RECURRENT APHTHOUS   
STOMATITIS  
Recurrent aphthous stomatitis (RAS) is the most common cause of mucosal ulcerations. The prevalence of aphthous ulcers in the general populations varies, depending upon the study source,  from 17% to 50%. People at the higher socioeconomic status are more likely to have RAS than those of low socioeconomic level.  

Etiology  
The etiology of RAS is unknown, although in recent years many speculations have been made over the pathogenesis. A common opinion is that immune factors (likely an antibody-mediated cellular cytotoxic phenomenon)  may be capable of triggering RAS in genetically susceptible individuals exposed to predisposing factors.   
Microbial agents have been called as potential culprits of RAS but the findings published in the literature remain controversial. Streptococci were originally thought to be involved but subsequent studies have not confirmed their role.   
Herpes simplex virus and  varicella-zoster virus have reported as responsible of RAS but their potential role still required further clarification. Several studies have attempted to demonstrate the association between RAS and histocompatibility (HLA) antigens, but again there is no definitive proof that specific HLA antigens, such as A2, Cw3, DR2, DR4, DR7 and others, show any association with the disease.   
Predisposing systemic factors that have been reported in association with RAS are cyclic neutropenia, HIV infection, hematinic deficiency,  gastrointestinal diseases (coeliac disease, ulcerative colitis and Crohn's disease), menstrual cycle and psychological stress. Behcet's syndrome  is a complex disease in which affected individuals develop CNS, ocular, and skin lesions and multiple oral and genital ulcers similar to those of RAS.  

Clinical aspects    
RAS has been classified as minor aphthous ulcers, major aphthous ulcers, and herpetiform ulcers. The most common variant is minor aphthous ulcers that are observed in about 80% of patients. Ulcers are single or multiple and have a diameter smaller than 1 cm. These ulcers have well-defined round margins with a yellowish slough center and peripheral erythema (Fig. 1).   
They  last seven to ten days and may recur at 1- to 6- month interval.  Major aphthous ulcers usually begin during childhood or adolescence  and  are usually larger (1 to 3 cm) and more persistent lasting 1 to 4 weeks (Fig. 2). These lesions can be very painful and be a source of profound discomfort. Scarring frequently occurs with major aphthae. In patients with HIV infection often is observed a severe form of RAS with large, long-lasting aphthous ulcers. Herpetiform ulcers develop in about 10% of patients with RAS. They appear as grouped (2 to 100), small, papulovesicles that have a tendency to coalesce and leave scars (Fig. 3).  

Management  
Treatment of RAS depends upon the number of lesions, size and duration, and particularly upon the frequency of recurrences. The choice of a specific treatment modality should be based upon the patient needs and balancing the potential side effects of drugs with the benefits.   
In case of  aphthous ulcers which are expression of systemic disease treatment  should be first directed to the underlying conditions.   
For example in patients with gluten-sensitive enteropathy ulcers resolve as the gut disease improves with diet restriction of gluten. In patients with documented deficit  of B12, folate  and iron, replacement therapy  yields  a  remission  or marked dimi-nution in recurrence of oral ulcers.   
In cases of idiopathic RAS symptomatic relief can be obtained with topical application of viscous lidocaine to the lesions.   
Also topical corticosteroids as ointment, gel or viscous bases can be quite effective (see Table I). Topical tetracycline can be also be useful to short the clinical course of  RAS. In patients suffering of severe, debilitating forms of RAS systemic therapy is indicated for palliation. Drugs such as prednisone, colchicine, dapsone and thalidomide may be beneficial.   
Unfortunately, these drugs may  have toxic reactions that can alter their beneficial therapeutic effects.   
Recently, several studies have reported on the efficacy of drugs such as azathioprine, gammaglobulines, isoprinosine, interferon, etretinate, monoamine oxidase inhibitors, and pentoxyphilline however the therapeutic use of these medications must view with caution until more scientific evidence are available.   
Clinical trials are needed to compare efficacy and toxicity of  these different treatment modalities.

