Unlocking the Immune Code: Advances in Lichen Planus Pathogenesis and Emerging Therapies

Once considered a relatively obscure dermatologic condition, lichen planus (LP) is gaining renewed scientific interest thanks to recent breakthroughs in immunopathology and targeted treatment development.

Affecting approximately 0.5% to 1% of the global population, LP presents a complex and often frustrating clinical picture—ranging from pruritic, violaceous papules on the skin to debilitating erosive lesions of the oral and genital mucosa. But behind these seemingly disparate phenotypes lies a shared, yet still only partially understood, immunologic engine.

LP’s pathogenesis is now believed to stem from a biphasic, T-cell–driven immune response. Environmental insults—such as trauma, infections, or stress—likely initiate a cascade of signals in genetically predisposed individuals, triggering keratinocyte distress and the release of damage-associated molecular patterns. These signals activate plasmacytoid dendritic cells, unleashing type I interferons and inflammatory cytokines like IL-1β and TNF-α, which then recruit and activate a highly specialized population of cytotoxic T cells.

Key to the progression of LP is the upregulation of the Janus kinase (JAK)-STAT and interleukin-17 (IL-17) pathways. IFN-γ and CXCL10, operating through the JAK-STAT axis, act in a feedback loop that sustains the recruitment and activation of CD8+ T cells, which ultimately mediate keratinocyte apoptosis via perforin and granzyme B. Simultaneously, IL-17 and IL-22, primarily released by Th17 and Tc17 cells, promote a chronic inflammatory milieu and further T cell proliferation.

This pathogenic complexity has translated into therapeutic stagnation—until now. First-line treatment with high-potency topical corticosteroids remains the standard for localized disease. Yet for more recalcitrant or extensive subtypes like lichen planopilaris (LPP) or oral LP (OLP), off-label systemic immunosuppressants or biologics are often employed with variable success. The absence of FDA-approved therapies specific to LP underscores a critical unmet need in dermatology and immunology alike.

Recent clinical investigations, however, are beginning to reshape the therapeutic landscape. Targeted biologics and small-molecule inhibitors—many repurposed from other autoimmune conditions—are now entering clinical trials with promising preliminary results.

Among the most notable advances are IL-17 inhibitors such as secukinumab and ixekizumab. Although secukinumab failed to meet its primary endpoint in a recent phase II trial for LP, subtype-specific responses in OLP and LPP hint at differential immunopathologic mechanisms across LP variants. Ixekizumab, while still awaiting published trial data, has shown encouraging results in case reports of scalp LPP with complete hair regrowth.

Parallel to this, JAK inhibitors are rapidly gaining traction. Baricitinib and ruxolitinib—originally developed for rheumatoid arthritis and atopic dermatitis, respectively—have demonstrated impressive efficacy in small LP cohorts, particularly for cutaneous and nail involvement. In one open-label study, over 80% of patients with CLP treated with baricitinib achieved rapid and sustained improvement. Ruxolitinib, tested in topical form, met its primary efficacy endpoint in a phase II trial with no serious adverse effects.

Deucravacitinib, a selective TYK2 inhibitor, may represent the next frontier. Currently under investigation in a randomized controlled trial for vulvar LP, the drug has shown encouraging early signs of symptom relief in OLP and CLP. Although not curative, these agents appear to interrupt key cytokine signaling pathways central to LP’s chronicity.

Not to be overlooked are alternative approaches under evaluation. Apremilast, a phosphodiesterase-4 inhibitor, has demonstrated symptom relief in refractory OLP and is undergoing phase IV evaluation. Meanwhile, erythropoietin hydrogel, known for its regenerative effects in wound healing, is being compared to topical corticosteroids in a phase III trial. Even paeoniflorin, a compound rooted in traditional Chinese medicine, is being studied in combination with photodynamic therapy for its mesenchymal stem cell-promoting effects in OLP.

Yet, despite these advances, challenges remain. Many of the current trials are small, open-label, or lack long-term follow-up data. Moreover, paradoxical reactions—such as LP-like eruptions induced by IL-17 inhibitors—raise questions about the nuanced immunologic balance at play.

Still, the trajectory is promising. As the immunopathogenic map of LP becomes more refined, so too will the therapeutic toolbox. The disease’s heterogeneity—once an obstacle to consistent treatment—may now offer an opportunity for precision medicine. Distinct immunologic fingerprints across subtypes could eventually guide tailored therapies, improving outcomes for patients who have long struggled with this stubborn disease.

In the meantime, clinicians managing LP should stay abreast of emerging trial data, weigh the risk-benefit profile of off-label agents carefully, and consider integrating these insights into patient-specific care plans. With more targeted, mechanism-driven therapies on the horizon, LP may finally be shifting from an enigmatic chronic disorder to a tractable immune-mediated disease.

FAQs:

1. What is the rationale for using JAK inhibitors like baricitinib in lichen planus?
Baricitinib targets the JAK-STAT signaling axis, which is increasingly recognized as a central driver in LP pathogenesis—especially through interferon-γ–mediated CD8+ T-cell activation and keratinocyte apoptosis. In small cohort studies, baricitinib has shown rapid and sustained improvement, particularly in cutaneous and nail LP.

2. How does LP’s immunopathology inform treatment selection?
LP involves a biphasic, T-cell–driven immune response with upregulation of JAK-STAT and IL-17 pathways. Recognizing subtype-specific immune signatures (e.g., stronger IL-17 involvement in LPP and OLP) can help guide the selection of targeted therapies such as JAK inhibitors, IL-17 blockers, or TYK2 inhibitors depending on the phenotype.

3. Are any targeted therapies currently FDA-approved for lichen planus?
No. Despite promising results from small trials and off-label use of agents like baricitinib, secukinumab, and deucravacitinib, there are currently no FDA-approved therapies specifically for LP. Ongoing studies may inform future regulatory pathways.

4. What are key considerations for clinicians when using off-label immunomodulators for LP?
Clinicians should assess the patient’s LP subtype, disease severity, and treatment history. Off-label agents require careful risk-benefit evaluation, monitoring for paradoxical reactions (e.g., LP-like flares from IL-17 inhibitors), and staying current with emerging clinical trial data to optimize individualized treatment plans.