Injection of hyaluronic acid and polynucleotides in patients with vulvar lichen sclerosus—a preliminary evaluation

Vulvar lichen sclerosus (VLS) is a chronic inflammatory dermatosis characterized by white plaques, pruritus, pain, and scarring, with an occasional increased risk of squamous cell carcinoma. Estimates in the literature place the lifetime risk broadly between ~2% and 7%, underscoring the need for effective long-term control of inflammation and disease progression. Although the condition is frequently underdiagnosed, its impact on quality of life and sexual function is significant. The standard therapeutic approach involves the use of ultrapotent topical corticosteroids (TCS), which are generally effective in reducing symptoms. Up to ~30% patients fails to achieve sufficient relief with TCS alone.1 Hyaluronic acid (HA) is an endogenous glycosaminoglycan that ensures tissue hydration and maintains the integrity of the extracellular matrix. Its highly polar structure promotes the formation of a hydrated, high-molecular weight network and enables it to act as a signaling molecule that modulates inflammatory responses. Polynucleotides (PN), derived from fish sources, support tissue hydration and stimulate fibroblast activity, thereby enhancing type III collagen synthesis. While HA provides a hydrated scaffold, PN promotes cellular repair, leading to improved tissue elasticity and reduced inflammation. Based on these properties, it was hypothesized that a combined HA + PN injectable formulation could offer both symptomatic relief and tissue regeneration in patients with VLS refractory to topical corticosteroids. A pilot case series was conducted at the “Alto Tevere” Hospital of Città di Castello, from January 2021 to December 2024, with the aim of evaluate the feasibility and preliminary efficacy of adjunctive injections of a HA and PN mixture in VLS patients who were poor responders to standard TCS therapy. Thirty patients with diagnosis of VLS were identified as poor responders after 6 months of a graduated regimen of mometasone furoate cream 0.1%: 1 application each day for 1 month, 1 application alternate days for 1 month and 1 application two times a week on a continuous basis. These patients continued with maintenance TCS therapy (administered twice weekly) while also receiving injections of an HA and PN mixture at a concentration of 10 mg/ml each (combined therapy) as follows (Figure S1). The injection protocol involved delivering 0.2-0.3 cc per wheal (25 wheal for each hemivulva), after applying local anesthetic cream (lidocaine 2.5% + prilocaine 2.5%, 30 min before injection), every 15 days for the initial 2 months, followed by maintenance injections every 45 days for a total treatment duration of 12 months, amounting to 14 administrations overall. No side effects were recorded during the administration of the therapy. Supplemental tables provide additional details on inclusion/exclusion criteria (Table S1), demographics, and clinical variables (Table S2). The study was conducted in accordance with the Declaration of Helsinki and approved by the Committee for Ethics of Umbria Region (Prot. N. CE-2980/25). Written informed consent was obtained from all participants. In order to evaluate symptom severity and sexual function improvement were used Visual Analogue Scale (VAS) and Female sexual function index (FSFI), orgasmometer-F, Sexual Quality of Life-Female (SQoL-F) administrated at baseline (T0), after 6 months of TCS therapy (T1) in order to identify “poor responders” patients and after 12 months of combined therapy (T2). Continuous, non-normally distributed variables are presented as median (interquartile range [IQR]). The Friedman test was used to compare repeated measures across T0, T1, and T2, with a two-tailed P ≤ .05 considered statistically significant. At baseline (T0), patients reported a median VAS score of 7 (IQR 6-8) and a median FSFI score of 19 (IQR 10-22). Similarly, baseline median Orgasmometer-F was 2 (IQR 1-2) and baseline median SQoL-F was 34 (IQR 25-49). After 6 months of topical corticosteroid (T1), modest improvements were observed in VAS (median 6, IQR 5-6), FSFI (median 22, IQR 14-26), Orgasmometer-F (median 2, IQR 2-3), and SQoL-F (median 37, IQR 26-53). The 30 “poor responders” patients were started the administration of HA+ PN combined therapy. At T2, further significant changes were recorded: median VAS decreased to 3 (IQR 2-4), while median FSFI increased to 30 (IQR 19-32). Median Orgasmometer-F at T2 was 4 (IQR 4-5) and median SQoL-F at T2 was 44 (IQR 35-58). Friedman tests demonstrated statistically significant changes over time for all measures (all P < .00001). The comparison between T0–T1, T0–T2, and T1–T2 with Bonferroni correction (adjusted α = 0.0167) showed that most differences reached statistical significance; effect sizes were moderate-to-large (Cohen’s d or rank-biserial reported as appropriate), indicating clinically relevant improvements in pain, sexual function, orgasm perception, and sexual quality of life (Table S3). The observed clinical improvements can be attributed to the synergistic actions of HA and PN. Similar mechanisms have been proposed in studies involving atopic dermatitis, where the use of HA resulted in improved skin barrier function through a reduction in transepidermal water loss and a decrease in erythema intensity.2 The median disease duration of 5 years in our cohort suggests more established scarring, which may explain partial response to TCS and supports a rationale for therapies that target tissue remodeling. Indeed HA and PN may address tissue changes in long-standing VLS that limit response to topical steroids and may confer meaningful clinical benefits like showed by Tedesco et al.3 Our study includes a heterogeneous patient cohort, reflecting the broad age range seen in clinical practice and underscoring the need for personalized treatment approaches because VLS presents with varying clinical severity and differing overall health statuses. The findings are encouraging. However, several limitations must be acknowledged. As a pilot case series without a control group, the design limits the ability to attribute observed improvements solely to the adjunctive therapy. The small sample size constrains generalizability. Concurrent use of maintenance TCS alongside HA/PN injections introduces potential confounding, making it difficult to determine the precise contribution of injections to overall improvement. The open-label design and lack of blinding may introduce bias in subjective outcomes such as pain and sexual function. Future research should employ randomized controlled trial designs with larger cohorts and, where possible, blinding of outcome assessors. Despite these limitations, the study provides valuable insight into a novel therapeutic approach for patients with VLS who do not adequately respond to conventional TCS therapy enhancing symptom control and improving quality of life. This is particularly relevant given the chronic and often recalcitrant nature of VLS, a condition that can have a profound impact on both physical and psychosocial well-being. Larger randomized controlled trials are warranted to further elucidate efficacy and safety of this combined strategy. Such studies should stratify patients by clinical variables including age, disease severity, and menopausal status to identify subgroups who may benefit most. Longer-term follow-up is needed to assess durability and monitor delayed adverse events. Mechanistic studies on molecular pathways modulated by HA and PN may deepen understanding of therapeutic potential. In conclusion, adjunctive HA and PN injections combined with maintenance TCS produced improvements in symptoms and sexual function in poor responders to standard treatment; however, given study’s design limitation and small sample size, these findings should be considered preliminary and interpreted with caution.4 Our deepest thoughts go to G.P. (1986-2025), who passed away prematurely, for having first inspired us in alternative therapies for vulvar lichen sclerosus. None declared. The authors declare no conflicts of interest.