Etiopathogenesis  
The primary event leading to lichen planus is basal cell damage that leads to a cell-mediated immunological response with deposition in the lamina propria of an inflammatory infiltrate composed mainly of T-cell lymphocytes (CD4+ and CD8+). OLP has been associated with  systemic disorders such as diabetes mellitus and hypertension and recently with HCV-related chronic hepatitis.   
Lichenoid lesions can be induced by a variety of medications such as antihypertensives, antibiotic, anti-inflammatory drugs and antimalarials. Metals dental restorations also can induce lichenoid reactions in the adjacent oral mucosa.  

Clinical aspects  
OLP presents as reticular white striae, white plaques, erythema or ulcerations. In any given patient OLP can have a multiform appearance. Reticular lesions are usually localized on the buccal mucosa (Fig. 4), gingiva, palate, ventrolateral tongue and lips. The erythematous and atrophic forms show a preference for the dorsum tongue, gingiva and buccal mucosa. White plaques with variable morphology may develop on the dorsum tongue (Fig. 5).   
The symptomatic forms are the erythematous, atrophic and ulcerative forms (Figg. 6 and 7). The last occurs most commonly on the buccal mucosa and ventrolateral surface of the tongue. The skin lesions of lichen planus appear as polygonal papules with on the surface a lace-like network of white lines (Wickham's striae) (Fig. 8).  
It is important to discuss that several reports have suggested an increased incidence  of dysplasia or squamous cell carcinoma occurring in patients with lichen planus. Recent studies have shown a potential statistical increase in oral cancer from 0.5% to 1.2%. Development of oral cancer appears to be more frequent in patients with long-standing ulcerations on the tongue.  However despite these reports, there is no certain evidence that cancerous transformation is very common in OLP.   

Pathology  
A biopsy specimen of  OLP should always be obtained to confirm the diagnosis and rule out dysplasia when plaque, erythematous or ulcerative lesions are present.   
The classic histopathological features of OLP consist of thickening of the granular layer, basal-cell degeneration, sawtooth ridging, atrophy of the epithelial layers, elongation of rete pegs, Civatte bodies and a bandlike lymphocytic infiltrate (Fig. 9).   
Direct immunofluorescence reveals fibrin below the basement membrane or in the Civatte bodies. However, these changes are nonspecific because they can be found in other bullous diseases.   
   
Management  
Treatment of OLP is usually instituted only when erosions or ulcerations are present. Since reticular lichen planus is asymptomatic no treatment would be necessary. Before commencing any local or systemic therapy it is important to eliminate all factors that may be responsible for initiating or precipitating oral lesions.   
Thus good hygiene should be instituted as well as removal of maloccluded or fractured teeth and old amalgam restorations. Patients with severe erosive lesions need aggressive treatment  with corticosteroids that still represent the mainstay therapeutic approach.   
Topical flucinonide or clobetasol ointment mixed with orabase are among the best local medications.  For gingival lesions, a medication splint, similar to a soft-bite splint but with longer flanges is very useful as a tray to held in place the ointment.   
Large ulcerations respond best to intralesional drugs as triamcinolone acetonide. Systemic prednisone may be occasionally indicated for severe erosive lichen planus at doses of 50-75 mg/day.   
Synthetic retinoids (etretinate) have been recently used in the treatment of OLP with positive results.   
Unfortunately side effects such as skin and lip dryness and hair loss limit the efficacy of these drugs. Caution should be used when using retinoids because of  their potential teratogenicity. Topical cyclosporin may be of benefit in erosive OLP although contradictory results have been reported.   
   
ERYTHEMA MULTIFORME  
Erythema multiforme (EM) is an ulcerative mucocutaneous disease of uncertain etiology. It usually occurs in young adults of the age of 20-30 years.   
Males are affected more frequently than women.   

