Dermatology: Practical and Conceptual Research Letter | Dermatol Pract Concept. 2023;13(1):e2023023 1 Localized Vitiligo and Post-Inflammatory Hypopigmentation at the Injection Site of a COVID-19 mRNA Vaccine Dora Mancha1, Joana Antunes1,2, Luís Soares-de-Almeida1,2,3, João Borges-Costa1,2,3,4, Paulo Filipe1,2,3 1 Dermatology Department, Hospital de Santa Maria, Centro Hospitalar Universitário de Lisboa Norte, Lisbon, Portugal 2 Dermatology Universitary Clinic, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal 3 Dermatology Research Unit, Instituto de Medicina Molecular, Universidade de Lisboa, Lisbon, Portugal 4 Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisbon, Portugal Key words: vitiligo, COVID-19, SARS-CoV2, mRNA, vaccine, BNT162b2 Citation: Mancha D, Antunes J, Soares-de-Almeida L, Borges-Costa J, Filipe P. Localized Vitiligo and Post-Inflammatory Hypopigmentation at the Injection Site of a COVID-19 mRNA vaccine. Dermatol Pract Concept. 2023;13(1):e2023023. DOI: https://doi.org/10.5826/ dpc.1301a23 Accepted: May 2, 2022; Published: January 2023 Copyright: ©2023 Mancha 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 have contributed significantly to this publication. Corresponding author: Dora Mancha, Dermatology Department, Hospital de Santa Maria, Centro Hospitalar Universitário de Lisboa Norte, Av. Prof. Egas Moniz MB, 1649-028 Lisboa, Portugal. Phone: +351 21 780 5243; E-mail: dora.mancha@gmail.com Introduction The COVID-19 pandemic has been a global emergency since January 2020. One of the most commonly used COVID-19 mRNA vaccines is Pfizer- BioNTech vaccine BNT162b2 [1]. In a registry-based study of 414 cutaneous reactions to mRNA COVID-19 vaccines, delayed and immediate injec- tion site reactions were the most common [2]. Herein, we discuss two similar cutaneous reactions following COVID mRNA vaccination in order to further characterize derma- tologic reactions. Case Presentation Case 1. A 38-year-old woman, Fitzpatrick type III, pre- sented to our consultation after the second dose of Pfizer vaccine BNT162b2. After vaccine administration, the pa- tient described an immediate local reaction on the injec- tion site characterized by an erythematous and edematous plaque. This reaction evolved to a hypopigmented patch with irregular borders measuring 20 mm (Figure 1A). Wood lamp examination of the lesion (Figure 1B) revealed nei- ther fluorescence nor accentuation, which is consistent with post-inflammatory hypopigmentation. This cutaneous lesion fainted after 2 months without treatment. Case 2. A 30-year-old woman, Fitzpatrick type V, pre- sented to our consultation after the first dose of Pfizer vaccine. Few hours after the vaccine, the patient noted an immediate local reaction characterized by an erythema- tous and edematous plaque with a central blister. Over two weeks, this reaction evolved to a hypopigmented patch with 25 mm of diameter and irregular borders, surrounded by 2 Research Letter | Dermatol Pract Concept. 2023;13(1):e2023023 another patch with two shades of brown (Figure 1, C-E). Wood lamp examination demonstrated a sharply demar- cated bright blue-white fluorescence (Figure 1F), consistent with vitiligo. Skin biopsy was also compatible with vitiligo (Figure 2) revealing a decrease or absence of melanin pig- ment in lesional skin with H&E and Masson-Fontana stains, respectively. Autoimmunity laboratory study (ANAs, ANA screening, anti-dsDNA, anti-thyroid antibodies) was nega- tive and SARS-CoV2 anti-spike antibody titers were positive of (50.8 AU/mL). She was