The Role of TYK2 Inhibitors in the Evolving Landscape of Rheumatologic and Dermatologic Treatment

Abstract

Tyrosine kinase 2 (TYK2) is a non-receptor tyrosine kinase and a key member of the Janus kinase (JAK) family, playing an essential role in the intracellular signaling of several cytokine pathways. Specifically, TYK2 mediates the signal transduction of interleukin-12 (IL-12), interleukin-23 (IL-23), and type I interferons (IFN-α/β), which are crucial regulators of innate and adaptive immune responses. These pathways are central to the pathogenesis of multiple autoimmune and inflammatory diseases, including psoriasis, psoriatic arthritis (PsA), systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD) [1, 2]. Unlike conventional JAK inhibitors, which target the active catalytic domain (JH1 domain) and broadly suppress multiple cytokine pathways, TYK2 inhibitors function through selective allosteric inhibition of the regulatory JH2 (pseudokinase) domain. This unique mechanism allows for precise modulation of TYK2 activity without directly affecting the ATP-binding site, thereby reducing off-target inhibition of JAK1, JAK2, and JAK3 [2]. By preserving partial physiological cytokine signaling, TYK2 inhibitors demonstrate a potentially improved safety profile compared to broader JAK inhibitors, particularly in terms of infection risk, malignancy concerns, and cardiovascular adverse events [1, 3].

From a clinical perspective, TYK2 inhibitors have emerged as promising therapeutic agents with an improved safety profile compared to conventional JAK inhibitors. Deucravacitinib, the first FDA-approved allosteric TYK2 inhibitor, has demonstrated efficacy in the treatment of moderate-to-severe plaque psoriasis, with ongoing trials exploring its potential in PsA and SLE [4-10]. Other TYK2 inhibitors, such as Brepocitinib and Ropsacitinib, are in earlier phases of clinical development and are being investigated for a range of autoimmune conditions [11-20]. This editorial aims to review the evidence-based medicine (EBM) level of TYK2 inhibitors across different autoimmune and dermatologic indications, compare their clinical positioning relative to biologic agents such as IL-17 and IL-23 inhibitors, and discuss the existing unmet needs and future research directions for TYK2-targeted therapies.

TYK2 inhibitors have been extensively studied across various immune-mediated diseases, with different levels of evidence supporting their use (Table 1). Among the available agents, Deucravacitinib has the most robust clinical data, particularly in psoriasis, where multiple Phase III trials confirm its efficacy, earning it Level 1A evidence [4-8]. Meanwhile, other TYK2 inhibitors such as Brepocitinib and Ropsacitinib remain in earlier phases of development, with supporting data primarily from Phase II trials, resulting in Level 2A or lower evidence across different indications [11-20].

In psoriasis, Deucravacitinib's FDA approval is backed by strong Phase III trial results, demonstrating PASI 75 response rates comparable to biologic agents. The real-world studies further support its durability, with long-term PASI 75 achievement rates exceeding 85% in observational settings [4-8]. These findings suggest that Deucravacitinib may represent a valuable oral systemic option for patients with moderate-to-severe psoriasis, especially those who prefer non-injectable treatments or encounter logistical or economic barriers to accessing biologics. Compared to apremilast, Deucravacitinib has demonstrated superior efficacy with a comparable safety profile, potentially expanding the role of oral therapies in this setting. Its selective allosteric inhibition of the TYK2 pseudokinase domain allows for targeted cytokine modulation—primarily IL-12, IL-23, and type I interferons—while avoiding broader JAK1–3 suppression. This selectivity may translate into a more favorable safety profile, with a lower risk of adverse effects such as cytopenias, thromboembolic events, or dyslipidemia. In contrast, Brepocitinib and Ropsacitinib remain in earlier clinical trials, with Phase II data suggesting promising efficacy, but without Phase III validation, they remain investigational for this indication [11, 19]. Within the current therapeutic landscape, which includes an array of biologics with proven efficacy, TYK2 inhibition offers a potential intermediary step in treatment sequencing—positioned after failure of conventional systemics but before escalation to biologics in appropriately selected patients.

