Acta Dermato-Venereologica 99-3CompleteContent | Page 13

298 INVESTIGATIVE REPORT Antipruritic Effects of Janus Kinase Inhibitor Tofacitinib in a Mouse Model of Psoriasis Takashi HASHIMOTO, Kent SAKAI, Kristen M. SANDERS, Gil YOSIPOVITCH and Tasuku AKIYAMA Department of Dermatology and Cutaneous Surgery, University of Miami, Miami Itch Center, Miami, FL, USA The Janus kinase 1/3 inhibitor tofacitinib has demon- strated an antipruritic effect in two phase ΙΙΙ studies in psoriasis. However, the mechanisms behind this antipruritic effect are still unknown. We presently in- vestigated whether tofacitinib affects spontaneous itch as well as expression of itch-related cytokines and epidermal nerve fiber density (ENFD) in the imiqui- mod-induced mouse model of psoriasis. Psoriasis-like skin lesions were produced by daily topical application of imiquimod to the back skin. Imiquimod treatment resulted in spontaneous scratching, which was signi- ficantly inhibited by tofacitinib treatment. Imiquimod treatment significantly increased mRNA expression of Il22, Il23, and Il31, reduced peptidergic ENFD, and in- creased nonpeptidergic ENFD compared to naive mice. Tofacitinib significantly decreased the expression of those cytokines and increased peptidergic ENFD with­ out a significant effect on nonpeptidergic ENFD. Tofa- citinib may inhibit psoriatic itch through inhibition of cytokine expression as well as modulation of epider- mal innervation. Key words: JAK inhibitor; chronic itch; psoriasis; scratching; IL-31. Accepted Nov 20, 2018; E-published Nov 21, 2018 Acta Derm Venereol 2019; 99: 298–303. Corr: Tasuku Akiyama, PhD, Department of Dermatology and Cuta- neous Surgery, University of Miami, Miami Itch Center, 1600 NW 10 th Ave RMSB2063, Miami, FL 33136, USA. E-mail: [email protected] T ofacitinib is a targeted small molecule that preferen- tially inhibits Janus kinase (JAK)-1/3. This inhibition of JAK-1/3 blocks γ-chain cytokines, including inter- leukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21, that could contribute to skin inflammation (1). Tofacitinib demonstrated a significant antipruritic effect in two phase ΙΙΙ studies of patients with moderate to severe plaque psoriasis and one phase ΙΙa study of patients with mild to moderate atopic dermatitis (2–4). Interestingly, tofaciti- nib has a rapid antipruritic effect which is independent from improvements in other clinical signs of psoriasis, such as erythema, induration, and scaling (5). A recent study suggests that tofacitinib acts directly on the trans- ient receptor potential vanilloid 1 ion channel expressed in sensory neurons to exert antipruritic effects (6). This could explain the rapid onset of improvement in pruritus. However, the mechanism behind the antipruritic effects of tofacitinib has not been fully understood. doi: 10.2340/00015555-3086 Acta Derm Venereol 2019; 99: 298–303 SIGNIFICANCE Tofacitinib, a drug that inhibits Janus kinases 1 and 3, has been shown to reduce itch in clinical trials of psoriasis. However, the exact mechanism for this anti-itch effect is still unclear. This study investigates the effects of tofaciti- nib treatment in a mouse model of psoriasis. Tofacitinib reduced scratching in this model. Additionally, tofacitinib rescued the increased mRNA levels of Il22, Il23, and Il31, 3 cytokines that are known to be related to itch. Finally, tofacitinib recovered the reduction in peptidergic nerves in the epidermis of psoriasis model mice. Therefore, tofaciti- nib could reduce itch through regulation of cytokines and epidermal nerves. Psoriasis is an inflammatory skin disease that is driven by Th1 and Th17 cells (7). IL-17A, IL-17F, IL-21, and IL-22 are found at increased levels in psoriatic skin (8, 9). Interestingly, RNA-seq analysis demonstrated that mRNA transcripts for Il17a, Il22, Il23, and Il31 were elevated in the itchy skin of both atopic dermatitis and psoriasis patients compared to non-itchy skin (10). Knockout mouse studies have revealed the role of cyto- kines (e.g. IL-31, thymic stromal lymphopoietin (TSLP), IL-4, IL-33, and tumor necrosis factor-α) in itch (11–15). Particularly, IL-31 and TSLP directly act on their cognate cytokine receptors expressed by primary sensory neurons and keratinocytes, respectively, to elicit itch. Dynamic changes in epidermal innervation have been observed under chronic itch conditions. Epidermal hyper­innervation by itch-signaling fibers is considered to be one cause of chronic itch (16), and increased epi- dermal nerve density has been frequently reported in humans with chronic itch conditions including psoriasis (16–20). In line with this, intraepidermal nonpeptidergic nerve density is increased in animal models of dry skin itch and psoriatic itch (21–23). In contrast, conflicting results have been reported for epidermal nerve density in human with chronic itch. Reduced epidermal nerve density has been reported in patients with psoriatic itch as well as prurigo nodularis (17, 24, 25). Additionally, intraepidermal peptidergic nerve density is decreased in animal models of psoriatic itch (23). In these cases, reduced primary afferent drive toward itch-inhibitory interneurons could contribute to disinhibition of itch. We presently investigated whether tofacitinib inhibited spontaneous itch in the imiquimod-induced mouse model This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2019 Acta Dermato-Venereologica.