systemic sclerosis leading to decreased skin tightness and improvement in mobility within several weeks depending on severity and the affected areas.33
Vitiligo
Oral and topical tofacitinib as well as oral ruxolitinib and baricitinib were found to be safe and effective for the treatment of vitiligo. Dosages included tofacitinib 5 to 10 mg twice daily, tofacitinib 2%, baricitinib 4 mg daily, and ruxolitinib 20 mg twice daily. Repigmentation occurred within 4 to 10 months depending on severity and location.34
Safety Concerns
The most common adverse events reported with JAK inhibitor use are anemia, thrombocytopenia, urinary tract infections, dizziness, and headaches. More serious adverse effects include reactivation of hepatitis B virus or herpes simplex virus, disseminated tuberculosis, and increase in risk of skin cancers, likely secondary to the immunosuppressive effects. The FDA approved a Boxed Warning for tofacitinib in 2019 after a postmarketing safety clinical trial showed an increased risk of cardiac adverse events, blood clots, cancer, and death, particularly at doses of tofacitinib 10 mg twice daily compared to patients taking a tumor necrosis factor inhibitor.35 Further research is needed to determine the efficacy, route of delivery, and optimal dosage for treating dermatologic conditions with JAK inhibitors.
Conclusion
Separate from the dermatologic indications for which JAK inhibitors are currently approved, much of the evidence for use in off-label dermatoses is summarized in this review. In addition, singular case reports exist utilizing JAK inhibitors for chronic urticaria, Sjögren's syndrome, hypereosinophilic syndrome, chronic mucocutaneous candidiasis, pembrolizumab-induced cutaneous lesions, Behcet’s syndrome, and synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome.36-42 While JAK inhibitors can successfully treat numerous dermatologic conditions, potential adverse events associated with these medications must be weighed against possible benefits, and, most importantly, an informed discussion should take place with patients regarding potential adverse events. For many difficultto- treat conditions, JAK inhibitors may transform treatment paradigms; however, further research and studies should be undertaken to elucidate the real-world efficacy and safety profiles of these new therapies.
Disclosure
The authors declare no conflicts of interest.
References
1. Damsky W, King B. JAK inhibitors in dermatology: the promise of a new drug class. J Am Acad Dermatol. 2017;76(4):736-744. doi: 10.1016/j. jaad.2016.12.005
2. Tegtmeyer K, Zhao J, Maloney N, Atassi G, Beestrum M, Lio P. Offlabel studies on tofacitinib in dermatology: a review. J Dermatolog Treat. 2021;32(4):399-409. doi:10.1080/09546634.2019.1673877
3. Almutairi N, Nour T, Hussain N. Janus Kinase Inhibitors for the Treatment of Severe Alopecia Areata: An Open-Label Comparative Study. Dermatology (Basel, Switzerland). 2019;235(2):130-136. doi:10.1159/000494613
4. Dillon K. A Comprehensive Literature Review of JAK Inhibitors in Treatment of Alopecia Areata. Clin, Cosmet Investig Dermatol.2021;14:691-714. doi:10.2147/CCID.S309215
5. Paudyal A, Zheng M, Lyu L, et al. JAK-inhibitors for dermatomyositis: A concise literature review. Dermatologic Therapy. 2021;34(3):e14939. doi:10.1111/dth.14939
6. Paik J, Casciola-Rosen L, Shin J, et al. Study of Tofacitinib in Refractory Dermatomyositis: An Open-Label Pilot Study of Ten Patients. Arthritis Rheumatol. 2021;73(5):858-865. doi:10.1002/art.41602
7. Ladislau L, Suárez-Calvet X, Toquet S, et al. JAK inhibitor improves type I interferon induced damage: proof of concept in dermatomyositis. Brain. 2018;141(6):1609-1621. doi:10.1093/brain/awy105
8. Aeschlimann F, Frémond M, Duffy D, et al. A child with severe juvenile dermatomyositis treated with ruxolitinib. Brain. 2018;141(11):e80. doi:10.1093/brain/awy255
9. Hornung T, Janzen V, Heidgen F, Wolf D, Bieber T, Wenzel J. Remission of recalcitrant dermatomyositis treated with ruxolitinib. New Engl J Med. 2014;371(26):2537-2538. doi:10.1056/NEJMc1412997
10. Spoerl S, Mathew N, Bscheider M, et al. Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood. 2014;123(24):3832-3842. doi:10.1182/blood-2013-12-543736