For psoriatic arthritis (PsA), Deucravacitinib has reached Phase II trials, demonstrating clinically meaningful efficacy, leading to a Level 2A evidence rating [9]. However, no Phase III trials have been completed, limiting its immediate clinical application. Brepocitinib has also shown positive results in Phase II trials for PsA, though larger studies are necessary to confirm its efficacy and safety in this population [20]. Compared to IL-17 and IL-23 inhibitors, which are supported by robust Phase III data and widespread real-world use, TYK2 inhibitors remain in earlier stages of clinical development for PsA. However, their mechanism—targeting IL-23 and type I interferon pathways—offers a distinct approach. Given their oral formulation and emerging safety data, TYK2 inhibitors such as Deucravacitinib may be considered in patients with mild-to-moderate or early PsA, particularly those with limited joint involvement and concurrent skin disease. In such cases, oral TYK2 inhibition may provide a practical alternative prior to initiating biologics, especially when patient preference, tolerability, or access are important considerations.

In systemic lupus erythematosus (SLE), Deucravacitinib has been evaluated in Phase II trials, showing potential benefits, but its evidence level remains at Level 2A due to the lack of Phase III confirmation [10]. Given the complexity of SLE, where multiple immune pathways are involved, additional studies are needed to establish TYK2 inhibitors as a viable treatment alternative.

For ulcerative colitis (UC), results have been mixed. While TYK2 inhibition is a biologically plausible target given its role in IL-23 signaling, clinical trials have produced inconsistent findings, with some failing to meet their primary endpoints [13]. Consequently, the evidence level remains at Level 2B or lower, and further optimization of dosing strategies or combination therapies may be required to improve outcomes.

Despite their therapeutic potential, TYK2 inhibitors face several critical challenges, particularly regarding long-term safety, real-world effectiveness, and broader clinical applications. A key concern is malignancy risk, as prolonged JAK inhibition has been linked to increased cancer incidence. While Deucravacitinib's selective allosteric inhibition suggests a lower oncogenic risk, long-term surveillance data are still lacking. Similarly, cardiovascular safety remains uncertain, given the association between JAK inhibitors and increased MACE risk [1, 3]. Although TYK2 inhibitors theoretically have a more favorable safety profile, definitive conclusions require extended follow-up and real-world studies.

Another major gap is the lack of large-scale real-world evidence, which is crucial for assessing drug persistence, effectiveness across diverse patient populations, and rare adverse events. While RCTs indicate that Deucravacitinib is superior to placebo and Apremilast in psoriasis, direct comparisons with biologics are limited, making it difficult to determine its true positioning in treatment guidelines [3-5].

Beyond psoriasis, expanding indications remains a challenge. Phase II trials in PsA and SLE have shown promising efficacy, but Phase III validation is still pending [9, 10, 20]. Similarly, Brepocitinib and Ropsacitinib, though showing potential in psoriasis and inflammatory conditions, remain in early-stage clinical development, requiring multi-center trials to establish efficacy and safety [11-20].

To fully integrate TYK2 inhibitors into clinical practice, long-term safety monitoring, real-world studies, and head-to-head trials against biologics and JAK inhibitors are essential to clarify their benefits and risks. Addressing these gaps will be crucial for defining their role in autoimmune disease management.

In conclusion, TYK2 inhibitors have emerged as a promising therapeutic option for immune-mediated diseases, offering a selective mechanism that distinguishes them from both traditional JAK inhibitors and biologic therapies. Their efficacy in psoriasis is well established, with Deucravacitinib achieving Phase III approval, while other indications, including PsA, SLE, and UC, remain under investigation. Despite their potential advantages in safety and convenience, long-term real-world data and direct comparative studies with biologics are essential to determine their optimal role in clinical practice. Future research should focus on head-to-head trials with IL-17 and IL-23 inhibitors, as well as expanding Phase III studies in autoimmune diseases beyond psoriasis to strengthen their evidence base. Additionally, real-world registries and long-term pharmacovigilance programs will be critical in confirming their long-term safety, particularly regarding malignancy and cardiovascular risks. With further validation, TYK2 inhibitors have the potential to bridge the gap between conventional systemic therapies and biologics, providing a well-tolerated, effective, and convenient oral option for patients with chronic inflammatory diseases. Their continued development could significantly reshape treatment paradigms, offering an alternative for patients who require long-term disease control with a favorable safety profile.

All authors contributed to the design and implementation of the study and original draft preparation. I-Chang Lai wrote the manuscript with critical support from Yung-Heng Lee, Po-Cheng Shih, and Meng-Che Wu, who provided critical feedback and helped revise the manuscript multiple times. All authors reviewed the results and approved the final version of the manuscript.

The authors have nothing to report.

The authors have nothing to report.

The authors declare no conflicts of interest.