Abstract
Lichen planus (LP) is an inflammatory disorder believed to result from CD8 + cytotoxic T-cell (CTL)-mediated autoimmune reactions against basal keratinocytes. We present a review of LP following COVID-19 infection and vaccination. Literature searches were conducted on PubMed and Google Scholar from 2019 to 7/2022. 36 articles were selected based on subject relevance, and references within articles were also screened. 39 cases of post-vaccination LP and 6 cases of post-infection LP were found among case reports and case series. 152 cases of post-vaccination LP and 12 cases of post-infection LP were found in retrospective and prospective studies. LP is a rare complication of COVID-19 infection and vaccination that may be mediated by overstimulation of T-cell responses and proinflammatory cytokine production. However, it does not represent a limitation against COVID-19 vaccination, and the benefits of vaccination considerably outweigh the risks.
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Introduction
Lichen planus (LP) is a chronic inflammatory disorder of unknown origin that frequently involves the skin and mucosa. Skin lesions classically present as flat-topped, purple papules that can be pruritic [1]. Oral lichen planus (OLP) is a subset of LP that can present as white reticular or erythematous lesions, papules, plaques, or painful erosions [1, 2]. LP pathogenesis is believed to result from an autoimmune reaction involving CD8+ cytotoxic T-cell (CTL) attack against basal keratinocytes in the epidermis and other unknown antigens [1]. LP has been associated with hepatitis C viral infection and autoimmune disorders including alopecia areata and ulcerative colitis [1]. However, there has been limited inquiry into the potential association between LP and COVID-19 infection and vaccination. We present a review of LP following COVID-19 infection and vaccination and its implications for adverse event monitoring.
Methods
Literature searches were conducted on PubMed and Google Scholar ranging from 2019 to 7/2022. Thirty-six articles were selected based on subject relevance; novel onset and flares of LP after COVID-19 infection and vaccination were included. References within selected articles were also screened. Selected articles included one review of LP, one prospective observational study, one retrospective registry-based study, one retrospective cohort study, one prospective cross-sectional study, one commentary, four case series, two letters responding to previously published studies, and twenty-four case reports.
Results
To date (7/2022), there have been 39 cases of LP after COVID-19 vaccination (Mage = 55.97 years, Rage = 28-86 years, Male:Female = 17:22) and 6 cases of LP after COVID-19 infection (Mage = 53.17 years, Rage = 41-63 years, Male:Female = 2:4) among published case reports and case series (Table 1, Appendix). Nine of the post-vaccination cases were flares. Tozinameran (Pfizer-BioNTech) was linked to 16 cases, Spikevax (Moderna) to four cases, Vaxzevria (Oxford-AstraZeneca) to eight cases, Sinopharm to eight cases, CoronaVac to two cases, and Jcovden (Johnson and Johnson) to one case; the administered vaccine was unspecified in two post-vaccination LP cases. Retrospective and prospective studies yielded 152 cases of LP after COVID-19 vaccination and 12 cases of LP after COVID-19 infection (Table 2, Appendix).
Discussion
Multiple authors have hypothesized that exposure to the COVID-19 spike protein antigen via infection or vaccination may trigger immune dysregulation including altered T-cell activity and elevated cytokines that mediate LP pathogenesis [2, 5, 7,8,9,10]. SARS-CoV-2 antigens in COVID-19 vaccines induce B-cell activation and a strong CD8+ cytotoxic T-cell (CTL) response that can escalate into an autoimmune reaction against basal keratinocytes in the epidermis, triggering keratinocyte apoptosis and subsequent LP development [2, 5]. Furthermore, the vaccines also activate CD4+ helper T-cells (Th1), which release proinflammatory cytokines including interleukin-2 (IL-2), tumor necrosis factor-ɑ (TNF-ɑ), and interferon-γ (IFN-γ) that maintain the CTL response, further upregulate Th1 activity, and induce tissue damage [2, 7,8,9,10]. TNF-ɑ, and IFN-γ result in basal keratinocyte apoptosis, the hallmark of LP. Their upregulation may thus help explain LP pathogenesis after COVID-19 infection and vaccination [4]. COVID-19 infection has also been associated with dysregulation of the mammalian target of rapamycin (mTOR) signaling pathway, which has been implicated in dysfunctional T-cell proliferation and OLP pathogenesis [2]. Moreover, it has been hypothesized that SARS-CoV-2 triggers the overexpression of TRIM21 (tripartite motif containing-21), which stimulates antiviral CTLs, increases cytokine production, and has been identified in OLP lesions using immunohistochemistry [2].
