Tofacitinib Citrate: Mechanism of Action and Clinical Applications in Psoriasis

General Description

Tofacitinib citrate is an oral Janus kinase inhibitor that primarily targets JAK1 and JAK3, crucial for immune cell activation and inflammatory responses in conditions like psoriasis. By inhibiting these kinases, Tofacitinib citrate reduces proinflammatory cytokine production and the activation of immune cells such as dendritic cells and CD4(+) T-cells. Clinical trials of Tofacitinib citrate have shown significant efficacy in moderate-to-severe psoriasis, with 10 mg bid achieving higher PASI 75 response rates compared to 5 mg bid and placebo. Long-term studies reveal that continuous treatment maintains responses better than placebo, and many patients can effectively recapture responses after relapse.

Figure 1. Tofacitinib citrate

Mechanism of Action

Mechanism in Immune Modulation

Tofacitinib citrate, an innovative oral medication, operates primarily as a Janus kinase (JAK) inhibitor, specifically targeting JAK1 and JAK3. These intracellular kinases play a crucial role in immune cell activation by mediating signals from various cytokines, including IL-6, which are pivotal in inflammatory responses associated with conditions like psoriasis. When tofacitinib citrate binds to JAK1 and JAK3, it inhibits the phosphorylation process that typically activates signaling pathways leading to the expression of proinflammatory genes. This inhibition effectively reduces the activation of immune cells, such as dendritic cells and CD4(+) T-cells, which are central to the pathogenesis of psoriasis. By disrupting these pathways, tofacitinib citrate can significantly curtail the hyperactivation of immune responses, alleviating the symptoms associated with psoriasis. ¹

Reduction of Proinflammatory Cytokines

Tofacitinib citrate also exerts an impressive influence on the differentiation and function of various immune cells. By inhibiting type I interferon signaling, tofacitinib citrate reduces the capacity of dendritic cells to present antigens and stimulate T-cells, leading to a decrease in proinflammatory cytokine production. Importantly, it diminishes the expression of crucial costimulatory molecules, such as CD80 and CD86, which are essential for T-cell activation. Furthermore, tofacitinib citrate limits the production of IL-17A, IL-17F, and IL-22, cytokines that drive the immune response in psoriasis. It also reduces the expression of the IL-23 receptor, which is vital for the differentiation of Th17 cells. By targeting these pathways, tofacitinib citrate effectively modulates multicytokine responses, offering a targeted approach to managing immune-mediated conditions. ¹

Clinical Applications in Psoriasis

Efficacy in Moderate-to-Severe Psoriasis

Tofacitinib citrate has demonstrated significant clinical efficacy in treating moderate-to-severe chronic plaque psoriasis, as revealed through multiple placebo-controlled and randomized clinical trials. In two pivotal Phase III studies, patients receiving a dosage of tofacitinib citrate at 10 mg twice daily (bid) showed considerable improvements compared to those on 5 mg bid and placebo. The results indicated that the rates of achieving a 75% reduction in the Psoriasis Area and Severity Index (PASI 75) were 39.9% and 59.2% for the 5 mg and 10 mg doses, respectively, after 16 weeks in the Opt Pivotal 1 study. Similarly, in the Opt Pivotal 2 study, the PASI 75 response rates were 46.0% for the 5 mg group and 59.6% for the 10 mg group. These findings underscore the efficacy of tofacitinib citrate, particularly at the higher dosage, in significantly reducing the severity of psoriasis lesions. ²

Comparison with Etanercept and Clinical Outcomes

In a head-to-head clinical trial comparing tofacitinib citrate with etanercept, only the 10 mg bid dosage of tofacitinib citrate showed noninferiority to etanercept, which is a standard treatment for psoriasis. This trial enrolled over 1,100 patients, all of whom had moderate to severe psoriasis and had previously shown inadequate responses to conventional systemic therapies. Patients on tofacitinib citrate 10 mg achieved PASI 75 responses in 63.6% of cases at week 12, which was comparable to 58.8% in the etanercept group. Additionally, 68.2% of patients on tofacitinib citrate 10 mg reported achieving a clear or almost clear assessment via the Physician Global Assessment (PGA) at the same time point. These outcomes illustrate that tofacitinib citrate can serve as a viable alternative to traditional therapies, providing effective management of psoriatic symptoms. ²

Long-term Effects and Treatment Duration

Further clinical investigations have explored the outcomes of tofacitinib citrate after treatment cessation. After a 24-week treatment period, 33.5% of patients on the 5 mg dose and 55.2% on the 10 mg dose achieved both PASI 75 and PGA responses. Notably, patients who continued on tofacitinib citrate maintained their treatment responses significantly better compared to those who received a placebo after cessation of treatment. Among those who experienced a relapse, up to 60% were able to regain a satisfactory response upon reinitiating therapy with tofacitinib citrate. This highlights the sustained effectiveness of tofacitinib citrate, particularly at the 10 mg bid dosage, for managing long-term psoriasis symptoms and achieving consistent patient outcomes. ²

Reference

1. Kubo S, Yamaoka K, Kondo M, et al. The JAK inhibitor, tofacitinib, reduces the T cell stimulatory capacity of human monocyte-derived dendritic cells. Ann Rheum Dis. 2014; 73(12): 2192-2198.

2. Di Lernia V, Bardazzi F. Profile of tofacitinib citrate and its potential in the treatment of moderate-to-severe chronic plaque psoriasis. Drug Des Devel Ther. 2016; 10: 533-539.