Etiopathogenesis  
EM  is considered to be an immunological mediated process similar to vasculitis. In about 50% of the affected patients it possible to recognize either a preceding exposure to antibiotics or analgesics, or an infection with Herpes simplex or Mycoplasma pneumonia.   
These agents may trigger the immunological process responsible for the disease. In situ hybridization and PCR techniques have demonstrated the presence of Herpes simplex DNA in samples from patients with recurrent EM. However, the etiopathogenetic role of  Herpes simplex virus remains inconclusive.  

Clinical aspects  
EM has an acute onset and presents a wide spectrum of clinical manifestations. On the mild side of the spectrum, only oral ulcerations are seen (minor EM). In the most severe forms, diffuse sloughghing and ulceration of the entire skin may be observed. These forms are the Stevens-Johnson syndrome and  Lyell's disease (toxic epidermal necrolysis) which may have a grave prognosis.  
Prodromal symptoms include fever, sore throat, headache, malaise that develops 1 week before onset.   
The disease, which is usually self-limiting, last 2 to 6 weeks but in about 20% of patients shows a tendency to recur, especially in the spring and autumn.  
Skin lesions, appearing on the extremities, consist of highly characteristic concentric red rings resembling a target (bull's-eye lesions). Lesions of the oral mucosa start as red patches that evolve into large, shallow erosions and ulcerations.   
The ulcers may be diffuse involving the majority of the mucosal surface. Hemorrhagic crusting of the vermilion zone of the lips is common  and quite peculiar (Figg. 10 a-d). A more severe form of the disease, recognized as major EM or Stevens-Johnson syndrome, is when ocular, genital and oral mucosa and skin are affected.   

Pathology  
Histopathologic examination of the perilesional mucosa in EM reveals a pattern that is characteristic but not specific. Because the immuno fluorescent features are also nonspecific the definitive diagnosis of EM is often based on the clinical presentation and exclusion of other disorders.   
Subepithelial vesciculation is usually  seen in association with necrotic keratinocytes of the basal layer. In the lamina propria is usually present a mixed inflammatory infiltrate formed by neutrophils, eosinophils and lymphocytes (Fig. 11).  

Management  
Treatment of EM  includes the use of corticosteroids, especially in the early stages. Usually dosage of prednisone ranges between 50 and 75 mg/day. In cases of recurrent episodes of  EM a possible initiating cause such as herpesvirus infection or drug exposure should be investigate. If EM is triggered by Herpes simplex chronic administration of oral acyclovir may be useful to prevent recurrence. Stevens-Johnson syndrome and Lyell's disease should be treated by a dermatologist.  

MUCOUS MEMBRANE PEMPHIGOID  
Mucous membrane pemphigoid (MMP) is an vesiculoulcerative autoimmune disease of skin and mucosae in which autoantibodies are directed against components of the basal membrane.   
This disease shows preference for women with an age of  50-60 years. The term pemphigoid arises because clinically the disease mimics pemphigus vulgaris.   
However,  MMP  is more common than oral pemphigus vulgaris and completely different as clinical and pathogenetic features. MMP is also called cicatricial pemphigoid because when the conjunctival mucosa is affected severe scarring and blindness may occur.   

Etiopathogenesis  
The blistering that characterizes this disease is due to an abnormal production of autoantibodies directed against an ill-defined antigen in the lamina lucida of the epithelial basement membrane.   
MMP lesions show a characteristic subepithelial clefting.  

Clinical aspects  
 MMP mainly involves the oral mucosa but other sites, such as genital, ocular, nasal, esophageal and laryngeal mucosa may be involved. Lesions of the oral mucosa appear as ulcers on the gingival, buccal and palatal mucosa. Sometime vesicle or bullae can be visible but they easily rupture leaving large ulcerated areas (Fig  12).   
When MMP involves only the gingiva produces a clinical aspect termed desquamative gingivitis.   
This pattern is not specific of MMP and may also be seen in lichen planus and pemphigus vulgaris. The most serious complication of MMP is ocular involvement that occurs in about 25% of patients with oral lesions.   
Ulceration and fibrosis of the conjunctival mucosa are the earliest changes that, especially if the patient is not treated, lead to progressive scarring and adhesions of the eyelids to the ocular globe (symblefaron) producing blindness.  

