Bogle, Rachael

Abstract Dermatomyositis is driven by overactivation of type I and II interferons and other proinflammatory cytokines that signal via the JAK-STAT pathway. We conducted a 12-week, open-label study of brepocitinib, an oral TYK2/JAK1 inhibitor, in five adults with severe cutaneous dermatomyositis. Treatment was associated with rapid, clinically meaningful improvement in cutaneous disease activity. Single-cell and spatial transcriptomic profiling of lesional skin showed marked suppression of interferon-responsive pathways and inflammatory cell states by week 4. Together with findings from a Phase 3 randomized trial in DM patients with skin and muscle involvement (VALOR, NCT05437263 ), these data support TYK2/JAK1 inhibition as a promising therapeutic strategy for DM.

Abstract Lichen Planopilaris (LPP) is a lymphocyte-mediated scarring alopecia characterized by progressive follicular destruction and fibrosis. In this clinical trial, patients with biopsy proven LPP were treated with deucravacitinib (an oral inhibitor of tyrosine kinase 2 (TYK2)) 6 mg BID for 24 weeks (NCT-06091956). Bulk and single-cell RNA sequencing was performed on paired pre- and post-treatment scalp biopsies from baseline and week 4. Patients (N=10) demonstrated improvements in PGA (88.9%, p=0.008), LPPAI (−2.3 points, SD 1.1, p=0.002) and Skindex-16 (−21.0 points, SD 22.1, p=0.014) scores at week 24. Bulk transcriptomic analysis of untreated LPP revealed upregulation of type I Interferon (IFN)-stimulated genes and pathways related to inflammation, immune activation, keratinization, and extracellular matrix remodelling, with downregulation of immune and inflammatory pathways following treatment. Single-cell RNA-seq of LPP was characterized by enrichment of CD8+GZMK+ T cells which showed downregulation of T-cell receptor signaling as well as antiviral pathways with treatment. Basal keratinocytes exhibited reduced cytokine and interferon signaling and decreased communication with NK cells following treatment. CCL19+ fibroblasts were prominent in untreated disease was attenuated after treatment, with downregulation of type I IFN signaling. Selective TYK2 inhibition with deucravacitinib effectively suppresses these inflammatory circuits in LPP and represents a promising therapeutic strategy.

BACKGROUND: Whereas antiphospholipid syndrome (APS) is best known for increasing the risk of macrovascular thrombosis, APS vasculopathy is characterized by the abnormal proliferation of endothelial and smooth muscle cells, leading to occlusion of small blood vessels in the skin, kidneys, and heart, among other organs. The underlying mechanisms remain unclear, and targeted treatment options for patients with APS are lacking. METHODS: To identify and analyze APS microvascular endothelial cells (MVECs), skin biopsies of patients with APS complicated by livedo racemosa were characterized using single-cell RNA sequencing. CCN1 (cellular communication network factor 1) and CCN2 were identified in skin and kidney biopsies by immunofluorescence microscopy and in plasma by ELISA. Healthy dermal MVECs were cultured with APS patient–derived serum or immunoglobulin G (IgG), and relevant signaling pathways were characterized using quantitative PCR, immunoblotting, and immunofluorescence microscopy. The proliferation and migration of vascular smooth muscle cells were determined after exposure to conditioned medium from APS IgG–stimulated MVECs. A mouse model of APS IgG–accelerated neointima formation was developed. Anti-CCN2 monoclonal antibodies were tested in vascular smooth muscle cell functional assays and the mouse model. RESULTS: Increased endothelial cell expression of CCN1 and CCN2 was identified by single-cell RNA sequencing and further confirmed in APS skin by microscopy as well as in APS plasma by ELISA. Exposure of healthy MVECs to patient IgG triggered the upregulation of CCN1 and CCN2 via Toll-like receptor 4– and YAP1 (yes-associated protein 1)–mediated signaling. CCN2, originating from APS IgG–stimulated MVECs led to the proliferation and migration of vascular smooth muscle cells, phenotypes that were inhibited by an anti-CCN2 antibody or depletion of EGFR (epidermal growth factor receptor). We further observed increased expression of CCN2, along with evidence of YAP1 nuclear translocation, in kidney vessels of APS nephropathy biopsies. Finally, CCN2 inhibition with an anti-CCN2 monoclonal antibody significantly reduced neointima thickening and cell proliferation in a mouse model of APS IgG–accelerated neointima formation. CONCLUSIONS: This study revealed activation of YAP1-mediated signaling in APS dermal microvessels and demonstrated that the YAP1 target CCN2 plays a role in facilitating pro-proliferative communication between MVECs and vascular smooth muscle cells. These findings offer insights into the cellular and molecular mechanisms underlying APS vasculopathy, providing potential therapeutic targets for patients.

BACKGROUND Cutaneous lichen planus (LP) is a recalcitrant, difficult-to-treat, inflammatory skin disease characterized by pruritic, flat-topped, violaceous papules on the skin. Baricitinib is an oral Janus kinase (JAK) 1/2 inhibitor that interrupts the signaling pathway of IFN-γ, a cytokine implicated in the pathogenesis of LP. METHODS In this phase II trial, 12 patients with cutaneous LP received 2 mg daily baricitinib for 16 weeks, accompanied by in-depth spatial, single-cell, and bulk transcriptomic profiling of pre- and posttreatment samples. RESULTS An early and sustained clinical response was seen, with 83.3% of patients responsive at week 16. Our molecular data identified a unique, oligoclonal IFN-γ, CD8 + , and CXCL13 + cytotoxic T cell population in LP skin and demonstrated a rapid decrease in IFN signature within 2 weeks of treatment, most prominently in the basal layer of the epidermis. CONCLUSION This study demonstrates the efficacy and molecular mechanisms of JAK inhibition in LP. TRIAL REGISTRATION NCT05188521 FUNDING Eli Lilly, Appignani Benefactor Funds, 5P30AR075043, Mayo Clinic Clinical Trials Stimulus Funds.