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№4' 2021

DERMATOVENEREOLOGY

International Medical Journal, Vol. 27., Iss. 4, 2021, P. 70−76.


DOI (https://doi.org/10.37436/2308-5274-2021-4-13)

JANUS KINASE INHIBITORS IN DERMATOLOGY: PRESENT AND FUTURE


Inessa Mykhailivna Serbina, Ovcharenko Yu. S.

Kharkiv Medical Academy of Postgraduate Education
V. N. Karazin Kharkiv National University, Ukraine

New facts about the importance of the JAK−STAT signaling system in development of a number of inflammatory and autoimmune diseases are now emerging. The JAK−STAT system, or pathway consisting of Janus kinase (JAK) and signal transducer protein as well as transcription activator (STAT), transmits information from extracellular polypeptide signals through transmembrane receptors directly to target gene promoters in the nucleus without the involvement of secondary messengers. The JAK−STAT system plays an important role in the implementation of immunological processes and is considered a therapeutic target in immune−mediated inflammatory diseases. JAK inhibitors are so−called yakinibs, low molecular weight chemically synthesized targeted drugs that inhibit intracellular JAK signaling molecules and interrupt the effect of interleukins on the cell. Drugs have an acceptable benefit−risk ratio. The most common side effects are infections of the upper respiratory tract, urinary tract and gastrointestinal tract. The safety profile of topical JAK inhibitors is better than that of oral drugs due to their minimal systemic absorption. For the first time, JAK inhibitors have been shown to be effective in rheumatoid arthritis and myelofibrosis. Disordered regulation of the JAK−STAT signaling pathway is observed in various inflammatory and autoimmune skin diseases. JAK molecules are overexpressed in epidermis, dermis in psoriasis, atopic dermatitis, alopecia areata and vitiligo. Decoding the new mechanisms of pathogenesis of psoriasis, atopic dermatitis, alopecia areata, vitiligo created the preconditions for improving their pharmacotherapy with the use of inhibitors of Janus kinases. Today, JAK inhibitors are the most promising specific target agents when treating the immune−mediated dermatoses.

Key words: JAK−STAT system, Janus kinase inhibitors, psoriasis, atopic dermatitis, alopecia areata, vitiligo.


REFERENCES


1. The emerging role of Janus kinase inhibitors in the treatment of autoimmune and inflammatory diseases / W. Damsky et al. // J. of Allergy and Clinical Immunology. 2021. Vol. 147, Iss. 3. P. 814−826. doi: 10.1016/j.jaci.2020.10.022

2. Garcia−Melendo C., Cubiró X., Puig L. Janus Kinase Inhibitors in Dermatology: Part 1 − General Considerations and Applications in Vitiligo and Alopecia Areata // Actas Dermo−Sifiliográficas (Engl. Ed.). 2021. Vol. 112, Iss. 6. P. 503−515. doi: https://doi.org/10.1016/j.adengl.2021.03.012

3. T−cell pathology in skin inflammation / R. W. K. Sabat, L. Loyal, W. D. Döcke, L. Ghoreschi // Semin. Immunopathol. 2019. Vol. 41. P. 359−377. doi: 10.1007/s00281−019−00742−7

4. Bonilla−Herna M. G., Miranda−Carús M. E., Martin−Mola E. New drugs beyond biologics in rheumatoid arthritis: the kinase inhibitors // Rheumatology (Oxford). 2011. Vol. 50, Iss. 9. P. 1542−1550. doi: 10.1093/rheumatology/ker192

5. Damsky W., King B. A. JAK inhibitors in dermatology: the promise of a new drug class // J. Am. Acad. Dermatol. 2017. Vol. 76, Iss. 4. P. 736−744. doi: 10.1016/j.jaad.2016.12.005

6. Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases / D. M. Schwartz, M. Bonelli, M. Gadina, J. J. O'Shea // Nat. Rev. Rheumatol. 2016. Vol. 12, Iss. 1. P. 25−36. doi: 10.1038/nrrheum.2015.167

7. Gündüz Ö. JAK/STAT pathway modulation: does it work in dermatology? // Dermatol. Ther. 2019. Vol. 32, Iss. 3. P. e12903. doi: 10.1111/dth.12903

