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Introduction: Aicardi–Goutières Syndrome (AGS) is a prototypic type I interferonopathy characterized by chronic interferon signalling, early-onset neuroinflammation, and frequently irreversible neurological damage. Janus kinase inhibitors (JAKi) have emerged as a targeted therapeutic option, but paediatric real-world data remain limited.

Methods: We retrospectively analysed four genetically confirmed paediatric AGS patients treated with ruxolitinib at a single centre and performed a systematic review of published AGS cases receiving JAKi. Clinical phenotype, treatment tolerance, and outcome were assessed descriptively.

Results: Our cohort included patients with IFIH1 (n=1), ADAR1 (n=2), and TREX1 (n=1) variants, spanning neonatal pseudo-TORCH disease to later-onset neurological phenotypes. Ruxolitinib was well tolerated and associated with clinically meaningful benefit in all four patients, including developmental progress, improved motor function, reduced feeding difficulties, and radiological stabilization or partial regression of cerebral abnormalities. The most pronounced benefit was observed when treatment was initiated during ongoing inflammatory activity before fixed damage had fully evolved, although relevant improvement was also seen after delayed initiation. The literature review identified 97 published AGS patients treated with JAKi. Among evaluable cases, 54.4% improved and 32.4% remained stable, whereas 4.4% deteriorated and 7.4% died. Neurological manifestations were present in 88% and improved or stabilized in most reported cases. Dermatological and constitutional features showed the highest response rates. Earlier treatment tended to be associated with greater functional gain. In contrast, changes in interferon signature did not consistently parallel clinical response.

Conclusion: JAK inhibition is a feasible and clinically meaningful treatment strategy in paediatric AGS, with benefits across neurological and extra-neurological domains. Clinical efficacy may occur despite persistently abnormal interferon biomarkers, highlighting the need for better response markers and optimized treatment concepts, particularly for CNS disease.

Disclosures: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

[1] Tüngler V, König N, Günther C, Engel K, Fiehn C, Smitka M, von der Hagen M, Berner R, Lee-Kirsch MA. Response to: 'JAK inhibition in STING-associated interferonopathy' by Crow et al. Ann Rheum Dis. 2016 Dec;75(12):e76. DOI: 10.1136/annrheumdis-2016-210565
[2] Kothur K, Bandodkar S, Chu S, Wienholt L, Johnson A, Barclay P, Brogan PA, Rice GI, Crow YJ, Dale RC. An open-label trial of JAK 1/2 blockade in progressive IFIH1-associated neuroinflammation. Neurology. 2018 Feb 6;90(6):289-291. DOI: 10.1212/WNL.0000000000004921
[3] McLellan KE, Martin N, Davidson JE, Cordeiro N, Oates BD, Neven B, Rice GI, Crow YJ. JAK 1/2 Blockade in MDA5 Gain-of-Function. J Clin Immunol. 2018 Nov;38(8):844-846. DOI: 10.1007/s10875-018-0563-2
