6.1.1. Ustekinumab

Ustekinumab is a human monoclonal antibody that binds to the p40 subunit that is shared by both IL-12 and IL-23 and inhibits the functions of both IL-12 and IL-23. In three clinical trials in patients with PsA, ustekinumab treatment demonstrated higher improvement of the disease activity [99–101]. Following these results, ustekinumab received FDA approval for the treatment of PsA in 2013. On the other hand, there is no evidence of the efficacy of ustekinumab in the treatment of AS. Three placebo-controlled clinical trials of ustekinumab were conducted for AS. However, after the insufficient effectiveness of the first clinical trial, the following two trials were discontinued before full patient enrollment [102].

**Figure 3.** Targeting the IL-23/IL-17 pathway. IL-23, interleukin-23; IL-12, interleukin-12; p19, p19 subunit of interleukin-23; p35, p35 subunit of interleukin-12; p40, p40 subunit of interleukin-12 or of interleukin-23; IL-17A, interleukin-17A; IL-17F, interleukin17F; IL-17RA, interleukin-17 receptor A; IL-17RC, interleukin-17 receptor C; Th1, T helper cell 1; Th17, T helper cell 17; TNF-α, tumor necrosis factor-α.

#### 6.1.2. Guselkumab

Guselkumab targets the p19 subunit that is shared between IL-23 and IL-39 [103]. While ustekinumab targets both IL-12 and IL-23 via binding to the p40 subunit, guselkumab inhibits IL-23 specifically. The results of two phase 3 clinical trials demonstrated the efficacy of guselkumab in the treatment of PsA [104,105]. The DISCOVER-1 trial aimed to assess the effects of guselkumab in patients with various levels of disease activity, while the DISCOVER-2 trial targeted biologic-naïve patients with active PsA. Guselkumab demonstrated greater improvement in the primary endpoint (American College of Rheumatology 20% improvement [ACR20] response at week 24) in both trials. These trials are being extended (DISCOVER-1 for 1 year and DISCOVER-2 for 2 years) to accumulate additional data related to the efficacy and safety of guselkumab [106].

#### 6.1.3. Tildrakizumab

Tildrakizumab is a high-affinity humanized antibody targeting IL-23 p19 and the second selective IL-23 antagonist and has been approved for the treatment of Ps by the FDA [107]. A phase 2b study for PsA reported the significant improvement of joint and skin manifestations. At week 24, patients receiving tildrakizumab achieved superior improvement in ACR20 and on the Psoriasis Area and Severity Index (PASI) 95 [108]. Furthermore, phase 3 trials are underway for PsA (NCT04314531 and NCT04314544) and AS (NCT-0355276). The most common treatment-emergent adverse events reported through week 24 were nasopharyngitis (tildrakizumab: 5.4%, placebo: 6.3%) and diarrhea (tildrakizumab: 1.3%, placebo: 0%).
