/JCI98814

• Children’s Hospital of Philadelphia. Online Pediatric Education Network. Aicardi Goutieres Syndrome: Diagnosis and Management. https://open.chop.edu/courses/aicardi-goutieres-syndrome-diagnosis-and-management/

• Baricitinib for use in monogenic interferonopathies (adults and children 2 years and over). The National Health Service (NHS). https://www.england.nhs.uk/publication/baricitinib-for-use-in-monogenic-interferonopathies-adults-and-children-2-years-and-over/

• Crow YJ, Shetty J, Livingston JH. Treatments in Aicardi-Goutières syndrome. Dev Med Child Neurol. 2020;62(1):42-47. doi:10.1111/dmcn.14268

• Adang L, Gavazzi F, De Simone M, et al. Developmental Outcomes of Aicardi Goutières Syndrome. J Child Neurol. 2020;35(1):7-16. doi:10.1177/0883073819870944

• Adang LA, Gavazzi F, Jawad AF, et al. Development of a neurologic severity scale for Aicardi Goutières Syndrome. Mol Genet Metab. 2020;130(2):153-160. doi:10.1016/j.ymgme.2020.03.008

• Kim H, Brooks KM, Tang CC, et al. Pharmacokinetics, Pharmacodynamics, and Proposed Dosing of the Oral JAK1 and JAK2 Inhibitor Baricitinib in Pediatric and Young Adult CANDLE and SAVI Patients. Clin Pharmacol Ther. 2018;104(2):364-373. doi:10.1002/cpt.936

• Children’s Hospital of Philadelphia.. Aicardi Goutières Syndrome (AGS) Diagnosis and Management Webinar. Jun 4, 2021. https://www.youtube.com/watch?v=iSDWelTzy_o

Clinical Trials

Baricitinib

• Phase 1 - A phase of research to describe clinical trials that focus on the safety of a drug. They are usually conducted with healthy volunteers, and the goal is to determine the drug's most frequent and serious adverse events and, often, how the drug is broken down and excreted by the body. These trials usually involve a small number of participants.

• Phase 2 - A phase of research to describe clinical trials that gather preliminary data on whether a drug works in people who have a certain condition/disease (that is, the drug's effectiveness).

It's important to note that researchers at CHOP decided that giving placebo to participants of the second phase trial would be inhumane because of the benefits that they observed in patients during the first phase. Still, they emphasized in PR materials that their phase 1 trial would not focus on assessing efficacy.

Dr. Vanderver emphasizes that the current project is not about testing whether or not baricitinib works. Instead, it focuses on the creation of appropriate assessments and biomarkers for testing the effectiveness of all proposed treatments for AGS.

Use of baricitinib in AGS spawned out of work by Dr. Goldbach-Mansky at the National Institute of Health (NIH). It was, in fact, the same phase 1 clinical trial. They transferred the study from the NIH to CHOP and began enrolling more children with AGS. The NIH did the original ground work of figuring out how to dose the drug and measure its effect on disease biomarkers. Unfortunately, we lost one child with AGS during the clinical trial; but the teams decided that it wasn't directly the cause of the drug and could be explained by complications from their disease.

The AGSAA provides the following resources to aid you when working with your doctors and insurances. Please email support@agsaa.org and we will provide you with all references and assist you.

JAK Inhibition, Insurance Appeal Letter Template

Most health insurances, whether national or private, will most likely summarily deny your initial request for coverage of JAK inhibitors. Your doctor may not involve you in this process, but we highly recommend advocating for yourself and submitting your own letter of appeal. We provide the following template which includes the appropriate references and rationale.