Tyrosine kinase 2 inhibitors in the therapy of inflammatory and autoimmune diseases.

Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family that mediates intracellular signaling from cytokines such as interleukin 12 (IL-12), interleukin 23 (IL-23), and type I interferons (IFN-α/β) via the JAK–signal transducer and activator of transcription (JAK-STAT) pathway. These cytokines are central to the pathogenesis of autoimmune and inflammatory diseases, including psoriasis, psoriatic arthritis, systemic lupus erythematosus, and inflammatory bowel disease. Selective TYK2 inhibition has emerged as a novel therapeutic approach offering targeted modulation of immune responses. This review summarizes current data on TYK2’s role in immune signaling and disease pathogenesis. It also presents clinical trial findings for the most advanced TYK2 inhibitors, focusing on efficacy and safety. Deucravacitinib, a selective allosteric TYK2 inhibitor, has shown significant clinical benefit and good tolerability in plaque psoriasis and is under investigation for other immune-mediated diseases. Brepocitinib, a dual TYK2/JAK1 inhibitor, demonstrates broader cytokine inhibition and therapeutic potential, though with an increased risk of class-related side effects. Selective TYK2 inhibitors provide an effective and potentially safer oral alternative to traditional JAK inhibitors and biologics. Their cytokine-specific mechanism of action allows for precise immunomodulation, with ongoing studies evaluating their long-term safety and broader clinical use. In addition, given the robust type I interferon signature and JAK–STAT activation in dermatomyositis (DM), TYK2/JAK1 inhibition is being actively investigated; ongoing phase III evaluation of brepocitinib in DM (VALOR, NCT0543726) reflects this rationale and unmet need. In addition, brepocitinib is under investigation in DM, a prototypic inflammatory myopathy with a strong type I interferon signature; details of the rationale and the ongoing VALOR phase III trial are provided in the dedicated subsection on DM (see section: TYK2 inhibition in DM). Topical formulations of brepocitinib have also been investigated in psoriasis and atopic dermatitis. Clinical trials demonstrated significant improvement in cutaneous disease activity with a favorable safety profile, largely limited to local application site reactions (e.g., erythema, pruritus), and without systemic adverse events typically associated with oral JAK inhibition.