11. Okiyama N, Furumoto Y, Villarroel V, et al. Reversal of CD8 T-cell-mediated mucocutaneous graft-versus-host-like disease by the JAK inhibitor tofacitinib. J Investig Dermatol. 2014;134(4):992-1000. doi:10.1038/ jid.2013.476
12. Damsky W, Thakral D, McGeary M, Leventhal J, Galan A, King B. Janus kinase inhibition induces disease remission in cutaneous sarcoidosis and granuloma annulare. J Am Acad Dermatol. 2020;82(3):612-621. doi:10.1016/j.jaad.2019.05.098
13. Wang A, Rahman N, McGeary M, et al. Treatment of granuloma annulare and suppression of proinflammatory cytokine activity with tofacitinib. J Allerg Clin Immunol. 2021;147(5):1795-1809. doi:10.1016/j.jaci.2020.10.012
14. Savage K, Santillan M, Flood K, Charrow A, Porter M, Kimball A. Tofacitinib shows benefit in conjunction with other therapies in recalcitrant hidradenitis suppurativa patients. JAAD Case Rep. 2020;6(2):99-102. doi:10.1016/j.jdcr.2019.10.010
15. A Study of Oral Upadacitinib Tablet Compared to Placebo in Adult Participants With Moderate to Severe Hidradenitis Suppurativa to Assess Change in Disease Symptoms. . ClinicalTrials.gove Identifier: NCT04430855. Updated March 24, 2022. Accessed August 2022. https:// clinicaltrials.gov/ct2/show/NCT04430855
16. Kozera E, Flora A, Frew J. Real-World Safety and Clinical Response of Janus Kinase Inhibitor Upadacitinib in the Treatment of Hidradenitis Suppurativa: A Retrospective Cohort Study. J Am Acad Dermatol. 2022;S0190- 9622(22)02407-0. doi:10.1016/j.jaad.2022.07.047
17. Damsky W, Wang A, Olamiju B, Peterson D, Galan A, King B. Treatment of severe lichen planus with the JAK inhibitor tofacitinib. J Allergy Clin Immunol. 2020;145(6):1708-1710.e2. doi:10.1016/j.jaci.2020.01.031
18. Yang C, Khanna T, Sallee B, Christiano A, Bordone L. Tofacitinib for the treatment of lichen planopilaris: A case series. Dermatol Ther. 2018;31(6):e12656. doi:10.1111/dth.12656
19. Lee J, English J. Improvement in ulcerative necrobiosis lipoidica after janus kinase-inhibitor therapy for polycythemia vera. JAMA Dermatol. 2018;154(6):733-734. doi:10.1001/jamadermatol.2018.0756
20. Damsky W, Singh K, Galan A, King B. Treatment of necrobiosis lipoidica with combination Janus kinase inhibition and intralesional corticosteroid. JAAD Case Rep. 2020;6(2):133-135. doi:10.1016/j.jdcr.2019.11.016
21. Berekmeri A, Mahmood F, Wittmann M, Helliwell P. Tofacitinib for the treatment of psoriasis and psoriatic arthritis. Expert Rev Clin Immunol. 2018;14(9):719-730. doi:10.1080/1744666X.2018.1512404
22. SÅ‚uczanowska-GÅ‚Ä…bowska S, Ziegler-Krawczyk A, Szumilas K, Pawlik A. Role of janus kinase inhibitors in therapy of psoriasis. J Clin Med. 2021;10(19):4307. doi:10.3390/jcm10194307
23. Tian F, Chen Z, Xu T. Efficacy and safety of tofacitinib for the treatment of chronic plaque psoriasis: a systematic review and meta-analysis. J Int Med Res. 2019;47(6):2342-2350. doi:10.1177/0300060519847414
24. Hsu L, Armstrong A. JAK inhibitors: treatment efficacy and safety profile in patients with psoriasis. J Immunol Res. 2014;2014:283617. doi:10.1155/2014/283617
Vitiligo
Oral and topical tofacitinib as well as oral ruxolitinib and baricitinib were found to be safe and effective for the treatment of vitiligo. Dosages included tofacitinib 5 to 10 mg twice daily, tofacitinib 2%, baricitinib 4 mg daily, and ruxolitinib 20 mg twice daily. Repigmentation occurred within 4 to 10 months depending on severity and location.34
Safety Concerns
The most common adverse events reported with JAK inhibitor use are anemia, thrombocytopenia, urinary tract infections, dizziness, and headaches. More serious adverse effects include reactivation of hepatitis B virus or herpes simplex virus, disseminated tuberculosis, and increase in risk of skin cancers, likely secondary to the immunosuppressive effects. The FDA approved a Boxed Warning for tofacitinib in 2019 after a postmarketing safety clinical trial showed an increased risk of cardiac adverse events, blood clots, cancer, and death, particularly at doses of tofacitinib 10 mg twice daily compared to patients taking a tumor necrosis factor inhibitor.35 Further research is needed to determine the efficacy, route of delivery, and optimal dosage for treating dermatologic conditions with JAK inhibitors.
