Jingjing Xie1,2*
Zhiling Li
Ertao Jia- 1The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
- 2The Department of Rheumatology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, China
- 3Guangzhou University of Chinese Medicine, Guangzhou, China
Polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes (POEMS) syndrome is a multisystem disorder that has limited treatment options. Here, we described a case of a 55-year-old female subject who was treated for multiple drugs, but the skin symptoms continued to progress; the patient responded well to baricitinib. This suggests that JAK/STAT signaling pathways play an essential role in the pathological process of POEMS syndrome.
1 Introduction
Polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes (POEMS) syndrome is a multisystem disorder that has limited treatment options (Brown and Ginsberg, 2019). Majority of patients with POEMS syndrome present with hyperpigmentation, hemangiomas, and hypertrichosis. However, most patients do not benefit from the current approaches available for the treatment of these cutaneous symptoms. Herein, we report the case of a patient with POEMS syndrome who presented with six types of skin changes and responded well to baricitinib, with all skin lesions resolving over the treatment period.
2 Case report
The patient is a 55-year-old female subject, who, in 2014, was initially diagnosed with systemic sclerosis due to pulmonary fibrosis and skin changes, including hypertrichosis of the limbs and jaws, thickening and swelling of the skin, hyperpigmentation, hemangiomas, Raynaud’s phenomenon, and swelling of the back and lower limbs. Skin biopsy of the right leg revealed hyperkeratosis of the epidermis, mild hyperplasia of the dermis, and sparse collagen fibers in the middle without dermal vascularization. In 2016, the patient complained of bilateral lower limb pain, numbness, and paresthesia. An electrophysiological examination suggested multiple peripheral neuropathies. Ultrasonography revealed bilateral lymphadenopathy in the neck and supraclavicular, axillary, inguinal, mesenteric, and retroperitoneal regions. Laboratory tests revealed diabetes mellitus and mild renal dysfunction, as well as serum vascular endothelial growth factor (VEGF) levels of 7,924 pg/mL (normal range: 0–600 pg/mL). Furthermore, serum protein electrophoresis revealed a monoclonal band of IgA lambda +. Consequently, the patient was diagnosed with POEMS syndrome due to multiple peripheral neuropathy symptoms, skin changes, and a high level of VEGF, based on the current diagnostic criteria for POEMS syndrome, i.e., the Dispenzieri diagnostic criteria (Miest et al., 2013).
The patient refused bortezomib; therefore, an alternative treatment regimen was adopted. Despite treatment with multiple drugs, including thalidomide, cyclophosphamide, glucocorticoids, and Kunxian capsules, supplemented with the usual dose, the skin symptoms continued to progress, while other non-skin symptoms improved. Hence, the treatment plan was modified, and oral baricitinib (2 mg/day) was administered. The cutaneous symptoms improved after 3 months of baricitinib treatment, and full recovery was noted after 1 year (Figure 1). The patient showed sustained improvement in the skin symptoms over 18 months of follow-up, and serum VEGF levels decreased considerably to 50.62 pg/mL.
FIGURE 1. Prior to the treatment with baricitinib, hyperpigmentation, skin thickening on the face, upper and lower limbs with hypertrichosis and hemangiomas in the extensor lateral forearms, and swollen lower limbs were observed (A). The skin changes have partially dissipated after 3 months of treatment (B) and have been almost fully reversed after 1 year (C).
3 Discussion
The Janus kinase (JAK)/STAT pathway is involved in various skin disorders, including alopecia areata, atopic dermatitis, lupus erythematosus, dermatomyositis, psoriasis, and vitiligo (Solimani et al., 2019). Vitiligo is an autoimmune skin disease in which melanocytes are reduced in association with the activation of the interferon-γ (IFN-γ) and CXCL-10 signaling pathways (Frisoli et al., 2020). The JAK inhibitor baricitinib, which has been shown to block IFN-γ signaling and contribute to re-pigmentation, has been approved for treatment of patients with vitiligo (Qi et al., 2021; Yan et al., 2022). Interestingly, in the present case, hyperpigmentation was treated with baricitinib, which is in contrast to the skin symptoms of vitiligo.
To the best of our knowledge, this is the first report on the successful use of baricitinib to treat skin symptoms associated with POEMS syndrome. The pathogenic mechanisms underlying the skin symptoms associated with POEMS syndrome are poorly understood. However, VEGF has been identified as a key cytokine involved in the pathogenesis of this disorder and is known to reflect the disease activity (Dispenzieri, 2017). Du et al. reported that VEGF expression is associated with JAK/STAT signaling in psoriasis (Du et al., 2020). The role of JAK/STAT in rheumatoid arthritis and new vessel formation has also been reported. Paola et al. explored the anti-angiogenic role of tofacitinib, another JAK inhibitor, in experimental arthritis, which was attributed to inhibition of the pro-angiogenic effects of VEGF (Di Benedetto et al., 2021). Further evidence has confirmed that among the tyrosine kinase cell receptor (VEGFR) 2-mediated signaling pathways, the JAK/STAT signaling pathway, especially the STAT3 signaling pathway, is a critical target and biomarker of angiogenesis (Zhang et al., 2011). Given these findings and our observation with the present case, we propose that angiogenesis is the primary process involved in the pathogenesis of cutaneous changes in patients with POEMS syndrome.
