JAK Inhibitors in Psoriasis: A Promising New Treatment Modality
August 2012 | Volume 11 | Issue 8 | Original Article | 913 | Copyright © August 2012
AbstractBackground: Inflammatory cytokines play a crucial role in the pathophysiology of psoriasis. New therapies are targeting Janus kinases (JAKs), enzymes involved with transduction of cytokine receptor signaling.
Objective: Review the utility of JAK inhibitors in the treatment of psoriasis.
Methods: A review was performed using PubMed and Google to identify research relevant to the treatment of psoriasis using JAK inhibitors.
Results: In a CD18 mutant PL/J mouse model with T-cell dependent psoriasiform skin disease, the JAK inhibitor R348 reduced skin inflammation, with reductions in CD4+, CD8+, and CD25+ T-cell infiltration and systemic decreases of IL-17, IL-19, IL-22, IL-23 and TNF-α. Two JAK inhibitors, CP-690,550 (tasocitinib) and INCB018424 (ruxolitinib), were effective in psoriasis clinical trials. In a phase 1, randomized, double-blind, dose escalation trial for plaque psoriasis, CP-690,050 led to improvements in Psoriatic Lesion Severity Sum score at doses greater than 5 mg. A phase 2 trial showed CP-690,050 administered at 2, 5, and 15 mg twice daily resulted in a 75% reduction in Psoriasis Area and Severity Index (PASI) in 25%, 40.8%, and 66.7% of patients, respectively, for moderate to severe psoriasis. A phase 3 study of CP-690,550 for plaque psoriasis was begun in September 2010 (NCT01163253). INCB018424, another JAK inhibitor, was used topically at 3 doses (0.5%, 1%, 1.5%) in a phase 2B, double-blind, placebo-controlled trial, resulting in improved total lesion score, global assessment, and PASI for all doses.
Conclusion: Janus Kinase inhibitors are promising potential therapeutic options for psoriasis.
J Drugs Dermatol. 2012;11(8):913-918.
Janus kinases are a key component of the molecular machinery involved in signal transduction through various cytokine receptors.1 Janus kinases, which are associated with the cytoplasmic domain of cytokine receptors, become activated when a cytokine binds to its receptor (Figure 1, panel a).2-4 Activation of JAKs leads to the phosphorylation of the cytokine receptor (Figure 1, panel b), and this event creates docking sites for proteins known as signal transducers and activators of transcription (STATs) (Figure 1, panel c). Binding of a STAT to the cytokine receptor results in its phosphorylation by JAKs (Figure 1, panel d). The phosphorylated STAT dissociates from the cytokine receptor and forms a dimer with another phosphorylated STAT (Figure 1, panels e - f), and the dimer translocates to the nucleus, where it modulates transcription of genes involved in cell growth, proliferation, and differentiation.2-5
Four subtypes of JAKs (JAK1, JAK2, JAK3, and Tyrosine kinase 2 [Tyk2]) have been identified, with seven functional domains common to all subtypes (Figure 2).4-6 The targeted deletion of genes for each subtype of JAK has provided information on their functions (Table 1).1,7,8 Both JAK1 and JAK2 genes are necessary for survival, as mice without JAK1 die perinatally and mice without JAK2 die as embryos on day 12.1,7 Mice lacking JAK3 do not die but develop severe combined immunodeficiency (SCID).8 Also, mice without JAK3 are defective in T, B, and NK cells.9,10 Finally, mice without Tyk2 show increased viral susceptibility.11 Studies have further investigated animals deficient in JAK3 and Tyk2 and identified the effects of these deficiencies on signaling through various cytokines (Table 1).
While JAK1, JAK2, and Tyk2 are expressed in most tissues, a unique feature of JAK3 is that it is mainly expressed in hematopoietic cells and mediates signaling only through cytokines whose receptors contain a gc-subunit.12 Thus, JAK3 participates in signaling through IL-2, IL-4, IL-7, IL-9, IL-13, IL-15, and IL-21. These cytokines are involved in the development, differentiation, proliferation, and survival of multiple cell types (T-cells, B cells, NK cells, mast cells, and dendritic cells) of the innate as well as adaptive immune systems. 12 Because JAK3 is expressed mainly in the immune system, its inhibition should only affect this system without affecting any other organ systems.6,13,14 This attribute of JAK3 makes it a good target to develop therapies for inflammation, allergy, autoimmune disease, and organ transplant rejection. However, it has not been possible to develop completely selective inhibitors of JAK3; previous inhibitors claiming to be JAK3 selective have been found to have some affinity for other JAK subtypes as well.