Impact of non-steroidal anti-inflammatory drugs on malignant transformation in oral lichen planus: insights from a real-world cohort study

Introduction: Oral lichen planus (OLP) is a chronic inflammatory condition with malignant potential for oral squamous cell carcinoma (OSCC). Differential risks of pharmacological treatments, particularly long-term use, remain unclear. We aimed to quantify OSCC risk across treatment modalities and assess potential benefit of combining immunosuppressive and anti-inflammatory agents to inform safer strategies. Methods: We conducted a large, retrospective cohort study with propensity score matching to balance demographic and clinical covariates. Patients with OLP treated with either systemic or topical glucocorticoids, calcineurin inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), or combinations were followed. OSCC incidence rates were compared between treatment groups, controlling for confounders and stratifying by route and duration of therapy. Results: Compared with glucocorticoid regimens, calcineurin inhibitors were associated with higher OSCC risk (glucocorticoids: HR 1.85, 95% CI 1.48–2.32; calcineurin inhibitors: HR 3.17, 1.48–6.76). The lowest risk was seen with topical glucocorticoids. Concomitant NSAIDs, particularly ketorolac and diclofenac, with topical glucocorticoids or calcineurin inhibitors, reduced OSCC risk (topical glucocorticoids: HR 0.73, 0.58–0.91; plus ketorolac: HR 0.63, 0.38–1.04; topical calcineurin inhibitors alone: HR 1.53, 1.03–2.28; plus ketorolac: HR 0.28, 0.15–0.54). Owing to retrospective design and reliance on ICD-10 coding, residual confounding and misclassification cannot be excluded. Conclusion: Calcineurin inhibitors carry high risk for malignant transformation in OLP, while topical glucocorticoids, especially NSAID/glucocorticoid combinations, offer safer profiles. These findings call for re-evaluation of treatment guidelines and prospective trials assessing novel or combination therapeutics that optimize long-term safety and symptom control in OLP.