Janus kinase inhibition in Down syndrome: 2 cases of therapeutic benefit for alopecia areata
Open accessAbstract
Individuals with Down syndrome (DS) display widespread immune dysregulation, with much increased risk of diverse autoimmune and autoinflammatory skin conditions, including alopecia areata (AA).1,2 However, the molecular basis of this autoimmune profile remains to be elucidated. Trisomy 21 (T21), the genetic cause of DS, consistently activates the interferon (IFN) response in multiple cell types, causing hypersensitivity to IFN ligands, hyperactivation of downstream Janus kinase/signal transducer activator of transcription (JAK/STAT) signaling, significant overexpression of IFN-stimulated genes,3 and changes in the circulating proteome indicative of chronic autoinflammation with many ties to increased IFN signaling.
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JAK inhibitors have been successfully used to treat alopecia areata, psoriatic arthritis, and other autoimmune skin conditions in individuals with DS.
“we have reported instances of successful use of JAK inhibitors to treat alopecia areata, psoriatic arthritis, and other autoimmune skin conditions in individuals with DS.”
From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [96]
The Introduction and Case reports describe two individuals with Down syndrome whose alopecia areata improved with the JAK inhibitor tofacitinib. The Discussion mentions approval of tofacitinib for psoriatic arthritis and the prevalence of other autoimmune skin conditions in Down syndrome, but does not report successful treatment of those conditions in individuals with Down syndrome. (LLM, conf=0.90)
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Trisomy 21 consistently activates the interferon response
Sullivan, K. D., Lewis, H. C., Hill, A. A., Pandey, A., Jackson, L. P., Cabral, J. M., Smith, K. P., Liggett, L. A., Gomez, E. B., Galbraith, M. D., et al. (2016) · eLife · doi:10.7554/elife.16220 · Cited by 362 · see citing works
Self-citationTrisomy 21 causes changes in the circulating proteome indicative of chronic autoinflammation
Sullivan, K. D., Evans, D., Pandey, A., Hraha, T. H., Smith, K. P., Markham, N., Rachubinski, A. L., Wolter-Warmerdam, K., Hickey, F., Espinosa, J. M., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-13858-3 · Cited by 228 · cited 2× · see citing works
“Trisomy 21 (T21), the genetic cause of DS, consistently activates the interferon (IFN) response in multiple cell types, causing hypersensitivity to IFN ligands, hyperactivation of downstream Janus kinase/signal transducer activator of transcription (JAK/STAT) signaling, significant overexpression of IFN-stimulated gen…”
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- [1]Madan V. Williams J. Lear J.T. Dermatological manifestations of Down's syndrome Clin Exp Dermatol 31 5 2006 623 629 16901300
- [2]Sureshbabu R. Kumari R. Ranugha S. Sathyamoorthy R. Udayashankar C. Oudeacoumar P. Phenotypic and dermatological manifestations in Down Syndrome Dermatol Online J 17 2 2011 3 21382286
- [5]Islam N. Leung P.S. Huntley A.C. Gershwin M.E. The autoimmune basis of alopecia areata: a comprehensive review Autoimmun Rev 14 2 2015 81 89 25315746
- [6]Schepis C. Barone C. Siragusa M. Pettinato R. Romano C. An updated survey on skin conditions in Down syndrome Dermatology 205 3 2002 234 238 12399669
- [7]Marmon S. De Souza A. Strober B.E. Psoriasis and Down syndrome: a report of three cases and a potential pathophysiologic link Dermatol Online J 18 6 2012 13 22747937
- [8]Hall J.C. Rosen A. Type I interferons: crucial participants in disease amplification in autoimmunity Nat Rev Rheumatol 6 1 2010 40 49 20046205 PMC3622245
- [9]Shreberk-Hassidim R. Ramot Y. Zlotogorski A. Janus kinase inhibitors in dermatology: A systematic review J Am Acad Dermatol 76 4 2017 745 753.e719 28169015
- [10]O'Shea J.J. Kontzias A. Yamaoka K. Tanaka Y. Laurence A. Janus kinase inhibitors in autoimmune diseases Ann Rheum Dis 72 Suppl 2 2013 ii111 ii115 23532440 PMC3616338
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Waugh, K. A., Araya, P., Pandey, A., Jordan, K. R., Smith, K. P., Granrath, R. E., Khanal, S., Butcher, E. T., Estrada, B. E., Rachubinski, A. L., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.10.038 · Cited by 150 · see citing works
Self-citationWaugh, K. A., Minter, R., Baxter, J., Chi, C., Galbraith, M. D., Tuttle, K. D., Eduthan, N. P., Kinning, K. T., Andrysik, Z., Araya, P., et al. (2023) · Nature Genetics · doi:10.1038/s41588-023-01399-7 · Cited by 117 · see citing works
Self-citationGalbraith, M. D., Rachubinski, A. L., Smith, K. P., Araya, P., Waugh, K. A., Enriquez-Estrada, B., Worek, K., Granrath, R. E., Kinning, K. T., Paul Eduthan, N., et al. (2023) · Science Advances · doi:10.1126/sciadv.adg6218 · Cited by 88 · see citing works
Self-citationAraya, P., Niemeyer, B., Schade, K., Dunn, L. N., Waugh, K., Busquet, N., Brindley, C., Brown, C., Winkler, C., Lyford, H. R., et al. (2025) · iScience · doi:10.1016/j.isci.2025.113130 · Cited by 7 · see citing works
“Furthermore, these data indicate that triplication of HSA21 orthologous genes can alter the neuropathology in AD mice, exacerbating a decreased neuronal density, which could contribute to the fact that 5xFAD-DP16 mice exhibit impaired spatial learning and memory relative to models of AD or DS. ,61,62 To determine whet…”
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- Authors
- Rachubinski, A. L., Estrada, B. E., Norris, D., Dunnick, C. A., Boldrick, J. C., & Espinosa, J. M.
- Affiliations
- University of Colorado Anschutz (US)
- Veterans Health Administration (US)
- Palo Alto Medical Foundation (US)
- University of Colorado Boulder (US)
- Corresponding author
- Espinosa, Joaquin M.
- Venue
- JAAD Case Reports
- Publisher
- Elsevier BV
- Published
- 2019-04
- Volume
- 5
- Issue
- 4
- Pages
- 365-367
- ISSN
- 2352-5126 (ISSN-L)
- PMC
- PMC6453941
- OpenAlex
- W2932131298
- Cited by
- 51
- References
- 2
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 12 · 2023: 6 · 2022: 8 · 2021: 8 · 2020: 3 · 2019: 5
- FWCI
- 7.67
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- JAAD Case Reports (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- University of Colorado Linda Crnic Institute
- Global Down Syndrome Foundation
- Anna and John J. Sie Foundation
- Topics
- Health Sciences › Medicine › Urology › Hair Growth and Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- Down syndrome, alopecia areata, Janus kinase inhibition, JAK/STAT signaling, interferon signaling, immune dysregulation, autoinflammatory skin disease, autoimmune skin disease, interferon-stimulated genes
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