Pathology  
Biopsy of perilesional mucosa shows the characteristic separation of the epithelial lamina from the lamina propria (Fig.13).   
In most cases only a mild chronic inflammatory infiltrate is present in the upper connective tissue. Direct immunofluorescence is often necessary to confirm the diagnosis demonstrating a continuous linear deposition of  IgG and C3 (Fig 14). Indirect immunofluorescence is rarely positive (5% of cases).  

Management  
Topical corticosteroids are  very effective in the treatment of MMP.  
Triamcinolone, flucinonide and clobetasol propionate applied with an adhesive base or a suitable tray are effective and do not cause side effects. Patients with severe oral manifestations or with ocular, laryngeal and genital involvement require more aggressive therapy with systemic prednisone (50-75 mg/day) plus immunosuppressive agents such as azatioprine (50-100 mg/day).   
An alternative systemic treatment can be dapsone, a sulpha drug derivative. Some authors report good results with this drug, while others have observed insufficient response and serious side effects. Contraindications to the use of dapsone are glucose-6-phosphate dehydrogenase deficiency or allergy.   

PEMPHIGUS   
Pemphigus is a complex autoimmune disease that presents four clinical variants. The most common variant is pemphigus vulgaris (PV). Pemphigus vegetans, erythematosus and foliaceus are rare and involvement of the oral cavity is very unusual.   
The incidence of  PV is of one to five cases per million people diagnosed each year. Although rare PV is an important disease because, if not treated, is life-threatening and may results in patient's death. Oral lesions often represent the first clinical manifestation.  

Etiopathogenesis  
Etiology of PV is related to an abnormal production of autoantibodies against a glycoproteic component of desmosomes.   
These structures have a pivotal role in maintaining the architecture of stratified epithelium. The immunologic damage causes detachment of the epithelial cells and formation of a characteristic intraepithelial clefting.  

Clinical aspects  
The average age at diagnosis of PV is 50 years. No sex preference has been observed. Rarely the disease is seen in childhood. In about 50 % of patients the oral manifestations appear before the skin involvement sometime even one year earlier. Oral lesions consist of  widespread superficial ulcers. Blisters are rarely seen. Palate, labial mucosa, buccal mucosa, ventral tongue and gingivae are the most common sites (Fig. 15a). Skin lesions manifest as vesicles, bullae or large ulcers (Fig. 15b).   
Recently, a new clinical form of  pemphigus called paraneoplastic pemphigus has been described. This type affects patients who have lymphomas or chronic lymphocytic leukemia.   

Pathology  
Biopsy of perilesional tissue shows acantholysis a feature that consists of detachment of the cells of the spinous layer and formation of an intraepithelial blister.   
The basal cells usually remain attached to the upper lamina propria forming the so-called  “row of tombstone” (Fig. 16).   
It is important to confirm the diagnosis by direct immunofluorescence that reveals the deposition of IgG or IgM and C3 in the intercellular spaces (Fig. 17) between the epithelial cells.   
Indirect immunofluorescence is also useful to detect  the serum circulating autoantibodies that are positive in 80-90% of cases.  

Management  
PV is a life-threatening disorder that needs to be treated aggressively with systemic corticosteroids.   
In an ideal situation the patient should be managed by a dermatologist with experience in immunosuppressive therapy. The dentist with expertise in oral medicine plays an important role in the initial diagnosis and treatment of the oral manifestations.   
The first line therapy consists in high dose of prednisone in association with azatioprine. Long term use of systemic corticosteroids may cause several  side effects and complications.