JAK inhibition offers promising treatment prospects for uncommon dermatoses

Emerging data, often still in the form of case reports, demonstrated the efficacy of Janus kinase (JAK) inhibition in the treatment of diseases such as lichen planus, systemic sclerosis, and hidradenitis suppurativa (HS). JAK inhibition might become established as a treatment option for many more autoimmune and inflammatory skin conditions in the near future.

The JAK/STAT pathway plays an important role in many autoimmune skin disorders that involve different immune response patterns mediated by diverse cytokines [1,2]. By now, the armamentarium of dermatologists has been amplified by various JAK inhibitors that have demonstrated efficacy in numerous dermatologic conditions [3]. These small molecules can target various downstream signalling cytokines that simultaneously contribute to a disease [4]. Currently, JAK inhibitors are also being investigated as a treatment for several diseases less common than psoriasis or atopic dermatitis.

JAK1 inhibitor INCB054707 for HS

As adalimumab is the only approved treatment for HS and this only yields a response in about 50% of the patients, the concept of JAK inhibition is presently being explored for HS. Two phase 2 trials assessed the JAK1 inhibitor INCB054707 for safety and efficacy in moderate-to-severe HS (NCT03569371 and NCT03607487). In the first study, 10 patients were treated open-label with INCB054707 once daily for 8 weeks. In the second study, 35 HS patients were randomised into 3 different dosage groups and placebo control.

In terms of efficacy, the active agent led to an overall response rate of 65% versus 57% on placebo after 8 weeks in study 2, with a ≥50% reduced total count of abscesses and inflammatory nodules (HS clinical response/HiSCR) [5]. “In this proof-of-concept study in HS, we see a dose-dependent decrease in nodules and abscesses but placebo does pretty well too,” commented Prof. Matthew Vesely (Yale School of Medicine, CT, USA) in his talk [1]. Furthermore, measures for quality of life and worst pain were meaningfully reduced. For example, in terms of quality of life measured by the Dermatology Life Quality Index (DLQI), 15% of patients stated that the disease had no or only a small effect at baseline. This proportion rose to 54% on INCB054707 [5]. Any treatment-emerging adverse events arose in 70% (study 1) and 81% (study 2) of participants, but none were of serious grade.

Tofacitinib for lichen planus and DRESS

Therapy with JAK inhibitors has also been explored for the inflammatory skin disease lichen planus and drug reaction with eosinophilia and systemic symptoms (DRESS). Although the pathogenesis of lichen planus has not yet been fully elucidated, the elevation of STAT-1, IL-21, and IFN-γ are suspected to play a part in the inflammatory process [6]. Over the course of treatment with twice-daily tofacitinib 5 mg, 3 patients with erosive lichen planus experienced a substantial improvement of their previous debilitating symptoms including eating and speaking difficulties [7]. No adverse events were observed. A successful change after 6 months of treatment was also seen for nail lichen planus in a patient treated with tofacitinib for alopecia universalis [8].

Different reports have recently been published on patients with DRESS, a potentially fatal type IV hypersensitivity reaction to an administered drug. For these patients, tofacitinib resulted in clinical amelioration, molecular improvement, and restored organ function [9,10]. “For severe DRESS that does not respond to therapy, JAKs may be an option,” said Prof. Vesely.

Baricitinib and tofacitinib for sclerosing skin disorders

JAK inhibition (with tofacitinib or baricitinib) has also led to beneficial outcomes in the treatment of sclerosing skin diseases such as morphea, systemic sclerosis, and eosinophilic fasciitis [11,12]. Consistent with this treatment concept, the immunohistochemical investigation of biopsy tissue of morphea patients revealed STAT-1 and STAT-3 in lymphocytes and some spindled fibroblasts [11].

A 1-year pilot trial compared the benefits of methotrexate with tofacitinib in 66 patients with systemic sclerosis [13]. After 52 weeks, the improvement in the modified Rodnan skin score was 44% higher in the tofacitinib group than in those on methotrexate. Greater ameliorations were also observed for skin thickness and the number of digital ulcers in participants on JAK inhibition.

Last but not least, JAK inhibition has demonstrated efficacy as a combination and/or rescue therapy in cases with refractory atopic dermatitis or recalcitrant HS [14,15].

In summary, these examples underline the considerable potential of JAK inhibitors, especially because of the varying cytokine activity that can be addressed by different types of JAK inhibitors [7].

 

1. 1. Vesely MD. JAK inhibitors for lichen planus, hidradenitis suppurativa, and other dermatoses. S032, AAD 2022 Annual Meeting, 25–29 March, Boston, MA, USA.
   2. Shao S, et al. J Allergy Clin Immunol. 2022;149(1):45–47.
   3. Solimani F, et al. Front Immunol. 2019;10:2847.
   4. Damsky W, et al. J Allergy Clin Immunol. 2021;147(3):814–826.
   5. Alavi A, et al. Br J Dermatol. 2022;186(5):803-813.
   6. Pietschke K, et al. Exp Dermatol. 2021;30(2):262–270.
   7. Damsky W, et al. J Allergy Clin Immunol. 2020;145(6):1708–1710.e2.
   8. Iorizzo M, Haneke E. JAMA Dermatol. 2021;157(3):352–353.
   9. Damsky WE, et al. JAAD Case Rep. 2019;5(12):1018–1026.
   10. Kim D, et al. Nat Med. 2020;26(2):236–243.
   11. Damsky W, et al. J Invest Dermatol. 2020;140(7):1446–1449.e4.
   12. Kim SR, et al. JAAD Case Rep. 2018;4(5):443–445.
   13. Karalilova RV, et al. Rheumatol Int. 2021;41(10):1743–1753.
   14. Peterson DM, Vesely MD. JAAD Case Rep. 2021;10:4–7.
   15. Savage KT, et al. JAAD Case Rep. 2020;6(2):99–102.

 

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Posted on 17 May, 202223 May, 2022