Immunologically Mediated Diseases of the Oral Cavity – A Systematic Review

Introduction

Immune-mediated disorders often have an impact on the oral mucosa, which is typically the first site of manifestation. The best hope for an early diagnosis and therapy that can stop the disease from spreading to the skin and/or other organs is a comprehensive clinical examination of an asymptomatic patient's oral mucosa. It is possible that some sores in the mouth are symptoms of an inflammatory disease.¹ Growing data suggests that autoimmune disorders have been on the rise over the past few decades. In reality, the growth in autoimmune disorders is comparable to the rise in allergy and cancer pathologies; however, infections have been found to be less prevalent in Western countries. Oral symptoms typically constitute the initial signs of autoimmune disorders.²

Classification

Hypersensitive reaction, Pemphigus vulgaris, Para-neoplastic pemphigus, Cicatricial or mucocutaneous pemphigoid, Cutaneous, bullous pemphigoid, Linear IgA, Epidermolysis bullosa, Lichen planus, Erythema multiforme, Systemic drug reaction, Lupus erythematosus, Scleroderma, Crest syndrome, Bechets syndrome, Reiter’s syndrome.³

Pemphigus vulgaris

The development of an intraepithelial bulla is a hallmark of chronic, autoimmune pemphigus vulgaris bullous illness. This pemphigus variant, which is the most common, affects the skin and/or mucosa. On the oral mucosa, pemphigus patients display the disease in about 50% of cases. Later, skin lesions spread to the neck, scalp, and trunk of the body, among other areas of the body. Furthermore, mucosa in the anal, vaginal, pharyngeal, esophageal, conjunctival, nasal, and pharyngeal regions are sensitive. Small bullae at the beginning of the oral lesions swiftly burst, leaving behind painful erosions that feel scorching. Lips, the soft palate, the buccal mucosa, and the gingiva are the main areas they affect, and desquamative gingivitis is prevalent.¹

Desmoglein-3 is a keratinocyte adhesion structure that is crucial for maintaining epithelial integrity. When immunoglobulin G (IgG) autoantibodies react with it, they produce acantholysis and the development of intraepithelial clefts, which is associated to the autoimmune mechanism of pemphigus.

Clinical, histological, and immunohistochemical tests are used in the differential diagnosis of pemphigus to separate it from other conditions with similar clinical signs, such as aphthae, erosive lichen planus, oral candidiasis, and pemphigoid, among others. The defining pathologic characteristics necessitate a biopsy of the perilesional mucosa and include acantholysis and a little inflammatory infiltration. Direct immunofluorescence reveals intercellular IgG and C3 deposits, and indirect immunofluorescence reveals autoantibody binding to the intercellular connection of the keratinocyte substrate by circulating in the patient's serum.⁴

Oral lichen planus

Lichen planus, an inflammatory chronic disease of the skin and mucosa, is one of the most prevalent dermatological conditions of the oral cavity. Skin lesions induce itching and are often self-limiting, in contrast to oral lichen planus (OLP) lesions which are persistent, potentially premalignant, sometimes cause morbidity and infrequently remit spontaneously. There are three progressive phases that can be identified clinically and microscopically: The early stage (6-12 months or longer) is distinguished clinically by white spots on the mucosa, which is followed by the second phase characterised by the development of white Wickham striae on the oral mucosa.⁵ Interpapillary rete pegs that initially appear saw-toothed histologically may eventually become atrophic, displaying a flat epithelium/corium interface and a more widespread (band-like) inflammatory infiltration. The oral mucosa is atrophic or hyperkeratotic in the last stage, which develops many years or even decades after the disease first appears, but still exhibits white plaques or Wickham striae. There are differing perspectives on the followup intervals needed for OLP patients. However, a short follow-up period can understate the prevalence of malignant transformation and the presence of risk factors for malignant transformation.⁶

Cicatricial pemphigoid

The development of painful bullae, especially on the mucosa, with or without skin involvement, and a predisposition to leave scars are hallmarks of cicatricial pemphigoid, an autoimmune, chronic, bullous, subcutaneous disease. Oral mucosa involvement occurs in 90% of cases, either as the sole mucosa affected or in association with involvement of additional locations such as the cutaneous, vaginal, nasopharyngeal, esophageal, laryngeal, and/or rectal mucosa.

The most common clinical sign of cicatricial pemphigoid in the mouth is desquamative gingivitis, which can present as anything from a mild, irregular erythema to a severe, generalised erythema with agonising bullae. Cicatrical pemphigoid often presents as a blister that rapidly bursts, leaving shallow ulcers with rough and bleeding bases that are painful and slowly improve in other affected sites, such as the buccal mucosa, alveola, palate, tongue, soft palate, and lower lip. Regarding the pathogenesis of cicatricial pemphigoid, there is uncertainty. It is difficult to diagnose the illness.

The only noteworthy finding from the histological analysis is the discovery of a subcutaneous bulla with an inflammatory infiltration. Direct and indirect immunofluorescence techniques are sensitive indicators but not particular for cicatricial pemphigoid due to the symptoms' similarity to other subcutaneous bullous disorders. Immunohistochemical techniques such as immunoblotting, enzyme-linked immunosorbent assay, and immunoprecipitation have expedited the diagnostic process by identifying new target proteins identified by antibodies in a variety of cicatricial pemphigoid subgroups.⁷

Erythema multiforme

Erythema multiforme is an acute, immune-mediated, self-limiting mucocutaneous illness defined by unique, pointed-appearing lesions. The hypersensitive reaction is thought to be caused by some drugs and illnesses. The oral lesions often appear as polymorphic erosive, ampullar, and erythematous lesions with blood-stained crusts in areas of non-keratinized mucosa. The disease's acute and recurring symptoms, along with the usual target-like lesions, are used to make the clinical diagnosis. Necrotic keratinocytes seen during the histological examination corroborate the diagnosis. Other autoimmune mucocutaneous blistering illnesses can be ruled out with direct immunofluorescent testing.⁸

Stevens-Johnson syndrome

Long thought to mimic erythema multiforme with mucosal involvement, toxic epidermal necrolysis is now recognised as a distinct disease entity that causes Stevens-Johnson syndrome. Severe mucosal erosions, diffuse, non-palpable, flat abnormal findings, and commonly fever that precedes them, are all traits both share. The main causes of the illness are drug usage, infections, and perhaps more risk factors that are still unknown.