8. Mazurov V. I., Belyaeva I. B. Klinicheskaya znachimost' ingibitorov yanus−kinaz v terapii revmatoidnogo artrita: dostizheniya i perspektivy // Sovremennaya revmatologiya. 2019. T. 13, № 4. S. 116−123. doi: 10/14412/1996−7012−2019−4−116−123

9. Selective JAKinibs: prospects in inflammatory and autoimmune diseases / A. T. Virtanen, T. Haikarainen, J. Raivola, O. Silvennoinen // BioDrugs. 2019. Vol. 33. P. 15−32. doi: 10.1007/s40259−019−00333−w

10. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases / D. M. Schwartz et al. // Nat. Rev. Drug. Discov. 2017. Vol. 16, Iss. 12. P. 843−862. doi: 10.1038/nrd.2017.201

11. JAK−STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects / S. Banerjee et al. // Drugs. 2017. Vol. 77, Iss. 5. P. 521−546. doi: 10.1007/s40265−017−0701−9

12. Baker K. F., Isaacs J. D. Novel therapies for immune−mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn's disease and ulcerative colitis? // Ann. Rheum. Dis. 2018. Vol. 77, Iss. 2. P. 175−187. doi: 10.1136/annrheumdis−2017−211555

13. García−Melendo C., Cubiró X., Puig L. Janus Kinase Inhibitors in Dermatology: Part 2: Applications in Psoriasis, Atopic Dermatitis, and Other Dermatoses // Actas Dermosifiliogr. (Engl Ed). 2021. Vol. 112, Iss. 7. P. 586−600. doi: https://doi.org/10.1016/j.adengl.2021.05.008

14. Baricitinib in patients with refractory rheumatoid arthritis / M. C. Genovese et al. // N. Engl. J. Med. 2016. Vol. 374. P. 1243−1252. doi: 10.1056/NEJMoa1507247

15. Systematic review and meta−analysis of serious infections with tofacitinib and biologic disease−modifying antirheumatic drug treatment in rheumatoid arthritis clinical trials / V. Strand et al. // Arthritis Res. Ther. 2015. Vol. 17. P. 362. doi: 10.1186/s13075−015−0880−2

16. Maneiro J. R., Souto A., Gomez−Reino J. J. Risks of malignancies related to tofacitinib and biological drugs in rheumatoid arthritis: Systematic review, meta−analysis, and network meta−analysis // Semin Arthritis Rheum. 2017. Vol. 47, Iss. 2. P. 149−156. doi: 10.1016/j.semarthrit.2017.02.007

17. Tofacitinib, an oral Janus kinase inhibitor: analysis of malignancies across the rheumatoid arthritis clinical development programme / J. R. Curtis et al. // Ann. Rheum. Dis. 2016. Vol. 75. P. 831−841. doi: 10.1136/annrheumdis−2014−205847

18. Aggressive B−cell lymphomas in patients with myelofibrosis receiving JAK1/2 inhibitor therapy / E. Porpaczy et al. // Blood. 2018. Vol. 132. P. 694−706. doi: https://doi.org/10.1182/blood−2019−01−895136

19. Sivaraman P., Cohen S. B. Malignancy and Janus kinase inhibition // Rheum. Dis. Clin. N. Am. 2017. Vol. 43. P. 79−93. doi: 10.1016/j.rdc.2016.09.008

20. A randomized phase 2b trial of baricitinib, an oral Janus kinase (JAK) 1/JAK2 inhibitor, in patients with moderate−to−severe psoriasis / K. A. Papp et al. // Br. J. Dermatol. 2016. Vol. 174. P. 1266−1276. doi: 10.1111/bjd.14403

21. Plosker G. L. Ruxolitinib: a review of its use in patients with myelofibrosis // Drugs. 2015. Vol. 75. P. 297−308. doi: 10.1007/s40265−015−0351−8

22. JAK−STAT in lipid metabolism of adipocytes / D. Xu, C. Yin, S. Wang, Y. Xiao // JAKSTAT. 2013. Vol. 2. P. e27203. doi: 10.4161/jkst.27203

