Felice Femiano

Guidelines for diagnosis and management of aphthous stomatitis

Aphthous ulcers are the most common oral mucosal lesions in the general population. These often are recurrent and periodic lesions that cause clinically significant morbidity. Many suggestions have been proposed but the etiology of recurrent aphthous stomatitis (RAS) is unknown. Several precipitating factors for aphthous ulcers appear to operate in subjects with genetic predisposition. An autoimmune or hypersensitivity mechanism is widely considered possible. Sometimes aphthous ulcers can be the sign of systemic diseases, so it is essential to establish a correct diagnosis to determine suitable therapy. Before initiating medications for aphthous lesions, clinicians should determine whether well-recognized causes are contributing to the disease and these factors should be corrected. Various treatment modalities are used, but no therapy is definitive. Topical medications, such as antimicrobial mouth-washes and topical corticosteroids (dexamethasone, triamcinolone, fluocinonide, or clobetasol), can achieve the primary goal to reduce pain and to improve healing time but do not improve recurrence or remission rates. Systemic medications can be tried if topical therapy is ineffective.

Oral malignant melanoma: a review of the literature

Primary oral melanoma (POM) is an uncommon malignant tumor that originates from the proliferation of melanocytes. Such tumors can be present at any location in the oral cavity; however, it affects more frequently the hard palate and the maxillary alveolar mucosa. POM is usually asymptomatic in the early stages and it presents normally as a pigmented patch or as a mass with a rapid growth rate. In the advanced stages, it can show ulceration, swelling, bleeding, rapid enlargement and loosening of teeth. Melanoma of the mouth is rare, most commonly occurring in the upper jaw of patients more than 65 years. Because of a frequent delay in diagnosis, the tumors are often diagnosed when they are deeper than the average cutaneous melanoma. The prognosis is extremely poor, especially in advanced stages. Therefore, pigmented lesions of undetermined origin should be routinely subjected to a biopsy examination. In this study, we aimed to present a review on primary malignancy.

Serum from pemphigus vulgaris reduces desmoglein 3 half-life and perturbs its de novo assembly to desmosomal sites in cultured keratinocytes

Defects of cell–cell adhesion underlie disruption of epithelial integrity observed in patients with pemphigus vulgaris (PV), an autoimmune disease characterized by severe mucosal erosions and skin blisters. Pathogenic PV autoantibodies found in patients’ sera target desmoglein 3 (Dsg3), a major component of the desmosome, but how does this phenomenon affect Dsg‐dependent adhesion and lead to acantholysis still remains controversial. Here, we show that PV serum determines a reduction of Dsg3 half‐life in HaCaT keratinocytes, although the total amount of Dsg3 remains unchanged. Immunofluorescence studies suggest that PV IgG exert their effect prevalently by binding non‐desmosomal Dsg3 without causing its massive internalization. Furthermore, PV IgG targeting desmosome‐assembled Dsg3 do not induce depletion of Dsg3 from the adhesion sites. Conversely, incorporation of PV IgG‐Dsg3 complexes into new forming desmosomes appears perturbed. With our study, the basic biochemical changes of Dsg3 in an in vitro model of PV have been defined.

Evidence of Key Role of Cdk2 Overexpression in Pemphigus Vulgaris

The pathogenesis of pemphigus vulgaris (PV) is still poorly understood. Autoantibodies present in PV patients can promote detrimental effects by triggering altered transduction of signals, which results in a final acantholysis. To investigate mechanisms involved in PV, cultured keratinocytes were treated with PV serum. PV sera were able to promote the cell cycle progression, inducing the accumulation of cyclin-dependent kinase 2 (Cdk2). Microarray analysis on keratinocytes detected that PV serum induced important changes in genes coding for one and the same proteins with known biological functions involved in PV disease (560 differentially expressed genes were identified). Then, we used two different approaches to investigate the role of Cdk2. First, small interfering RNA depletion of Cdk2 prevented cell-cell detachment induced by PV sera. Second, pharmacological inhibition of Cdk2 activity through roscovitine prevented blister formation and acantholysis in the mouse model of the disease. In vivo PV serum was found to alter multiple different pathways by microarray analysis (1463 differentially expressed genes were identified). Major changes in gene expression induced by roscovitine were studied through comparison of effects of PV serum alone and in association with roscovitine. The most significantly enriched pathways were cell communication, gap junction, focal adhesion, adherens junction, and tight junction. Our data indicate that major Cdk2-dependent multiple gene regulatory events are present in PV. This alteration may influence the evolution of PV and its therapy.

Burning mouth syndrome: the efficacy of lipoic acid on subgroups

Objective  We have examined the effect of alpha‐lipoic acid (ALA, tioctic acid; Tiobec), a free radical scavenger, on the discomfort of burning mouth syndrome (BMS) in patients who had used tranquillizers previously, compared with those who had not.