[4] Sanchez GAM, Reinhardt A, Ramsey S, Wittkowski H, Hashkes PJ, Berkun Y, Schalm S, Murias S, Dare JA, Brown D, Stone DL, Gao L, Klausmeier T, Foell D, de Jesus AA, Chapelle DC, Kim H, Dill S, Colbert RA, Failla L, Kost B, O'Brien M, Reynolds JC, Folio LR, Calvo KR, Paul SM, Weir N, Brofferio A, Soldatos A, Biancotto A, Cowen EW, Digiovanna JJ, Gadina M, Lipton AJ, Hadigan C, Holland SM, Fontana J, Alawad AS, Brown RJ, Rother KI, Heller T, Brooks KM, Kumar P, Brooks SR, Waldman M, Singh HK, Nickeleit V, Silk M, Prakash A, Janes JM, Ozen S, Wakim PG, Brogan PA, Macias WL, Goldbach-Mansky R. JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies. J Clin Invest. 2018 Jul 2;128(7):3041-3052. DOI: 10.1172/JCI98814
[5] Meesilpavikkai K, Dik WA, Schrijver B, van Helden-Meeuwsen CG, Versnel MA, van Hagen PM, Bijlsma EK, Ruivenkamp CAL, Oele MJ, Dalm VASH. Efficacy of Baricitinib in the Treatment of Chilblains Associated With Aicardi-Goutières Syndrome, a Type I Interferonopathy. Arthritis Rheumatol. 2019 May;71(5):829-831. DOI: 10.1002/art.40805
[6] Tüngler V, Doebler-Neumann M, Salandin M, Kaufmann P, Wolf C, Lucas N, Harmuth F, Reichbauer J, Krägeloh-Mann I, Schüle R, Lee-Kirsch MA. Aicardi-Goutières syndrome due to a paternal mosaic IFIH1 mutation. Neurol Genet. 2019 Dec 19;6(1):e384. DOI: 10.1212/NXG.0000000000000384
[7] Zheng S, Lee PY, Wang J, Wang S, Huang Q, Huang Y, Liu Y, Zhou Q, Li T. Interstitial Lung Disease and Psoriasis in a Child With Aicardi-Goutières Syndrome. Front Immunol. 2020 May 20;11:985. DOI: 10.3389/fimmu.2020.00985
[8] Cattalini M, Galli J, Zunica F, Ferraro RM, Carpanelli M, Orcesi S, Palumbo G, Pinelli L, Giliani S, Fazzi E, Badolato R. Case Report: The JAK-Inhibitor Ruxolitinib Use in Aicardi-Goutieres Syndrome Due to ADAR1 Mutation. Front Pediatr. 2021 Oct 27;9:725868. DOI: 10.3389/fped.2021.725868
[9] Neven B, Al Adba B, Hully M, Desguerre I, Pressiat C, Boddaert N, Duffy D, Rice GI, Seabra L, Frémond ML, Blanche S, Crow YJ. JAK Inhibition in the Aicardi-Goutières Syndrome. N Engl J Med. 2020 Nov 26;383(22):2190-2191. DOI: 10.1056/NEJMc2031081
[10] Frémond ML, Hully M, Fournier B, Barrois R, Lévy R, Aubart M, Castelle M, Chabalier D, Gins C, Sarda E, Al Adba B, Couderc S, D' Almeida C, Berat CM, Durrleman C, Espil C, Lambert L, Méni C, Périvier M, Pillet P, Polivka L, Schiff M, Todosi C, Uettwiller F, Lepelley A, Rice GI, Seabra L, Sanquer S, Hulin A, Pressiat C, Goldwirt L, Bondet V, Duffy D, Moshous D, Bader-Meunier B, Bodemer C, Robin-Renaldo F, Boddaert N, Blanche S, Desguerre I, Crow YJ, Neven B. JAK Inhibition in Aicardi-Goutières Syndrome: a Monocentric Multidisciplinary Real-World Approach Study. J Clin Immunol. 2023 Aug;43(6):1436-1447. DOI: 10.1007/s10875-023-01500-z
[11] He T, Xia Y, Yang J. Systemic inflammation and chronic kidney disease in a patient due to the RNASEH2B defect. Pediatr Rheumatol Online J. 2021 Jan 22;19(1):9. DOI: 10.1186/s12969-021-00497-2
