Dermatology: Practical and Conceptual Research Letter | Dermatol Pract Concept. 2025;15(2):5139 1 Upadacitinib for Treatment-Resistant Urticarial Vasculitis: A Case Study and Therapeutic Insight Francesca Falcinelli1, Edoardo Conticini2, Luca Cantarini2, Bruno Frediani2, Pietro Rubegni1, Laura Calabrese1,3 1 Dermatology Unit and Skin Bank, Department of Medical, Surgical and Neurosciences, Siena University Hospital, Siena – Italy 2 Rheumatology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Italy 3 Institute of Dermatology, Catholic University of the Sacred Heart, Rome, Italy Citation: Falcineli F, Conticini E, Cantarini L, Frediani B, Rubegni P, Calabrese L. Upadacitinib for Treatment-Resistant Urticarial Vasculitis: A Case Study and Therapeutic Insight. Dermatol Pract Concept. 2025;15(2):5139. DOI: https://DOI.org/10.5826/ dpc.1502a5139 Accepted: December 2, 2024; Published: April 2025 Copyright: ©2025 Falcinelli et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors read and approved the final version of the article. F.F. contributed to design, writing, editing. E.C. carried out data collection, therapy, and review. L.C. contributed to design, writing, therapy, and review. P.R., B.F., L.C. carried out review. Corresponding Author: Francesca Falcinelli, MD; Department of Dermatology - Division of Medical, Surgical and Neurosciences, University of Siena Le Scotte Hospital, Viale Bracci 16, 53100 Siena (Italy); ORCID ID: 0000-0002-3149-8695 E-mail: f.falcinelli@student. unisi.it Informed Consent: The patient in this manuscript has given written informed consent to the publication of her case details. Key words: Urticarial Vasculitis, Leukocytoclastic Vasculitis, Upadacitinib, Jak Inhibitors, Janus Kinase Inhibitors Introduction Urticarial vasculitis (UV) is a rare entity characterized by recurrent episodes of wheal-like lesions and evidence of leukocytoclastic vasculitis on skin biopsy. Although its etio- pathogenesis remains undefined, it seems to be driven by a type III immune reaction, and its treatment is often chal- lenging [1]. Case Presentation A 77-year-old woman presented for itchy urticarial lesions, widespread on the limbs and trunk, that had been present for about 15 years with a chronic relapsing course. She had a his- tory of chronic urticaria, psoriatic arthritis, and mild psoriasis vulgaris that had been effectively treated over the years with corticosteroids, antihistamines, and cyclosporin, which was gradually tapered due to prolonged remission. After a SARS- CoV-2 infection, the patient reported a flare of oligoar- thritis [Disease Activity in PSoriatic Arthitis (DAPSA) 28], which was treated with methotrexate, then discontinued due to gastrointestinal intolerance, and subsequently with adalimumab 40 mg every other week. After three months of treatment with adalimumab, a partial improvement in ar- thritis was observed (DAPSA 18), despite a severe worsening of urticarial skin lesions, whereby the patient came to our attention. On skin examination, diffuse pinkish and orange- colored wheals were present on the limbs and trunk, asso- ciated with ecchymotic hyperpigmentation (Figure 1A–C). No sign of psoriasis was present [Psoriasis Area and Severity 2 Research Letter | Dermatol Pract Concept. 2025;15(2):5139 Index (PASI) 0]. Upon considering the persistence of the le- sions present longer than 24 hours, their color, and failure to disappear upon pressure, urticarial vasculitis was suspected, and a biopsy was performed, showing leukocytoclastic vascu- litis. Blood examinations revealed increased C-reactive pro- tein, normal C1q and complement levels as well as negative autoimmunity antibodies screening. Based on clinical and histopathologic data, a diagnosis of UV was made. Therapy with adalimumab was suspended and upadacitinib 15 mg daily was started. After one month, the patient reported partial improvement of cutaneous and articular symptoms, with clear worsening eight hours after taking medication. Therefore, we decided to increase the dosage of upadaci- tinib to 15 mg twice a day, resulting in complete remission of urticarial lesions and significant improvement in artrithis (DAPSA 5), at follow-up after three months (Figure 1D–F). Conclusion Upadacitinib is a selective JAK-1 inhibitor recently ap- proved for the treatment of psoriatic arthritis and atopic dermatitis. Nevertheless, the drug targets multiple inflam- matory cytokines involved in the pathogenesis of various inflammatory diseases [2]. With regard to JAKi, the litera- ture reports a successful use of the pan-JAKi tofacitinib in one case of UV [3] and in one case of leukocytoclastic vas- culitis [4]. However, evidence of the role of the JAK/STAT pathway in cutaneous vasculitis is increasingly growing. Several studies have reported the involvement of the JAK/ STAT pathway in ANCA-associated vasculitis [5] as well as in leukocytoclastic vasculitis. Indeed, Ebata et al. recently demonstrated, by immunofluorescence, a significantly in- creased expression of phosphorylated JAK1/JAK2 in skin Figure 1. (A-C) Clinical appearance at presentation: wheal-like lesions widespread on the limbs and trunk associated with ecchymotic hyperpigmentation. (D-F) Complete remission of skin lesions after three months of treatment with upadacitinib. Research Letter | Dermatol Pract Concept. 2025;15(2):5139 3 samples of cutaneous leukocytoclastic vasculitis compared to healthy controls [6]. Our case provides evidence of the promising efficacy of upadacitinib for the treatment of refractory UV and also highlights the potential of this drug in cases featuring mul- tiple concomitant immune-mediated comorbidities, quite frequent in clinical practice, thanks to its pleiotropism of action. Nevertheless, further investigations should be en- couraged to determine the role of the JAK/STAT pathway in UV and the possible effective and safe use of JAKi in this condition. References 1. Marzano AV, Maronese CA, Genovese G, et al. Urticarial vasculi- tis: Clinical and laboratory findings with a particular emphasis on differential diagnosis. J Allergy Clin Immunol. Apr 2022;149(4): 1137-1149. DOI:10.1016/j.jaci.2022.02.007. PMID: 35396080 2. Mohamed MF, Bhatnagar S, Parmentier JM, Nakasato P, Wung P. Upadacitinib: Mechanism of action, clinical, and translational science. Clin Transl Sci. Jan 2024;17(1):e13688. DOI:10.1111/cts.13688. PMID: 37984057 3. Mansouri P, Mozafari N, Chalangari R, Martits-Chalangari K. Efficacy of oral tofacitinib in refractory chronic sponta- neous urticaria and urticarial vasculitis. Dermatol Ther. Dec 2022;35(12):e15932. DOI:10.1111/dth.15932. PMID: 36226796 4. Zhu KJ, Yang PD, Xu Q. Tofacitinib Treatment of Refractory Cutaneous Leukocytoclastic Vasculitis: A Case Report. Front Immunol. 2021;12:695768. DOI:10.3389/fimmu.2021.695768. PMID: 34248994 5. Rathore U, Thakare DR, Patro P, Agarwal V, Sharma A, Misra DP. A systematic review of clinical and preclinical evi- dences for Janus kinase inhibitors in large vessel vasculitis. Clin Rheumatol. Jan 2022;41(1):33-44. DOI:10.1007/s10067-021 -05973-4. PMID: 34729652 6. Ebata A, Ogawa-Momohara M, Fukaura R, et al. Increased Janus kinase activation in cutaneous vasculitis. J Am Acad Dermatol. Mar 2024;90(3):627-629. DOI:10.1016/j.jaad.2023.10.056. PMID: 37924954