treated with topical tacrolimus twice daily with poor response. After the second dose of the vaccine, two months later, she had no skin reaction. At four months of follow-up only the vitiligo lesion remains, the brown patch is fading away. Conclusions Post-inflammatory hypopigmentation is an acquired partial or total loss of skin pigmentation occurring after cutaneous inflammation. There is limited information about the mecha- nism and pathogenesis. Melanogenesis is a complex process. It is controlled by multiple mediators (eg, growth factors, cytokines) acting on melanocytes, keratinocytes and fibro- blasts. Through the release of these mediators, cutaneous Figure 1. Skin hypopigmentation. Case 1. (A) Hypopigmented patch with irregular borders on the left arm at three weeks following the second dose of Pfizer vaccine. (B) Wood lamp examination revealed neither fluorescence nor accentuation. Case 2. (C-E) Site injection reac- tion on the left arm evolved from an erythematous and edematous plaque with a central blister to a hypopigmented patch over a period of hours to two weeks following the first dose of Pfizer vaccine. (F) Under Wood lamp examination the hypopigmented patch showed sharply demarcated bright blue-white fluorescence. Research Letter | Dermatol Pract Concept. 2023;13(1):e2023023 3 inflammation may cause aberration of melanogenesis leading to loss of melanocytes [3]. In Case 1, inflammation resulted in hypopigmented patches at the injection site. The hypopig- mentation improved overtime after the inflammation ceased. Vitiligo is an autoimmune disease. Cytotoxic CD8+ T cells are responsible for the destruction of melanocytes. The potential for vaccines to act as triggers of autoimmune reac- tions is well known [4,5]. The pathophysiology underlying the relationship between SARS- CoV-2 vaccination and vitil- igo remains unclear. mRNA vaccines encoding the SARS-CoV-2 spike protein encapsulated in lipid nanoparticles gain entry into dendritic cells (DCs) at the injection site. In addition, innate sensors are triggered resulting in production of type I interferon and multiple pro-inflammatory cytokines and chemokines. In particular, vaccine-driven production of type I interferon (IFN-1) promotes differentiation of CD4+ and CD8+ effec- tor T cells producing inflammatory and cytotoxic media- tors, and CD4+ T follicular helper cells, which promote B cell differentiation into antibody-secreting plasma cells [6]. In the pathogenesis of vitiligo, both IFN-1 and DCs were demonstrated to play a significant role. The activation of DCs and the release of IFN-1 seem to be key events in vitiligo following COVID-19 vaccination. Additionally, nonspecific activation of autoreactive CD8+/CD4+ T and B cells could stimulate the immune system to produce antibodies against SARS- CoV2 spike protein and incidentally against melano- cytes [7-9]. On the other hand, studies with anti-melanoma vaccines demonstrated that vitiligo observed around the injection site does not occur unless autoreactive T cells are recruited into the skin by inflammatory stimuli, suggesting that vitiligo can be initiated by some form of trauma to the skin [10]. To date, there are only five reported cases of new-onset vitiligo following COVID-19 mRNA vaccine (Table 1). In case 1, the hypopigmented patch was a result of an inflam- matory response that can occur in any patient and should be differentiated from vitiligo. Case 2 is the first report of site injection site vitiligo after an mRNA vaccine. Vaccines gen- erate an immune response which can be a trigger to develop Figure 2. Vitiligo, Case 2. Skin biopsy performed on the edge of the hypopigmented patch. (A) Basal epidermal hyperpigmentation explained by the patient phototype. Scarce inflammatory infiltrate in the superficial dermis (H&E stain, magnification x100). (B) Slight Decrease in melanin pigment in lesional skin (H&E stain, magnification x400). (C,D) Masson-Fontana stain highlights loss of melanin on the left side of the biopsy (Fontana-Masson stain, magnification x100 and x400). 