## 4 Discussion
### Cases' Characteristics  
No predilection for cases' age was presently found, similar to [PERSON] et al. 's results [61; 62]. The female gender, generally more prone to immune-inflammatory dysregulation and abnormal immune system reactions [63], mainly attributable to hormonal and immune factors [64], was found even more inclined to the development of reactive lesions of the peri-implant mucosa, as previously described for the gingival ones [65]. Noteworthy, a higher frequency of lesions resembling peri-implant mucositis and peri-implantitis was recorded in females, contrary to prevalence rates reported for the general population [66; 67]. Females were also more inclined to orofacial, periodontal, and peri-implant hypersensitivity reactions (M/F = 139:368), as also suggested by [PERSON] et al. [23]. Compared to males, the last finding may be partially explained by prolonged contact with cosmetic products containing various metals, including Nickel and Titanium. Indeed, overt lesions manifesting hypersensitivity reactions develop after repeated exposures in weeks or months to the antigen/allergen at sub-threshold concentration [68]. Nonetheless, a history of allergies was reported in only 19 cases [36], and the allergens were not specified. Such a datum, resulting largely missing, could be particularly relevant for hypersensitivity reactions, which are well known to occur against single or multiple antigens/allergens in genetically susceptible individuals [23; 69], especially considering that some Titanium dental implants may contain minute traces of Nichel [70], a highly sensitizing allergen in the general population. The paucity of data on cases' pre-existing allergic diathesis has also precluded the possibility of hypothesizing on a possible cross-reactivity with other antigens/allergens underlying hypersensitivity lesions, although a definitive causative role of systemic allergens for oral hypersensitivity reactions has not been confirmed [23]. Analogously, comorbidities and systemic conditions potentially affecting oral, periodontal, and peri-implant mucosa [71; 72] were only reported in one case with psoriasis and seborrheic eczema [35]. Such finding may be explained by the evidence that certain diseases such as connective tissue disease (e.g., systemic lupus erythematosus, Sjogren's syndrome, rheumatoid arthritis) are notoriously associated with an increased frequency of delayed hypersensitivity reactions to mercury, palladium, silver, nickel, and titanium [70]. Nevertheless, the predisposing or contributing role of autoimmune and dysimmune systemic disorders, such as Oral Lichen Planus, in periodontitis remains controversial [73]. Moreover, it is well known that, during pregnancy, periodontal and, presumably, peri-implant vasculature, immune cells, and microbiome [74] undergo typical modifications due to the higher sex hormones levels, thus enhancing tissue reactivity and promoting the development of exophytic reactive lesions [75; 76; 77]. However, given the paucity of retrieved data concerning cases' comorbidities, it could not be speculated on the putative predisposing or contributing role of systemic conditions, disorders, and related therapies on lesions development, progression, and treatment responsiveness. Furthermore, the lack of data concerning ongoing pharmacological therapies would have also prevented differentiating oral lichenoid lesions, frequently linked to systemically administered medicaments, from oral lichenoid contact lesions, topographically related to the causative material [24; 69], in any case not presently recorded. No data were retrieved concerning smoking habit and plaque index, whose role in peri-implantitis is defined by a medium level of evidence [62]. In addition, biofilm accumulation has long been reported among low-grade irritants, along with ill-fitting appliances, cervical cavities, and grossly carious teeth, concurring in developing reactive lesions [75].