[12] Mura E, Masnada S, Antonello C, Parazzini C, Izzo G, Garau J, Sproviero D, Cereda C, Orcesi S, Veggiotti P, Zuccotti G, Dilillo D, Penagini F, Tonduti D. Ruxolitinib in Aicardi-Goutières syndrome. Metab Brain Dis. 2021 Jun;36(5):859-863. DOI: 10.1007/s11011-021-00716-5
[13] Haslak F, Kilic H, Sahin S, Hotaman B, Cebi NM, Yildiz M, Adrovic A, Gunalp A, Konte EK, Aslan E, Gul U, Akay N, Zindar Y, Ulug F, Guler S, Kiykim A, Aydemir S, Barut K, Saltik S, Cokugras HC, Kasapcopur O. Children With Type I Interferonopathy: Commonalities and Diversities in a Large Patient Cohort. J Rheumatol. 2024 Dec 1;51(12):1208-1217. DOI: 10.3899/jrheum.2024-0294
[14] Alburaiky S, Dale RC, Crow YJ, Jones HF, Wassmer E, Melki I, Boespflug-Tanguy O, Do Cao J, Gras D, Sharpe C. Opsoclonus-myoclonus in Aicardi-Goutières syndrome. Dev Med Child Neurol. 2021 Dec;63(12):1483-1486. DOI: 10.1111/dmcn.14969
[15] Zhang S, Song J, Yang Y, Miao H, Yang L, Liu Y, Zhang X, Liu Y, Wang T. Type I interferonopathies with novel compound heterozygous TREX1 mutations in two siblings with different symptoms responded to tofacitinib. Pediatr Rheumatol Online J. 2021 Jan 6;19(1):1. DOI: 10.1186/s12969-020-00490-1
[16] Casas-Alba D, Darling A, Caballero E, Mensa-Vilaró A, Bartrons J, Antón J, García-Cazorla À, Vanderver A, Armangué T. Efficacy of baricitinib on chronic pericardial effusion in a patient with Aicardi-Goutières syndrome. Rheumatology (Oxford). 2022 Apr 11;61(4):e87-e89. DOI: 10.1093/rheumatology/keab860
[17] Jones HF, Stoll M, Ho G, O'Neill D, Han VX, Paget S, Stewart K, Lewis J, Kothur K, Troedson C, Crow YJ, Dale RC, Mohammad SS. Autosomal dominant ADAR c.3019G>A (p.(G1007R)) variant is an important mimic of hereditary spastic paraplegia and cerebral palsy. Brain Dev. 2022 Feb;44(2):153-160. DOI: 10.1016/j.braindev.2021.10.001
[18] Kuang SY, Li Y, Yang SL, Han X. Child Neurology: Aicardi-Goutières Syndrome Presenting as Recurrent Ischemic Stroke. Neurology. 2022 Aug 30;99(9):393-398. DOI: 10.1212/WNL.0000000000200952
[19] Li W, Wang W, Wang W, Zhong L, Gou L, Wang C, Ma J, Quan M, Jian S, Tang X, Zhang Y, Wang L, Ma M, Song H. Janus Kinase Inhibitors in the Treatment of Type I Interferonopathies: A Case Series From a Single Center in China. Front Immunol. 2022 Mar 28;13:825367. DOI: 10.3389/fimmu.2022.825367
[20] Panigrahy N, Bakhru S, Lingappa L, Chirla D. Aicardi-Goutières syndrome (AGS): recurrent fetal cardiomyopathy and pseudo-TORCH syndrome. BMJ Case Rep. 2022 Dec 29;15(12):e249192. DOI: 10.1136/bcr-2022-249192
[21] Pararajasingam A, Bradley RE, Evans J, Lowe A, Goodwin R, Jolles S. Case Report: Generalised Panniculitis as a Post-COVID-19 Presentation in Aicardi-Goutières Syndrome Treated With Ruxolitinib. Front Pediatr. 2022 Apr 25;10:837568. DOI: 10.3389/fped.2022.837568
