## 4 Discussion  
In the present prospective, randomized, controlled study with crossover design, the topical application of HA had no significant beneficial effect in the treatment of OLP, compared to a placebo. The first line of medical therapy is aimed at eliminating atrophic and ulcerative lesions, alleviating symptoms, and eventually decreasing the risk of malignant transformation [5]. New therapeutic modalities have been tested, due to the adverse effects of standard immunosuppressive treatments. Due to its beneficial properties for tissue regeneration and wound healing, topical HA has been shown to be a useful adjuvant in the treatment of gingivitis and chronic periodontitis, as well as during the postoperative period for faster healing and to reduce patients' discomfort [22]. Data obtained from a review by [PERSON] et al., comprising 20 clinical studies, demonstrate that regarding tissue repair and wound healing, topical administration of HA could play a role not only in postoperative dental surgery, but also in the treatment of patients affected by inflammatory disease, with a significant improvement in quality of life [40]. These HA-related improvements could not be reproduced in the present study; the findings considering clinical appearance, pain, and gingival inflammation could not be verified either. Despite its promising properties, data for the treatment of OLP are scarce and remain conflicting. Salivary IL-6 was suggested as a diagnostic and therapeutic biomarker in OLP patients [28]. However, although possible confounders (smoking, periodontal disease, caries) were avoided by the inclusion criteria in our study, we could not observe a meaningful trend of IL-6 in neither the HA nor in the placebo group. These conflicting results may have several reasons: while some studies reported IL-6 level changes with types and severity of OLP [41; 42], a systematic review found no influence between patients with erosive OLP and patients with nonerosive OLP [43]. Furthermore, different kits have been used for salivary IL-6 quantification [44], and most studies for the evaluation of salivary IL-6 levels have used small sample sizes prone to heterogeneity. Elevated levels of extracellular caprotectin are present in diverse inflammatory disorders. This makes it a potential biomarker for inflammation [45; 46]. Salivary calprotectin concentration is positively correlated with the intensity of fungal infection [47] with the presence of Sjogren's syndrome [48], with periodontitis and the presence of _Teponema denticola_[32]. Our findings did not allow useful comparison or discrimination between groups or treatment phases, although there was a decrease with HA and placebo. This is somehow surprising, as calprotectin is overexpressed at sites of inflammation. Accordingly, levels found in stimulated saliva of patients with aggressive periodontitis [32] or Sjogren's syndrome [48] were 10\({}^{6}\) higher than our findings. The sampling procedure and site of collection may be of major importance [49]. Still, a possible future role as adiagnostic marker in OLP patients is underpinned by the fact that for differentiation of bowel diseases, already-validated commercial tests are available [50]. Two cross-sectional studies found higher amounts of periodontal pathogens in OLP patients compared to patients with plaque-induced gingivitis, with subgingival sampling method, and suggested a possible association between periodontal pathogens and OLP [51; 52]. In our study, the microbiological analysis was performed from saliva, as this has been shown to be a promising alternative [34]. Interestingly, patients in our study presented with amounts of putative pathogens mostly below therapeutic thresholds before therapy, and levels did not differ significantly between groups. Hence, it was clear that the inflammatory parameters, II-6 and calprotectin, did not origin from microorganisms. Also, the microflora changes under HA treatment, which is antimicrobial, could not be observed.