4 Conclusion
Baricitinib is a promising treatment for skin symptoms in patients with POEMS, which can be attributed to the targeting of JAK/STAT signaling to inhibit angiogenesis. However, further studies are required to better understand the pathogenic mechanisms underlying POEMS syndrome, specifically the role of JAK/STAT3 signaling and angiogenesis.
Data availability statement
The original contributions presented in the study are included in the article/Supplementary material; further inquiries can be directed to the corresponding authors.
Ethics statement
Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article. Written informed consent was obtained from the participant/patient(s) for the publication of this case report.
Author contributions
JX, ZL, and YJ prepared the study documents. DT, XQ, and EJ were responsible for patient contact and data collection. JX and JZ drafted the manuscript. All authors contributed to the article and approved the submitted version.
Funding
This study was funded by the Sanming Project of Medicine in Shenzhen (SZSM201612080).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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References
Brown, R., and Ginsberg, L. (2019). POEMS syndrome: clinical update. J. Neurol. 266, 268–277. (1432-1459 (Electronic)). doi:10.1007/s00415-018-9110-6
Di Benedetto, P., Ruscitti, P., Berardicurti, O. A-O., Panzera, N., Grazia, N., Di Vito Nolfi, M., et al. (2021). Blocking Jak/STAT signalling using tofacitinib inhibits angiogenesis in experimental arthritis. Arthritis Res. Ther. 23, 213. (1478-6362 (Electronic)). doi:10.1186/s13075-021-02587-8
Dispenzieri, A. (2017). POEMS syndrome: 2017 update on diagnosis, risk stratification, and management. Am. J. Hematol. 92, 814–829. (1096-8652 (Electronic)). doi:10.1002/ajh.24802
Du, Y., Jiang, S., Cheng, L., and Liu, J. (2020). JAK/STAT and VEGF/PAK1 signaling as emerging targets for topical treatment of psoriasis: a pilot study. Int. J. Clin. Exp. Pathol. 13, 3111–3119. (1936-2625 (Electronic)).
Frisoli, M. L., Essien, K., and Harris, J. E. (2020). Vitiligo: mechanisms of pathogenesis and treatment. Annu. Rev. Immunol. 38, 621–648. (1545-3278 (Electronic)). doi:10.1146/annurev-immunol-100919-023531
Miest, R. Y., Comfere, N., Dispenzieri, A., Fau-Lohse, C. M., and el-Azhary, R. A. (2013). Cutaneous manifestations in patients with POEMS syndrome. Int. J. dermatology 52, 1349–1356. (1365-4632 (Electronic)). doi:10.1111/j.1365-4632.2012.05648.x
Qi, F., Liu, F., and Gao, L. (2021). Janus kinase inhibitors in the treatment of vitiligo: a review. Front. Immunol. 12, 790125. (1664-3224 (Electronic)). doi:10.3389/fimmu.2021.790125
Solimani, F., Meier, K., and Ghoreschi, K. (2019). Emerging topical and systemic JAK inhibitors in dermatology. Front. Immunol. 10, 2847. (1664-3224 (Electronic)). doi:10.3389/fimmu.2019.02847
Yan, T. M., Zhang, H., Wu, X. Y., and Zhang, Z. Y. (2022). Successful treatment of generalized granuloma annulare with baricitinib. J. Eur. Acad. Dermatol Venereol. 36, e500–e502. (1468-3083 (Electronic)). doi:10.1111/jdv.18031
Keywords: POEMS syndrome, Janus kinase inhibitor (JAKI), JAK/STAT signaling, skin changes, case report
Citation: Xie J, Li Z, Jiang Y, Tang D, Qiu X, Jia E and Zhang J (2023) Baricitinib treatment for refractory skin changes in POEMS syndrome: a case report. Front. Pharmacol. 14:1191158. doi: 10.3389/fphar.2023.1191158
Received: 21 March 2023; Accepted: 23 August 2023;
Published: 12 September 2023.
Edited by:
Yan Huang, Anhui Medical University, ChinaReviewed by:
Su-Peng Yeh, China Medical University Hospital, TaiwanMaria Giovanna Danieli, Università Politecnica delle Marche, Italy
Copyright © 2023 Xie, Li, Jiang, Tang, Qiu, Jia and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Jingjing Xie, xiaotu0901@126.com; Jianyong Zhang, 13823396319@163.com