Conclusion
Separate from the dermatologic indications for which JAK inhibitors are currently approved, much of the evidence for use in off-label dermatoses is summarized in this review. In addition, singular case reports exist utilizing JAK inhibitors for chronic urticaria, Sjögren's syndrome, hypereosinophilic syndrome, chronic mucocutaneous candidiasis, pembrolizumab-induced cutaneous lesions, Behcet’s syndrome, and synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome.36-42 While JAK inhibitors can successfully treat numerous dermatologic conditions, potential adverse events associated with these medications must be weighed against possible benefits, and, most importantly, an informed discussion should take place with patients regarding potential adverse events. For many difficultto- treat conditions, JAK inhibitors may transform treatment paradigms; however, further research and studies should be undertaken to elucidate the real-world efficacy and safety profiles of these new therapies.
Disclosure
The authors declare no conflicts of interest.
References
1. Damsky W, King B. JAK inhibitors in dermatology: the promise of a new drug class. J Am Acad Dermatol. 2017;76(4):736-744. doi: 10.1016/j. jaad.2016.12.005
2. Tegtmeyer K, Zhao J, Maloney N, Atassi G, Beestrum M, Lio P. Offlabel studies on tofacitinib in dermatology: a review. J Dermatolog Treat. 2021;32(4):399-409. doi:10.1080/09546634.2019.1673877
3. Almutairi N, Nour T, Hussain N. Janus Kinase Inhibitors for the Treatment of Severe Alopecia Areata: An Open-Label Comparative Study. Dermatology (Basel, Switzerland). 2019;235(2):130-136. doi:10.1159/000494613
4. Dillon K. A Comprehensive Literature Review of JAK Inhibitors in Treatment of Alopecia Areata. Clin, Cosmet Investig Dermatol.2021;14:691-714. doi:10.2147/CCID.S309215
5. Paudyal A, Zheng M, Lyu L, et al. JAK-inhibitors for dermatomyositis: A concise literature review. Dermatologic Therapy. 2021;34(3):e14939. doi:10.1111/dth.14939
6. Paik J, Casciola-Rosen L, Shin J, et al. Study of Tofacitinib in Refractory Dermatomyositis: An Open-Label Pilot Study of Ten Patients. Arthritis Rheumatol. 2021;73(5):858-865. doi:10.1002/art.41602
7. Ladislau L, Suárez-Calvet X, Toquet S, et al. JAK inhibitor improves type I interferon induced damage: proof of concept in dermatomyositis. Brain. 2018;141(6):1609-1621. doi:10.1093/brain/awy105
8. Aeschlimann F, Frémond M, Duffy D, et al. A child with severe juvenile dermatomyositis treated with ruxolitinib. Brain. 2018;141(11):e80. doi:10.1093/brain/awy255
9. Hornung T, Janzen V, Heidgen F, Wolf D, Bieber T, Wenzel J. Remission of recalcitrant dermatomyositis treated with ruxolitinib. New Engl J Med. 2014;371(26):2537-2538. doi:10.1056/NEJMc1412997
10. Spoerl S, Mathew N, Bscheider M, et al. Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood. 2014;123(24):3832-3842. doi:10.1182/blood-2013-12-543736
