Genetic Diagnosis Guides Treatment of Autoimmune Enteropathy

Charbit‐Henrion, Fabienne; Haas, Manon; Chaussade, Stanislas; Cellier, Christophe; Cerf‐Bensussan, Nadine; Malamut, Georgia; Khater, Shérine; Khiat, Anis; Cording, Sascha; Parlato, Marianna; Dragon-Durey, Marie-Agnès; Beuvon, Frédéric; Brousse, Nicole; Terris, Benoı̂t; Pïcard, Capucine; Fusaro, Mathieu; Rieux-Laucat, Frédéric; Stolzenberg, Marie-Claude; Jannot, Anne‐Sophie; Mathian, Alexis; Allez, Matthieu; Malphettes, Marion; Fieschi, Claire; Aubourg, Alexandre; Zallot, Camille; Roblin, Xavier; Abitbol, Véred; Belle, Arthur; Wils, Pauline; Cheminant, Morgane; Matysiak‐Budnik, Tamara; Vuitton, Lucine; Pouderoux, Philippe; Abramowitz, Laurent; Castelle, Martin; Suarez, Félipe; Hermine, Olivier; Ruemmele, Frank M; Mouthon, Luc

doi:10.1016/j.cgh.2022.07.030

Cited by 6 publications

(2 citation statements)

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“…A bias in recruitment is plausible. Indeed, we and others have reported GI inflammation, notably affecting the small bowel and manifesting as celiac-like autoimmunity refractory to gluten-free diet, in a substantial fraction of patients with pathogenic variants leading to JAK-STAT hyperactivation, including STAT3 GOF, STAT1 GOF, JAK1 GOF variants, and PTNP2 HI [ 4 , 5 , 10 , 19 ]. The present observations of Crohn’s disease-like ileo-colic chronic inflammation in P1 and CIPO caused by lymphocytic leiomyositis in P2 expands the phenotypic spectrum of SOCS1 HI and further stress the importance to strictly control the JAK-STAT pathway to preserve intestinal homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…Yet, obtaining a molecular diagnosis as early as possible is crucial to guide treatment and to offer the possibility of genetic counseling. Moreover, as we have recently shown in patients with autoimmune enteropathy, identification of a genetic variant was associated with increased and early risk of malignancy, including lymphoma [ 19 ], stressing the need of close follow-up. Along this line, the CD8 + T-cell expansion infiltrating P2’ muscularis mucosa contained a conspicuous T-cell clone.…”

Section: Discussionmentioning

confidence: 99%

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Insights into the expanding intestinal phenotypic spectrum of SOCS1 haploinsufficiency and therapeutic options

et al. 2023

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Purpose Hyper activation of the JAK-STAT signaling underlies the pathophysiology of many human immune–mediated diseases. Herein, the study of 2 adult patients with SOCS1 haploinsufficiency illustrates the severe and pleomorphic consequences of its impaired regulation in the intestinal tract. Methods Two unrelated adult patients presented with gastrointestinal manifestations, one with Crohn’s disease-like ileo-colic inflammation refractory to anti-TNF and the other with lymphocytic leiomyositis causing severe chronic intestinal pseudo-occlusion. Next-generation sequencing was used to identify the underlying monogenic defect. One patient received anti-IL-12/IL-23 treatment while the other received the JAK1 inhibitor, ruxolitinib. Peripheral blood, intestinal tissues, and serum samples were analyzed before-and-after JAK1 inhibitor therapy using mass cytometry, histology, transcriptomic, and Olink assay. Results Novel germline loss-of-function variants in SOCS1 were identified in both patients. The patient with Crohn-like disease achieved clinical remission with anti-IL-12/IL-23 treatment. In the second patient with lymphocytic leiomyositis, ruxolitinib induced rapid resolution of the obstructive symptoms, significant decrease of the CD8+ T lymphocyte muscular infiltrate, and normalization of serum and intestinal cytokines. Decreased frequencies of circulating Treg cells, MAIT cells, and NK cells, with altered CD56bright:CD16lo:CD16hi NK subtype ratios were not modified by ruxolitinib. Conclusion SOCS1 haploinsufficiency can result in a broad spectrum of intestinal manifestations and need to be considered as differential diagnosis in cases of severe treatment-refractory enteropathies, including the rare condition of lymphocytic leiomyositis. This provides the rationale for genetic screening and considering JAK inhibitors in such cases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%