[22] Bin Khathlan Y, Almutairi S, Albadr FB, Alangari AA, Alsultan A. Case report: Durable response to ruxolitinib in a child with TREX1-related disorder. Front Pediatr. 2023 Apr 28;11:1178919. DOI: 10.3389/fped.2023.1178919
[23] Nimri J, Nguyen J, Lalani S, Patel K, Mysore K, O’Garro G, et al. Response to Tofacitinib in an Infant with Aicardi-Goutie`res Syndrome due to Biallelic Variants in RNU7-1. Clin Immunol. 2023;205 Supplement:109539. DOI: 10.1016/j.clim.2023.109539
[24] Sorokina LS, Raupov RK, Kostik MM. Juvenile Dermatomyositis and Infantile Cerebral Palsy: Aicardi-Gouteres Syndrome, Type 5, with a Novel Mutation in SAMHD1-A Case Report. Biomedicines. 2023 Jun 12;11(6):1693. DOI: 10.3390/biomedicines11061693
[25] Galli J, Cattalini M, Loi E, Ferraro RM, Giliani S, Orcesi S, Pinelli L, Badolato R, Fazzi E. Treatment response to Janus kinase inhibitor in a child affected by Aicardi-Goutières syndrome. Clin Case Rep. 2023 Jul 31;11(8):e7724. DOI: 10.1002/ccr3.7724
[26] Kanazawa N, Ishii T, Takita Y, Nishikawa A, Nishikomori R. Efficacy and safety of baricitinib in Japanese patients with autoinflammatory type I interferonopathies (NNS/CANDLE, SAVI, And AGS). Pediatr Rheumatol Online J. 2023 Apr 22;21(1):38. DOI: 10.1186/s12969-023-00817-8
[27] Wang W, Wang W, Peng S, Gao S, Quan M, Gou L, Wang C, Sun Z, Li Z, Lian D, Song H. Tocilizumab reduces the unmanageable inflammatory reaction of a patient with Aicardi-Goutières syndrome type 7 during treatment with ruxolitinib. Pediatr Rheumatol Online J. 2023 Oct 12;21(1):117. DOI: 10.1186/s12969-023-00899-4
[28] Ryckmans C, Donge M, Marchèse A, Mastouri M, Thomee C, Stouffs K, Lieser SL, Scalais E. TREX-1 related Aicardi-Goutières syndrome improved by Janus kinase inhibitor. Am J Med Genet A. 2024 May;194(5):e63510. DOI: 10.1002/ajmg.a.63510
[29] Jafarpour S, Suddock J, Hawes D, Santoro JD. Neuropathologic Impacts of JAK Inhibitor Treatment in Aicardi-Goutières Syndrome. J Clin Immunol. 2024 Feb 21;44(3):68. DOI: 10.1007/s10875-024-01672-2
[30] Gabaldon-Albero A, Martin-Grau C, Marti-Masanet M, Lopez-Jimenez A, Llorens R, Beseler-Soto B, Martin-Zamora S, Lopez B, Calvo I, Hernandez-Muela S, Rosello M, Orellana C, Martinez F. Aicardi-Goutières syndrome type 6: report of ADAR variant and clinical outcome after ruxolitinib treatment in the neonatal period. Pediatr Rheumatol Online J. 2024 Dec 28;22(1):110. DOI: 10.1186/s12969-024-01036-5
[31] Spracklen TF, Akhalwaya S, Ackermann S, Uggenti C, Seabra L, Crow YJ, Webb K. Baricitinib Treatment in RNU7-1-Associated Aicardi-Goutières Syndrome in a South African Child: A Case Report. Am J Med Genet A. 2025 May;197(5):e63978. DOI: 10.1002/ajmg.a.63978
[32] Železnik M, Soltirovska Šalamon A, Debeljak M, Goropevšek A, Šuštar N, Ključevšek D, Ihan A, Avčin T. Case report: Pneumocystis jirovecii pneumonia in a severe case of Aicardi-Goutières syndrome with an IFIH1 gain-of-function mutation mimicking combined immunodeficiency. Front Immunol. 2023 Jan 4;13:1033513. DOI: 10.3389/fimmu.2022.1033513