11. Okiyama N, Furumoto Y, Villarroel V, et al. Reversal of CD8 T-cell-mediated mucocutaneous graft-versus-host-like disease by the JAK inhibitor tofacitinib. J Investig Dermatol. 2014;134(4):992-1000. doi:10.1038/ jid.2013.476
12. Damsky W, Thakral D, McGeary M, Leventhal J, Galan A, King B. Janus kinase inhibition induces disease remission in cutaneous sarcoidosis and granuloma annulare. J Am Acad Dermatol. 2020;82(3):612-621. doi:10.1016/j.jaad.2019.05.098
13. Wang A, Rahman N, McGeary M, et al. Treatment of granuloma annulare and suppression of proinflammatory cytokine activity with tofacitinib. J Allerg Clin Immunol. 2021;147(5):1795-1809. doi:10.1016/j.jaci.2020.10.012
14. Savage K, Santillan M, Flood K, Charrow A, Porter M, Kimball A. Tofacitinib shows benefit in conjunction with other therapies in recalcitrant hidradenitis suppurativa patients. JAAD Case Rep. 2020;6(2):99-102. doi:10.1016/j.jdcr.2019.10.010
15. A Study of Oral Upadacitinib Tablet Compared to Placebo in Adult Participants With Moderate to Severe Hidradenitis Suppurativa to Assess Change in Disease Symptoms. . ClinicalTrials.gove Identifier: NCT04430855. Updated March 24, 2022. Accessed August 2022. https:// clinicaltrials.gov/ct2/show/NCT04430855
16. Kozera E, Flora A, Frew J. Real-World Safety and Clinical Response of Janus Kinase Inhibitor Upadacitinib in the Treatment of Hidradenitis Suppurativa: A Retrospective Cohort Study. J Am Acad Dermatol. 2022;S0190- 9622(22)02407-0. doi:10.1016/j.jaad.2022.07.047
17. Damsky W, Wang A, Olamiju B, Peterson D, Galan A, King B. Treatment of severe lichen planus with the JAK inhibitor tofacitinib. J Allergy Clin Immunol. 2020;145(6):1708-1710.e2. doi:10.1016/j.jaci.2020.01.031
18. Yang C, Khanna T, Sallee B, Christiano A, Bordone L. Tofacitinib for the treatment of lichen planopilaris: A case series. Dermatol Ther. 2018;31(6):e12656. doi:10.1111/dth.12656
19. Lee J, English J. Improvement in ulcerative necrobiosis lipoidica after janus kinase-inhibitor therapy for polycythemia vera. JAMA Dermatol. 2018;154(6):733-734. doi:10.1001/jamadermatol.2018.0756
20. Damsky W, Singh K, Galan A, King B. Treatment of necrobiosis lipoidica with combination Janus kinase inhibition and intralesional corticosteroid. JAAD Case Rep. 2020;6(2):133-135. doi:10.1016/j.jdcr.2019.11.016
21. Berekmeri A, Mahmood F, Wittmann M, Helliwell P. Tofacitinib for the treatment of psoriasis and psoriatic arthritis. Expert Rev Clin Immunol. 2018;14(9):719-730. doi:10.1080/1744666X.2018.1512404
22. SÅ‚uczanowska-GÅ‚Ä…bowska S, Ziegler-Krawczyk A, Szumilas K, Pawlik A. Role of janus kinase inhibitors in therapy of psoriasis. J Clin Med. 2021;10(19):4307. doi:10.3390/jcm10194307
23. Tian F, Chen Z, Xu T. Efficacy and safety of tofacitinib for the treatment of chronic plaque psoriasis: a systematic review and meta-analysis. J Int Med Res. 2019;47(6):2342-2350. doi:10.1177/0300060519847414
24. Hsu L, Armstrong A. JAK inhibitors: treatment efficacy and safety profile in patients with psoriasis. J Immunol Res. 2014;2014:283617. doi:10.1155/2014/283617
