Efficacy of JAK1/2 inhibition in the treatment of chilblain lupus due to TREX1 deficiency

Briand, C.; Frémond, Marie-Louise; Bessis, Didier; Carbasse, Aurélia; Rice, Gillian I.; Bondet, Vincent; Duffy, Darragh; Chatenoud, Lucienne; Blanche, Stéphane; Crow, Yanick J.; Neven, Bénédicte

doi:10.1136/annrheumdis-2018-214037

Cited by 53 publications

(37 citation statements)

References 7 publications

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“…Accordingly, JAK inhibitors provided beneficial effects in diseases featuring ID including graft-versushost disease (36) and dermatomyositis (37) besides other inflammatory skin conditions (38). In CLE, JAK1/2 inhibitors ruxolitinib (39,40) and baricitinib (41) as well as JAK1/3 inhibitor tofacitinib (42) have been reported to be successful in patient's treatment, and these drugs significantly decrease the expression of CLE-typical chemokines in vitro (43,44).…”

Section: Discussionmentioning

confidence: 99%

Selective Janus Kinase 1 Inhibition Is a Promising Therapeutic Approach for Lupus Erythematosus Skin Lesions

et al. 2020

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Background: Cutaneous lupus erythematosus (CLE) is an interferon (IFN)-driven autoimmune skin disease characterized by an extensive cytotoxic lesional inflammation with activation of different innate immune pathways. Aim of our study was to investigate the specific role of Janus kinase 1 (JAK1) activation in this disease and the potential benefit of selective JAK1 inhibitors as targeted therapy in a preclinical CLE model. Methods: Lesional skin of patients with different CLE subtypes and healthy controls (N = 31) were investigated on JAK1 activation and expression of IFN-associated mediators via immunohistochemistry and gene expression analyses. The functional role of JAK1 and efficacy of inhibition was evaluated in vitro using cultured keratinocytes stimulated with endogenous nucleic acids. Results were confirmed in vivo using an established lupus-prone mouse model. Results: Proinflammatory immune pathways, including JAK/STAT signaling, are significantly upregulated within inflamed CLE skin. Here, lesional keratinocytes and dermal immune cells strongly express activated phospho-JAK1. Selective pharmacological JAK1 inhibition significantly reduces the expression of typical proinflammatory mediators such as CXCL chemokines, BLyS, TRAIL, and AIM2 in CLE in vitro models and also improves skin lesions in lupus-prone TREX1 −/−-mice markedly. Conclusion: IFN-associated JAK/STAT activation plays a crucial role in the pathophysiology of CLE. Selective inhibition of JAK1 leads to a decrease of cytokine expression, reduced immune activation, and decline of keratinocyte cell death. Topical treatment with a JAK1-specific inhibitor significantly improves CLE-like skin lesions in a lupus-prone TREX1 −/−-mouse model and appears to be a promising therapeutic approach for CLE patients.

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Section: Discussionmentioning

confidence: 99%

Selective Janus Kinase 1 Inhibition Is a Promising Therapeutic Approach for Lupus Erythematosus Skin Lesions

et al. 2020

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“…Although the current state of investigation does not allow for clear linkage of the distinct molecular pathways underlying each of these monogenic disorders to specific clinical manifestations of multigenic complex diseases, such as SLE, it is reasonable to propose that in addition to the immunopathologic effects of type I IFN, the pathogenesis of SLE may also require the production of autoantibodies and immune complexes that contribute to organ inflammation. AGS, CANDLE or SAVI have been refractory to most of the immunosuppressive medications used in SLE, but promising data are emerging from studies of Jak inhibition [131][132][133] . The Jak inhibitor baricitinib results in particularly striking responses in patients with CANDLE 133 .…”

Section: Ifn Signatures In Autoinflammatory Diseasesmentioning

confidence: 99%

Interferon target-gene expression and epigenomic signatures in health and disease

2019

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Multiple type I interferons and interferon-γ (IFN-γ) are expressed under physiological conditions and are increased by stress and infections, and in autoinflammatory and autoimmune diseases. Interferons activate the Jak-STAT signaling pathway and induce overlapping patterns of expression, called 'interferon signatures', of canonical interferon-stimulated genes (ISGs) encoding molecules important for antiviral responses, antigen presentation, autoimmunity and inflammation. It has now become clear that interferons also induce an 'interferon epigenomic signature' by activating latent enhancers and 'bookmarking' chromatin, thus reprogramming cell responses to environmental cues. The interferon epigenomic signature affects ISGs and other gene sets, including canonical targets of the transcription factor NF-κB that encode inflammatory molecules, and is involved in the priming of immune cells, tolerance and the training of innate immune memory. Here we review the mechanisms through which interferon signatures and interferon epigenomic signatures are generated, as well as the expression and functional consequences of these signatures in homeostasis and autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis and systemic sclerosis.

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“…Of note, a handful of recent reports suggest encouraging results with the use of Janus kinase (JAK) inhibition in several distinct type I interferonopathies, with JAK1 comprising an essential component of the type I interferon receptor complex. We have seen definite improvement in TREX1‐related skin disease and IFIH1‐determined systemic inflammation with the JAK1/2 inhibitor, ruxolitinib. We also described a child with a gain‐of‐function mutation in IFIH1 , apparently demonstrating significant developmental gains, against a background of previous regression and then stagnation, with ruxolitinib therapy .…”

Section: Implications For Therapies Derived From Insights Into Pathogmentioning

confidence: 81%

Treatments in Aicardi–Goutières syndrome

Crow

Shetty

Livingston

2019

Develop Med Child Neuro

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AGSAicardi-Gouti eres syndrome RTI Reverse transcriptase inhibitor Comprehensive reviews of the clinical characteristics and pathogenesis of Aicardi-Gouti eres syndrome (AGS), particularly its contextualization within a putative type I interferonopathy framework, already exist. However, recent reports of attempts at treatment suggest that an assessment of the field from a therapeutic perspective is warranted at this time. Here, we briefly summarize the neurological phenotypes associated with mutations in the seven genes so far associated with AGS, rehearse current knowledge of the pathology as it relates to possible treatment approaches, critically appraise the potential utility of therapies, and discuss the challenges in assessing clinical efficacy.

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Efficacy of JAK1/2 inhibition in the treatment of chilblain lupus due to TREX1 deficiency

Cited by 53 publications

References 7 publications

Selective Janus Kinase 1 Inhibition Is a Promising Therapeutic Approach for Lupus Erythematosus Skin Lesions

Selective Janus Kinase 1 Inhibition Is a Promising Therapeutic Approach for Lupus Erythematosus Skin Lesions

Interferon target-gene expression and epigenomic signatures in health and disease

Treatments in Aicardi–Goutières syndrome

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