*5.3.5 Janus kinase inhibitors (JAKi)*

The JAK–STAT pathway is a signal transduction and intracellular transcription regulation pathway in which numerous pro-inflammatory pathways converge [65] (**Figure 6**). The pathway involves the JAK family of four kinases (JAK1, JAK2, JAK3, and tyrosine kinase 2 [TYK2]), which are located in the intracellular domains of type I and II cytokine receptors [65, 95]. Their activation when ligand binds to the receptor leads to binding and phosphorylation of the STAT family of proteins, which bind DNA and mediate processes of cell proliferation, differentiation, migration, and apoptosis [65]. Recently, the involvement of several JAK–STAT pathway-dependent cytokines in the pathogenesis of AA (IL-2, IL-7, IL-15, IL-21, and interferon-gamma) has been described [65]. Key genes in the JAK–STAT pathway related to hair growth includeSTAT5A/B, STAT3, JAK1, JAK3, and Socs2/3, highly expressed in the catagen and telogen phases but suppressed in the early anagen phase [95]. In AA, inhibition of JAK– STAT interferes with the positive feedback loop between follicular cell and cytotoxic CD8+ NKG2D+ CD8+ T cells in AA [95]. Given the involvement of this pathway and its dependent cytokines in the pathogenesis of AA, JAK–STAT has become a potential therapeutic target [65, 69, 70, 95].

#### **Figure 6.** *JAK–STAT pathway. This image was created using Biorender.com.*

#### *An Updated in the Management of Alopecia Areata DOI: http://dx.doi.org/10.5772/intechopen.111921*

JAKi are oral drugs that have demonstrated effectiveness and safety for the treatment of diseases such as rheumatoid arthritis and psoriatic arthritis [95, 100]. JAKi are selective, but not specific for a single JAK and, therefore, can affect several immune pathways [95]. The FDA has issued warnings for oral JAKi due to concerns about an increased risk of serious infections, mortality, malignancy, major adverse cardiovascular events, and thrombosis [69, 70, 95].

### *5.3.5.1 Baricitinib*

It is a selective and reversible JAK1 and JAK2 inhibitor, it has also been shown to indirectly inhibit IL-6, and Il-23 activity, and to a lesser extent inhibit JAK3 [95]. Baricitinib has demonstrated efficacy for severe alopecia areata [95, 100, 101]. In 2022, the FDA approved baricitinib for the treatment of adults with severe alopecia areata [65, 95]. In two randomized, placebo-controlled, phase 3 trials BRAVE-AA1 (n = 654) and BRAVE-AA2 (n = 546), adults with severe alopecia areata (SALT ≥50) were randomized to baricitinib 4 mg per day, baricitinib 2 mg per day, or placebo [101]. At week 36, the proportion of patients in the baricitinib 4 mg, baricitinib 2 mg, and placebo groups who achieved a SALT score of ≤20 in BRAVE-AA1 was 39, 23, and 6%. In BRAVE-AA2, 36, 19, and 3% of patients in the 4 mg, 2 mg, and placebo groups achieved this end point, respectively [101]. The dose of baricitinib is 2 mg once daily with an increase to 4 mg once daily if response is inadequate. Patients with near complete or total scalp hair loss may be treated initially with 4 mg once daily. The dose is reduced to 2 mg once daily upon adequate response [65, 95, 101]. The most common adverse effects encountered with baricitinib are acne, urinary tract infections, and elevated serum creatinine kinase and low-density lipoprotein (LDL) and high-density lipoprotein (HDL) [101].

### *5.3.5.2 Tofacitinib*

It selectively inhibits JAK1 and JAK3 and blocks STAT phosphorylation induced by IFN-γ, IL-2, IL4, IL-7, IL-15, and IL-21 [65, 69, 95]. Treatment with oral tofacitinib has been shown to achieve hair regeneration in patients with AA in case series and retrospective studies, and patients are typically treated with 5 mg twice daily [65, 69]. In a retrospective study of 90 adult patients with severe AA (SALT >40), including AA totalis or AA universalis, the efficacy of oral tofacitinib at doses of 5–10 mg/day for at least 4 months was demonstrated (77% clinical response in AA of less than 10 years duration). Duration longer than 10 years and having AA totalis or AA universalis were defined as predictors of low response to tofacitinib. The relapse rate 3 months after discontinuation of oral tofacitinib treatment is high [102]. Treatment with oral tofacitinib increases the risk of infections [102]. Cases of serious infections and malignancies have been reported in patients receiving tofacitinib treatment [69].

#### *5.3.5.3 Ruxolitinib*

It selectively inhibits JAK1 and JAK2 and, to some extent, TYK2 [95]. The utility of oral ruxolitinib in the management of AA has been reported in case reports, case series, and an open-label trial [65, 69, 95, 103]. In an open-label clinical trial of 12 patients with moderate to severe AA, the efficacy of oral ruxolitinib, 20 mg twice daily, was evaluated during 3–6 months of treatment, and 9 patients (75%) achieved at least 50% hair growth at the end of treatment [103].