Another hypothesis is that molecular mimicry is responsible for triggering the autoimmune CTL and Th1 responses that mediate LP in both infection and vaccination [2, 4, 22, 32]. The SARS-CoV-2 antigen has demonstrated cross-reactivity with multiple endogenous human antigens, including those found on the basal keratinocytes of the epidermis [2, 4, 22, 32]. Some attribute this antigen cross-reactivity to genetic similarities or shared epitopes [4, 22]. Specifically, SARS-CoV-2 proteins demonstrated similarities to human mitochondrial M2 proteins, F-actin, and TPO proteins on selective epitope mapping [2]. However, others suggest that the propensity for SARS-CoV-2 to target the ACE2 receptor for host cell entry may be implicated, as ACE2 receptors are found in abundance among cells in the skin and oral mucosa [2, 13, 33]. Binding of the SARS-CoV-2 spike protein to ACE2 receptors on epidermal cells may trigger Th1 recruitment and the subsequent autoimmune cascade responsible for LP pathogenesis [13, 33].
Some also suggest that COVID-19 infection and vaccination can induce a hyperinflammatory reaction mediated by the reticuloendothelial system, leading to the development of LP or LP-like lesions [18, 30]. Meanwhile, specific ingredients in the formulations of COVID-19 vaccines might trigger type IV hypersensitivity reactions that can manifest as oral lichenoid lesions (OLL) [28]. Finally, there are concerns that immunocompromising comorbidities including hypertension, diabetes, vitamin D deficiency, and vitiligo are risk factors that may increase susceptibility to LP after COVID-19 infection or vaccination [2, 25]. Diabetes and hypertension have been identified as risk factors for OLP development and COVID-19 mortality, and vitamin D has been found to modulate Th1 cells and regulate T-cell-mediated immune activity [2].
The association between COVID-19 infection and LP remains under debate. A prospective observational study of 74 COVID-19 positive patients found that 16.2% of them had oral lesions attributed to LP [33]. However, the authors did not specify whether the diagnosis was confirmed by histopathological analysis or only based on clinical findings [35].
The potential relationship between COVID-19 vaccination and OLP was investigated through a retrospective cohort study that matched 217,863 vaccinated patients to 217,863 unvaccinated patients using the TriNetX database [28]. Incidence of OLP/OLL was significantly higher among vaccinated patients relative to unvaccinated patients (risk difference = 0.04%; p < 0.001; 95% confidence interval = 0.00027; 0.00053) [28]. The authors acknowledged that they were unable to clinically differentiate between OLL and OLP or entirely eliminate distribution differences in the frequency of NSAID use between the two cohorts [28]. Such adverse reactions are rare, often experience spontaneous remission, and should not be considered a contraindication to COVID-19 vaccination at a population level [28]. Both the retrospective cohort study (N = 435,726) and another retrospective registry-based study (N=58) found that mRNA-based vaccines were most commonly implicated in post-vaccination LP onset [28, 34]. Similarly, mRNA-based vaccines (Tozinameran and Spikevax) accounted for 20/39 cases of post-vaccination LP identified by this review. We hypothesize that the stronger immune responses induced by mRNA-based vaccines relative to other vaccines correlate with a higher risk of autoimmune T-cell-mediated reactions that can manifest as LP.
Conclusions
LP is a rare complication following COVID-19 infection and vaccination, and patients with immunocompromising comorbidities may be particularly vulnerable. OLP and OLL are considered premalignant, and healthcare providers should carefully monitor for LP-like adverse effects among vaccinated and unvaccinated patients as well as those with a history of COVID-19. Nonetheless, there is no definitive causal link between COVID-19 vaccination and LP. Moreover, there is scientific consensus that LP-related adverse effects do not constitute a contraindication against vaccination and that the benefits of COVID-19 vaccination continue to outweigh the risks significantly.
Data availability
All data generated or analyzed during this study are included in this published article.
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HZ (lead) and Dr. SD (supporting) were responsible for conceptualization, data curation, formal analysis, investigation, methodology, project administration, and original draft preparation. Funding acquisition, resources, and software are not applicable for this study. Dr. SD (lead) and HZ (supporting) were responsible for supervision, validation, and visualization. HZ (equal) and Dr. SD (equal) wrote, reviewed, and edited the manuscript.
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Zou, H., Daveluy, S. Lichen planus after COVID-19 infection and vaccination. Arch Dermatol Res 315, 139–146 (2023). https://doi.org/10.1007/s00403-022-02497-y
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DOI: https://doi.org/10.1007/s00403-022-02497-y