ESPEYB21 8. Adrenals New Hope (3 abstracts)
8.13. The role of interferon-[gamma] in autoimmune polyendocrine syndrome Type 1
Oikonomou V , Smith G , Constantine GM , Schmitt MM , Ferré EMN , Alejo JC , Riley D , Kumar D , Dos Santos Dias L , Pechacek J , Hadjiyannis Y , Webb T , Seifert BA , Ghosh R , Walkiewicz M , Martin D , Besnard M , Snarr BD , Deljookorani S , Lee CR , DiMaggio T , Barber P , Rosen LB , Cheng A , Rastegar A , de Jesus AA , Stoddard J , Kuehn HS , Break TJ , Kong HH , Castelo-Soccio L , Colton B , Warner BM , Kleiner DE , Quezado MM , Davis JL , Fennelly KP , Olivier KN , Rosenzweig SD , Suffredini AF , Anderson MS , Swidergall M , Guillonneau C , Notarangelo LD , Goldbach-Mansky R , Neth O , Monserrat-Garcia MT , Valverde-Fernandez J , Lucena JM , Gomez-Gila AL , Garcia Rojas A , Seppänen MRJ , Lohi J , Hero M , Laakso S , Klemetti P , Lundberg V , Ekwall O , Olbrich P , Winer KK , Afzali B , Moutsopoulos NM , Holland SM , Heller T , Pittaluga S & Lionakis MS
N Engl J Med. 2024; 390(20): 1873-1884. https://pubmed.ncbi.nlm.nih.gov/38810185/
Brief Summary: This study suggests that excessive interferon-γ–mediated responses have a pathogenic role in APS-1 and provides the foundation for therapies that affect interferon-γ–mediated disease.
Commentary: Autoimmune polyendocrine syndrome type 1 (APS-1), also known as autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED), is an autosomal recessive multiorgan syndrome caused by loss-of-function variants in AIRE, the gene encoding autoimmune regulator (1-3). In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. APS-1 manifests in childhood with a characteristic triad of chronic mucocutaneous candidiasis, adrenal insufficiency, and hypoparathyroidism, alongside numerous other endocrine and nonendocrine diseases (4-6). Mortality can exceed 30% despite supportive care (7). Although progress has been made in the treatment of certain tissue-specific autoimmune manifestations, no therapy targets the multiorgan nature of APS-1.
These authors performed exploratory studies in patients with APS-1 and in Aire−/− mice to study mechanisms of T-cell–mediated tissue injury and to test therapeutic strategies. Their findings suggested that APS-1 is an interferon-γ– mediated disease. Patients with APS-1 had enhanced interferon-γ responses in blood and in all examined autoimmunity-affected tissues. Aire-/- mice had selectively increased interferon-γ production by T cells and enhanced interferon-γ, phosphorylated signal transducer and activator of transcription 1 (pSTAT1), and CXCL9 signals in multiple organs. Ifng ablation or ruxolitinib-induced JAK-STAT blockade in Aire-/- mice normalized interferon-γ responses and averted T-cell infiltration and damage in organs. They then treated 5 patients with APS-1 with ruxolitinib, a Food and Drug Administration (FDA)–approved Janus kinase (JAK) 1 and 2 inhibitor (15-17). Ruxolitinib led to decreased levels of T-cell-derived interferon-γ, normalized interferon-γ and CXCL9 levels, and remission of alopecia, oral candidiasis, nail dystrophy, gastritis, enteritis, arthritis, Sjögren’s-like syndrome, urticaria, and thyroiditis. No serious adverse effects were observed.
These findings indicate that APS-1 is characterized by excessive, multiorgan interferon-γ-mediated responses. JAK inhibition with ruxolitinib in five patients showed promising results.
These data provide new insights into the mechanism and pathophysiological basis of APS-1 and uncover important targets for therapeutic intervention.
References: 1. Oftedal BE, Hellesen A, Erichsen MM, et al. Dominant mutations in the autoimmune regulator AIRE are associated with common organ-specific autoimmune diseases. Immunity 2015; 42: 1185-96.2. Ricotta EE, Ferré EMN, Schmitt MM, DiMaggio T, Lionakis MS. Prevalence of APECED-like clinical disease in an electronic health record database, USA. J Clin Immunol 2022; 42: 904-6.3. Constantine GM, Lionakis MS. Lessons from primary immunodeficiencies: autoimmune regulator and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Immunol Rev 2019; 287: 103-20.4. Ahonen P, Myllärniemi S, Sipilä I, Perheentupa J. Clinical variation of autoimmune polyendocrinopathy-candidiasisectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med 1990; 322: 1829-36.5. Bruserud Ø, Oftedal BE, Landegren N, et al. A longitudinal follow-up of autoimmune polyendocrine syndrome type 1. J Clin Endocrinol Metab 2016; 101: 2975-83.6. Ferre EMN, Rose SR, Rosenzweig SD, et al. Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. JCI Insight 2016; 1(13): e88782.7. Borchers J, Pukkala E, Mäkitie O, Laakso S. Patients with APECED have increased early mortality due to endocrine causes, malignancies and infections. J Clin Endocrinol Metab 2020; 105(6): e2207-e2213.8. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med 2015; 372: 426-35.9. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 2012; 366: 799-807.10. Zeiser R, Polverelli N, Ram R, et al. Ruxolitinib for glucocorticoid-refractory chronic graft-versus-host disease. N Engl J Med 2021; 385: 228-38.
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