Pemphigus vulgaris with oral involvement: evaluation of two different systemic corticosteroid therapeutic protocols

Background Pemphigus vulgaris is a potentially life‐threatening disease characterized by cutaneous and mucosal blistering. Systemic corticosteroids remain the mainstay of therapy, transforming an invariably fatal disease into one with a mortality that is now less than 10%. Nevertheless, oral lesions are often recalcitrant and corticosteroid therapy can provoke adverse effects.

Cleavage of desmoglein 3 can explain its depletion from keratinocytes in pemphigus vulgaris

Abstract:  We have previously demonstrated that serum of patients with pemphigus vulgaris induces reduction of desmoglein 3 (Dsg3) half‐life in keratinocytes (FEBS Lett 2006: 580: 3276). This phenomenon seems to occur as a consequence of the progressive depletion of Dsg3 from desmosomes. Here we reported that reduction of full‐length Dsg3 may be due to its progressive cleavage, leading to the formation of two fragmentation products with apparent molecular masses of about 60 kDa (fragment 1) and 70 kDa (fragment 2), as revealed by Western blotting. Unexpectedly, analysis of fragmentation pattern suggested cleavage to occur intracellularly. Consistently, fragment 1 was shed and localized within the cytosol, as shown by living cell immunofluorescence microscopy. Total amounts of full‐length plakoglobin and Dsg1 were apparently unchanged. Taken together, our findings provide evidence that proteolytic processing of Dsg3 can lead to depletion of Dsg3 from the cell.

Pilot study on recurrent aphthous stomatitis (RAS): a randomized placebo-controlled trial for the comparative therapeutic effects of systemic prednisone and systemic montelukast in subjects unresponsive to topical therapy.

BACKGROUND Recurrent aphthous stomatitis (RAS) is characterized by recurrent painful oral ulcers whose etiology remains largely unknown. Numerous therapeutic protocols have been tried so far, but effectiveness remains an issue. OBJECTIVE To test a new drug for patients with recurrent oral aphthae nonresponsive to local corticosteroid therapy, we compared the therapeutic effectiveness and adverse effects of systemic prednisone and systemic montelukast in a placebo-controlled trial. STUDY DESIGN Sixty patients suffering from minor RAS for > or =6 months were studied and randomly assigned to 3 groups of 20 each in a double-blind study. Patients of group A took 25 mg prednisone orally daily for 15 days, 12.5 mg daily for 15 days, 6.25 mg daily for 15 days, then 6.25 mg on alternate days for 15 days. Patients of group B took 10 mg montelukast orally every evening and then on alternate days for the second month. Patients of group C took 100 mg cellulose (placebo) by mouth daily for the first month and on alternate days for the second month. Outcomes assessed were days til pain cessation, days to ulcer healing, and number of aphthae occurring during the follow-up period. RESULTS Both prednisone and montelukast were effective in reducing the number of lesions and improving pain relief and ulcer healing when compared with placebo. Prednisone was more effective than montelukast in pain cessation (P < .0001) and in accelerating ulcer healing (P < .0001). However, adverse drug reactions recorded during the entire trial were more common in the prednisone group compared with montelukast (10%) and placebo (10%). CONCLUSIONS These data suggest that the effectiveness of systemic montelukast is similar to that of systemic prednisone in patients with RAS. The lack of serious side effects makes montelukast a candidate drug to use in cases of RAS where pharmacologic therapy for long periods is needed.

The N-terminal fraction of desmoglein 3 encompassing its immunodominant domain is present in human serum: implications for pemphigus vulgaris autoimmunity.

Pemphigus vulgaris (PV) is considered as an autoimmune disease against a tissue-restricted antigen, desmoglein 3, a 130 kDa glycoprotein expressed by keratinocytes of skin and mucous membranes. Therefore, a breakdown of peripheral tolerance is generally invoked to explain this horror autotoxicus. The availability of a self-antigen and the strength of antigenic stimulation represent critical points in the regulation of immune system homeostasis. Our study shows for the first time that the immunodominant fraction of the PV self-antigen is present in sera of healthy individuals and patients as a circulating 30 kDa fragment (sDsg3). These findings provide a good explanation for the N-terminal specificity of antibody production and peptide recognition in PV patients by B and T cell, respectively. Moreover, the presence of the sDsg3 in human sera could allow to reconsider pemphigus as a disease against a circulating antigen; once produced, PV-autoantibodies also recognize the 130 kDa epidermal antigen desmoglein 3 on keratinocyte surface (kDsg3), thus triggering the acantholysis and the clinical manifestations of pemphigus.

Matrix metalloproteinase gene expression in oral lichen planus: erosive vs. reticular forms

Background  Oral lichen planus (OLP) is an autoimmune disease of unknown aetiology. The pathogenesis is characterized by apoptosis of basal keratinocytes, triggered by contact between CD8+‐activated lymphocytes and an unknown antigen expressed on the surface of the basal cells. Basement membrane (BM) degradation, which allows lymphocytes to migrate, involves proteolytic enzymes known as matrix metalloproteinases (MMPs).