[33] Beerepoot S, Grinwis L, Vanderver AL, van der Knaap MS, Kuijpers TW. Tofacitinib treatment for psoriatic skin lesions associated with Aicardi-Goutières syndrome 7/Singleton-Merten syndrome 1. Orphanet J Rare Dis. 2025 Apr 2;20(1):155. DOI: 10.1186/s13023-025-03675-7
[34] Hou L, Zhou P, Du Y, Wang X, Zhao C. Short-term efficacy of tofacitinib, a JAK inhibitor, in IFIH1-related Aicardi-Goutières syndrome. Eur J Med Genet. 2025 Jun;75:105006. DOI: 10.1016/j.ejmg.2025.105006
[35] Kollia M, Mouskou S, Mentesidou L, Syggelou A, Anagnostopoulou K, Maritsi DN. Myasthenia Gravis as a Manifestation of Aicardi-Goutières Syndrome Due to a SAMHD1 Variant Successfully Treated With Baricitinib. Cureus. 2025 Sep 2;17(9):e91485. DOI: 10.7759/cureus.91485
[36] Roest KL, Hak ALE, van Leeuwen EMM, de Bree GJ, Kwakernaak AJ. Mimickers of Systemic Lupus Erythematosus: Case Series and Literature Overview. J Clin Med. 2025 Oct 7;14(19):7070. DOI: 10.3390/jcm14197070
[37] Yamazaki S, Kaneko S, Shimbo A, Irabu H, Ogino R, Miyamoto T, Izawa K, Segawa Y, Kakizaki J, Mori M, Shimizu M. Overlapping Aicardi-Goutières and Singleton-Merten syndromes with a heterozygous gain-of-function mutation in IFIH1 mimicking juvenile idiopathic arthritis. Immunol Med. 2025 Sep;48(3):256-260. DOI: 10.1080/25785826.2025.2479148
[38] Liu R, Kretschmer S, Switala P, Attia M, Lee-Kirsch MA, Wolf C. Discordant phenotype caused by TREX1 variant in siblings with Aicardi-Goutières syndrome. Pediatr Rheumatol Online J. 2025 Nov 5;23(1):110. DOI: 10.1186/s12969-025-01168-2
[39] Yoganathan S, Seth S, Venkateswaran S, Lim WK, LeBlanc-Millar A, Breitbart S, Pai V, Doja A, Fasano A, Ibrahim GM, Gorodetsky C. Deep Brain Stimulation in a Child with Aicardi-Goutières Syndrome-7 (AGS7): A Case Report and Literature Review. Mov Disord Clin Pract. 2025 Dec;12(12):2375-2378. DOI: 10.1002/mdc3.70204
[40] Emreol HE, Ünal D, Ayvaz DNC, Bilginer Y, Özen S. One mutation, divergent journeys: expanding the clinical spectrum of homozygous SAMHD1 deficiency in childhood. Rheumatology (Oxford). 2026 Jan 8;65(1):keaf695. DOI: 10.1093/rheumatology/keaf695
[41] Marinella G, Vaia Y, Politano D, Galli J, Nicita F, Popple MM, Pichiecchio A, Pasquariello R, Parazzini C, Pinelli L, Longo D, Severino M, Fazzi E, Orcesi S, Tonduti D, Battini R; AGS Study Group; Orsini A, Zunica F, Arrigoni F, Nicolosi S, Insalaco A, Cattalini M, Cordelli DM, Soliani L, Fetta A, Operto FF, Amadori E, Mancardi MM, Volpi S, Orsi SM. Efficacy of JAK1/2 inhibitors in AGS genes-related interferonopathies: A multicenter retrospective observational study with treated vs untreated comparison. Mol Genet Metab. 2026 Jun;148(2):109907. DOI: 10.1016/j.ymgme.2026.109907
[42] Gonzalez Saez-Diez E, Ferrer Socorro M, Yang K, Battaglia N, Zaman Z, Bennett M, Vanderver A, Lee PY, Henderson LA, Andzelm MM, Ebrahimi-Fakhari D. Movement Disorders in Aicardi-Goutières Syndrome and Response to Immunomodulation. Ann Clin Transl Neurol. 2026 Apr 25. DOI: 10.1002/acn3.70407