23. Human TYK2 deficiency: mycobacterial and viral infections without hyper−IgE syndrome / A. Y. Kreins et al. // J. Exp. Med. 2015. Vol. 212. P. 1641−1662. doi: 10.1084/jem.20140280

24. Topical tofacitinib for atopic dermatitis: a phase IIa randomized trial / R. Bissonnette et al. // Br. J. Dermatol. 2016. Vol. 175. P. 902−911. doi: 10.1111/bjd.14871

25. Craiglow B. G., Tavares D., King B. A. Topical ruxolitinib for the treatment of alopecia universalis // JAMA Dermatol. 2016. Vol. 152. P. 490−491. doi: 10.1001/jamadermatol.2015.4445

26. Solimani F., Meier K., Ghoreschi K. Emerging Topical and Systemic JAK Inhibitors in Dermatology // Front Immunol. 2019. Vol. 10. P. 2847. doi: 10.3389/fimmu.2019.02847

27. Calautti E., Avalle L., Poli V. Psoriasis: a STAT3−centric view // Int. J. Mol. Sci. 2018. Vol. 19. P. 171. doi: 10.3390/ijms19010171

28. Hawkes J. E., Chan T. C., Krueger J. G. Psoriasis pathogenesis and the development of novel targeted immune therapies // J. Allergy Clin. Immunol. 2017. Vol. 140. P. 645−653. doi: 10.1016/j.jaci.2017.07.004

29. 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. Vol. 10. P. 533−539. doi: 10.2147/DDDT.S82599

30. Tofacitinib versus etanercept or placebo in moderate−to−severe chronic plaque psoriasis: a phase 3 randomised non−inferiority trial / H. Bachelez et al. // Lancet. 2015. Vol. 386, Iss. 9993. P. 552−561. doi: 10.1016/S0140−6736(14)62113−9

31. Shreberk−Hassidim R., Ramot Y., Zlotogorski A. Janus kinase inhibitors in dermatology: A systematic review // J. Am. Acad. Dermatol. 2017. Vol. 76, Iss. 4. P. 745−753. doi: 10.1016/j.jaad.2016.12.004

32. Treatment of plaque psoriasis with an ointment formulation of the Janus kinase inhibitor, tofacitinib: a Phase 2b randomized clinical trial / K. A. Papp et al. BMC Dermatol. 2016. Vol. 3, Iss. 16 (1). P. 15. doi: 10.1186/s12895−016−0051−4

33. Downmodulation of key inflammatory cell markers with a topical Janus kinase 1/2 inhibitor / N. Punwani et al. // Br. J. Dermatol. 2015. Vol. 173, Iss. 4. P. 989−999. doi: 10.1111/bjd.13994

34. Craiglow B. G., King B. A. Tofacitinib citrate for the treatment of vitiligo: a pathogenesis−directed therapy // JAMA Dermatol. 2015. Vol. 151, Iss. 10. P. 1110−1112. doi: 10.1001/jamadermatol.2015.1520

35. Oral tofacitinib: a promising treatment in atopic dermatitis, alopecia areata and vitiligo / M. Vu et al. // Clin. Exp. Dermatol. 2017. Vol. 42, Iss. 8. P. 942−944. doi: 10.1111/ced.13290

36. Micro−focused phototherapy associated to Janus kinase inhibitor: a promising valid therapeutic option for patients with localized vitiligo / S. Gianfaldoni et al. // Open Access Maced. J. Med Sci. 2018. Vol. 6. P. 46−48. doi: 10.3889/oamjms.2018.042

37. Open−label pilot study of tofacitinib 2 % for the treatment of refractory vitiligo / P. Mobasher et al. // Br. J. Dermatol. 2020. Vol. 182, Iss. 4. P. 1047−1049. doi: 10.1111/bjd.18606

38. McKesey J., Pandya A. G. A pilot study of 2 % tofacitinib cream with narrowband ultraviolet B for the treatment of facial vitiligo // J. Am. Acad. Dermatol. 2019. Vol. 81, Iss. 2. P. 646−648. doi: 10.1016/j.jaad.2019.04.032