4 Research Letter | Dermatol Pract Concept. 2023;13(1):e2023023 5. Militello M, Ambur AB, Steffes W. Vitiligo Possibly Trig- gered by COVID-19 Vaccination. Cureus. 2022;14(1):e20902. doi: 10.7759/cureus.20902. PMID: 35145806. PMCID: PMC8809499. 6. Teijaro JR, Farber DL. COVID-19 vaccines: modes of im- mune activation and future challenges. Nat Rev Immunol. 2021;21(4):195-197. DOI: 10.1038/s41577-021-00526-x. PMID: 33674759. PMCID: PMC7934118. 7. Kaminetsky J, Rudikoff D. New-onset vitiligo following mRNA-1273 (Moderna) COVID-19 vaccination. Clin Case Rep. 2021;9(9):e04865.. DOI: 10.1002/ccr3.4865. PMID: 34603727. PMCID: PMC8465924. 8. Uğurer E, Sivaz O, Kıvanç Altunay İ. Newly-developed vitil- igo following COVID-19 mRNA vaccine. J Cosmet Dermatol. 2022;21(4):1350-1351. DOIi:10.1111/jocd.14843. PMID: 35152540. PMCID: PMC9115282. 9. Ciccarese G, Drago F, Boldrin S, Pattaro M, Parodi A. Sud- den onset of vitiligo after COVID-19 vaccine.  Dermatol Ther. 2022;35(1):e15196. DOI:10.1111/dth.15196. PMID: 34751491. PMCID: PMC8646249. 10. Lane Lane C, Leitch J, Tan X, Hadjati J, Bramson JL, Wan Y. Vaccination-induced autoimmune vitiligo is a consequence of secondary trauma to the skin. Cancer Res. 2004;64(4):1509- 1514. DOI: 10.1158/0008-5472.can-03-3227. PMID: 14973051. vitiligo. We can hypothesize that in case 2, autoreactive T cells responses triggered by a local injection site inflamma- tion along with activation of DCs and the release of IFN-1 might be responsible for the development of vaccine-induced vitiligo at injection site. References 1. Rijkers GT, Weterings N, Obregon-Henao A, et al. Antigen presentation of mRNA-based and virus-vectored SARS-CoV2 vaccines. Vaccines (Basel). 2021;9(8):848. DOI: 10.3390/vac- cines9080848. PMID: 34451973. PMCID: PMC8402319. 2. McMahon DE, Amerson E, Rosenbach M, et al. Cutaneous re- actions reported after Moderna and Pfizer COVID-19 vaccina- tion: A registry-based study of 414 cases. J Am Acad Dermatol. 2021;85(1):46-55. DOI: 10.1016/j.jaad.2021.03.092. PMID: 33838206. PMCID: PMC8024548. 3. Vachiramon V, Thadanipon K. Postinflammatory hypopigmen- tation. Clin Exp Dermatol. 2011;36(7):708-714. DOI:10.1111/ j.1365-2230.2011.04088.x. PMID: 21671990. 4. Aktas H, Ertuğrul G. Vitiligo in a COVID-19-vaccinated pa- tient with ulcerative colitis: coincidence?. Clin Exp Derma- tol. 2022;47(1):143-144. DOI:10.1111/ced.14842. PMID: 34236714. PMCID: PMC8444736. Table 1. Literature review: reported cases of new-onset vitiligo following COVID-19 mRNA vaccine. Authors/year Age (years) Sex Vaccine Local Timing Aktas H, Ertuğrul G [4] 2021 58 Male Pfizer-BioNTech BNT162b2 Face 1 week after 1st dose Kaminetsky J, Rudikoff D [7] 2021 61 Female mRNA-1273 (Moderna) Face, neck, chest, abdomen Several days after 1st dose Ciccarese G [9] 2022 33 Female Pfizer-BioNTech BNT162b2 Trunk, neck, back 1 week after 1st dose Militello et al. [5] 2022 67 Female mRNA-1273 (Moderna) Hands 2 weeks after the vaccine Uğurer E et al. [8] 2022 47 Male Pfizer-BioNTech BNT162b2 Axilla, forearms 1 week after 1st dose