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.