39. Importance of light in the treatment of vitiligo with JAK−inhibitors / D. Joshipura et al. // J. Dermatol. Treat. 2018. Vol. 29, Iss. 1. P. 98−99. doi: 10.1080/09546634.2017.1339013

40. Weidinger S., Novak N. Atopic dermatitis // Lancet. 2016. Vol. 387. P. 1109−1122. doi: 10.1016/S0140−6736(15)00149−X

41. The transcription factor STAT3 is required for T helper 2 cell development / G. L. Stritesky et al. // Immunity. 2011. Vol. 34, Iss. 1. P. 39−49. doi: 10.1016/j.immuni.2010.12.013

42. Bao L., Zhang H., Chan L. S. The involvement of the JAK−STAT signaling pathway in chronic inflammatory skin disease atopic dermatitis. JAKSTAT. 2013. Vol. 2, Iss. 3. P. e24137. doi: 10.4161/jkst.24137

43. Levy L. L., Urban J., King B. A. Treatment of recalcitrant atopic dermatitis with the oral Janus kinase inhibitor tofacitinib citrate // J. Am. Acad. Dermatol. 2015. Vol. 73. P. 395−399. doi: 10.1016/j.jaad.2015.06.045

44. Abrocitinib versus Placebo or Dupilumab for Atopic Dermatitis / T. Bieber et al. // N. Engl. J. Med. 2021. Vol. 384. P. 1101−1112. doi: 10.1056/NEJMoa2019380

45. Olumiant. European Medicines Agency. URL: https://www.ema.europa.eu/en/medicines/human/EPAR/olumiant

46. Serbina I. M. Patogenez gnezdnoi alopetsii: immunnye mekhanizmy // Mezhdunar. med. zhurn. 2016. T. 22, № 3. S. 65−71.

47. Paus R. The Evolving Pathogenesis of Alopecia Areata: Major Open Questions // J. Investig. Dermatol. Symp. Proc. 2020. Vol. 20, Iss. 1. P. S6−S10. doi: 10.1016/j.jisp.2020.04.002

48. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition / L. Xing et al. // Nat. Med. 2014. Vol. 20. P. 1043−1049. doi: 10.1038/nm.3645

49. Janus kinase (JAK) inhibitors for the treatment of skin and hair disorders: a review of literature / A. Samadi et al. // J. Dermatolog. Treat. 2017. Vol. 28, Iss. 6. P. 476−483. doi: 10.1080/09546634.2016.1277179

50. Iorizzo M., Tosti A. Emerging drugs for alopecia areata: JAK inhibitors // Expert Opin. Emerg. Drugs. 2018. Vol. 23, Iss. 1. P. 77−81. doi: 10.1080/14728214.2018.1444750

51. Craiglow B. G., King B. A. Killing two birds with one stone: oral tofacitinib reverses alopecia universalis in a patient with plaque psoriasis // J. Invest. Dermatol. 2014. Vol. 134. P. 2988−2990. doi: 10.1038/jid.2014.260

52. Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata / M. K. Crispin et al. // JCI Insight. 2016. Vol. 1, Iss. 15. P. e89776. doi: 10.1172/jci.insight.89776

53. Craiglow B. G., Liu L., King B. Tofacitinib for the treatment of alopecia areata and variants in adolescents // J. Am. Acad. Dermatol. 2017. Vol. 76. P. 29−32. doi: 10.1016/j.jaad.2016.09.006

54. Oral ruxolitinib induces hair regrowth in patients with moderate−to−severe alopecia areata / J. Mackay−Wiggan et al. // JCI Insight. 2016. Vol. 1, Iss. 15. P. e89790. doi: 10.1172/jci.insight.89790

55. Topical Janus kinase inhibitors for the treatment of pediatric alopecia areata / C. B. Bayart et al. // J. Am. Acad. Dermatol. 2017. Vol. 77, Iss. 1. P. 167−170. doi: 10.1016/j.jaad.2017.03.024

56. Putterman E., Castelo−Soccio L. Topical 2 % tofacitinib for children with alopecia areata, alopecia totalis, and alopecia universalis // J. Am. Acad. Dermatol. 2018. Vol. 78, Iss. 6. P. 1207−1209. doi: 10.1016/j.jaad.2018.02.031

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