2026-07-11 | USP18 regulates skeletal muscle regeneration independently of its deISGylation activity.

USP18 is a multifunctional protein that attenuates type I interferon (IFN-I) signalling and regulates ISG15-mediated ISGylation. Although USP18 has been suggested to suppress myogenic differentiation in vitro, its role in muscle regeneration and inflammatory muscle disease remains unclear. This study aimed to define the spatial localization and functional contribution of USP18 and ISG15 in inflamed and regenerating muscle. USP18 function in myogenesis was examined using inducible knockout and catalytic-inactive mutant muscle cell models. Spatial expression of USP18 and ISG15 was analyzed by quantitative imaging in mouse models of muscular dystrophy, cardiotoxin-induced injury, and healthy muscle, with validation in dermatomyositis patient biopsies. USP18 depletion enhanced myogenesis and mitochondrial activity in vitro. Importantly, a catalytic-inactive USP18 mutant regulated myogenesis comparably to the wild-type protein, demonstrating that USP18 acts independently of its deISGylation activity. In vivo, USP18 and ISG15 expression diverged in low-inflammatory regions but colocalized in highly inflamed regenerative areas, highlighting context-dependent regulation. Regenerating myofibres exhibited high USP18 expression in the absence of ISG15, whereas fibrotic regions displayed persistent ISG15 with reduced USP18 levels. In vitro, USP18 increased MYOG expression during early differentiation while suppressing mature myosin heavy chain expression, indicating that USP18 promotes early myogenic commitment but limits myofibre maturation. USP18 acts as a context-dependent regulator of muscle regeneration independent of its deISGylation function. These findings identify USP18 as a dual modulator of myogenesis and highlight its potential as a therapeutic target in inflammatory muscle disease.

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2026-07-08 | Off-Label Uses of Deucravacitinib for Inflammatory Skin Conditions: Cases and Literature Review.

Deucravacitinib is an oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor approved for the treatment of moderate-to-severe plaque psoriasis and psoriatic arthritis. Deucravacitinib may offer a more selective approach compared to traditional Janus kinase (JAK) inhibitors. Emerging data support the use of deucravacitinib in inflammatory dermatoses beyond psoriatic disease. We present our clinical experience using deucravacitinib off-label in patients with challenging inflammatory skin disease and contextualize our findings within the current literature. We report three female patients aged 31-63 years with refractory inflammatory skin conditions, including two with dermatomyositis and one with pityriasis rubra pilaris (PRP). All patients had persistent disease despite multiple systemic therapies, such as oral corticosteroids (OCS), acitretin, azathioprine, mycophenolate mofetil (MMF), JAK inhibitors, intravenous immunoglobulin (IVIG), and/or rituximab. Deucravacitinib 6 mg daily was initiated as adjunctive or alternative therapy. Both patients with dermatomyositis experienced meaningful cutaneous improvement; one also demonstrated improved proximal muscle strength and a sustained response over 2 years without adverse events. The other showed gradual resolution of facial erythema but developed a mild acneiform eruption. The patient with PRP achieved marked improvement by 6 months and near-complete remission by 10 months, without reported adverse events. This case report supports the potential efficacy and adequate tolerability of deucravacitinib as an off-label option for refractory inflammatory dermatoses, specifically dermatomyositis and PRP. Larger prospective studies are needed to better define its long-term safety and therapeutic role beyond psoriasis.

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2026-07-08 | Dermatomyositis is characterized by TYK2-dependent STAT3 activation.

Dermatomyositis (DM) is characterized by activation of cytokine pathways that signal through the Janus kinase/signal transducer and activator of transcription (JAK/STAT) axis, although the relative contribution of individual JAK family members remains unclear. Peripheral blood mononuclear cells were isolated from patients with active DM (n = 5), rheumatoid arthritis (RA, n = 7), systemic sclerosis (SSc, n = 7), and healthy donors (HD, n = 5). Phosphorylated STAT3 (pSTAT3) levels were assessed by flow cytometry in CD4+ and CD14+ cells under basal conditions and following selective inhibition of JAK1 (abrocitinib), JAK2 (gandotinib), JAK3 (decernotinib), or TYK2 (deucravacitinib). Under basal conditions, DM displayed the highest pSTAT3 levels in CD4+ cells (median 38.3%), significantly exceeding those observed in HDs (0.9%, P < 0.05) and SSc (8.6%, P < 0.05), while RA showed intermediate levels (17.7%). CD14+ cells from DM patients also demonstrated increased pSTAT3 compared with HDs (9.7% vs 1.4%, P < 0.05), without significant differences versus RA or SSc. Selective JAK inhibition revealed distinct disease-specific patterns. In DM, only TYK2 inhibition significantly reduced pSTAT3 levels in both CD4+ and CD14+ cells (P < 0.05), whereas in RA, pSTAT3 was modulated by inhibition of multiple JAK family members. No significant effects were observed in HDs or SSc patients. These findings identify a selective TYK2-dependent STAT3 activation signature in circulating immune cells from patients with DM, distinguishing this disease from other autoimmune conditions and supporting TYK2 as a potential therapeutic target in DM.

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