Supportive therapy is crucial for improving these patients' circumstances, possibly even more so than particular immunomodulatory treatments. The death rate is significant despite all therapeutic attempts and increases with illness severity, patient age, and any underlying health conditions. In addition to long-term consequences on their mucosal membranes, survivors may suffer from significant eye problems.⁸

Systemic lupus erythematosus

Systemic lupus erythematosus (SLE), a model systemic autoimmune illness, is defined by immunological abnormalities and a loss of tolerance to nuclear antigens. Most often occurring mucosal symptom of chronic SLE is an oral discoid lesion. A clearly defined, spherical or irregular red region that may be atrophic or ulcerated makes up the typical clinical appearance, which mimics the classic cutaneous discoid lupus and is accompanied by white radiating keratotic striae and telangiectases.

The “intense keratotic white lesions,’’ the “honeycomb plaques’’ with mucosal scarring as a clinical feature, and the “linear fissured, ulcerative, and keratotic lesions’’ that may form in the buccal mucosa are morphologic variations of chronic oral lupus. Because the lesions of clinically comparable disorders like OLP are often symmetrical, the distribution of lesions in the mouth is typically asymmetrical (palate, buccal mucosa, tongue), and this asymmetry is important for the differential diagnosis. Lip involvement is a frequent marker of SLE, and the clinical symptoms may include discoid lesions that are clearly demarcated or even generalised cheilitis. The presence of mucin in the lamina propria is a crucial sign for separating SLE from OLP.⁹

Sjogren’s syndrome

Because lymphocytic infiltration of the lacrimal and salivary glands occurs as a result of this widespread autoimmune illness, dry mouth and eyes are common symptoms. Patients typically have difficulty speaking, eating, and swallowing when it comes to the oral cavity. Additionally, they frequently have xerostomia, a disorder that causes dry mouth, oral mucosal burning, and pain in the salivary glands after eating. Candida albicans causes chronic erythematous candidiasis, which affects the commissures of the tongue, palate, and lips in 70–80% of all patients. The most popular supplementary diagnostic tests for Sjogren's syndrome are lower lip minor salivary gland biopsy and sialometry.¹⁰

Linear IgA dermatosis

It is an uncommon form of autoimmune blistering syndrome marked by subepidermal blisters and linear IgA autoantibody deposition at the dermoepidermal interface. The lesions typically show as annular vesiculobullous lesions all over the body. The antigen in the pathogenic processes of linear IgA dermatosis is the carboxy terminus of the BPAg2 or BP180. IgA autoantibodies attack the molecular building blocks of the hemidesmosomes, causing disruption and development of lesions. Vancomycin is not absorbed when taken orally; however intravenous vancomycin treatment is the most common cause of drug-induced dermatosis. But no cases have been documented after it was administered orally.⁹

Bullous pemphigoid

It is a painful condition that mainly affects elderly persons. Some of its clinical characteristics include generalised, pruritic tense blisters and crusts, generally in erythematous lesions or in skin that appears normal, as well as in infiltrating and urticarial plaques, papules, or eczematous lesions. In 10-30% of the patients, the oral cavity is involved, and in these situations, there are repeated erosions of the marginal gingiva. The histological features of bullous pemphigoid include subepidermal blisters with inflammatory infiltrates frequently rich in eosinophils but also containing lymphocytes, histiocytes, or neutrophils. Because these can also be observed in a number of other linked disorders, additional diagnostic testing is required.¹¹

Paraneoplastic pemphigus

Oral erosions typically cause considerable discomfort and bleeding and is uncommon. This type frequently co-occurs with hematologic neoplasms. It has been discovered that cancer has immunological effects on the local immune system rather than directly infiltrating the tissue or causing tissue damage as a result of metastasis. Using the bladder epithelium of rats, histological evidence of acantholysis, intercellular, and basement membrane staining for circulating autoantibodies was obtained using direct immunofluorescence and indirect immunofluorescence staining. When three of the major criteria, or two major and two minor ones are present, these criteria are regarded as diagnostic. Most of the time, poor treatment response and significant rates of morbidity and mortality result.¹²

Dermatitis herpetiformis

The grouping of the skin lesions and the chronic nature of the bullous skin eruptions which typically affects the knees, elbows, buttocks, and shoulders are characteristics of the condition. Mucosal involvement has been seen on the tongue, cheeks, and even the larynx, while being quite rare. Even though majority of patients do not have any particular gastrointestinal symptoms, celiac disease will always be found in all individuals who underwent small intestine biopsy. A gluten enteropathy is the cause of the rash.¹³

Recurrent aphthous stomatitis (RAS)

It is the most common kind of ulcerative illness of the oral mucosa, affecting 20% of the general population. Numerous factors, including genetic, immunological, microbiological, dietary, hormonal, emotional, traumatic, and others, have a role in the aetiology of recurrent aphthous stomatitis. Recurrent aphthous stomatitis often manifests as recurrent, self-limiting ulcers that mostly affect non-keratinized oral mucosa. Unfortunately, no clear explanation exists for how each of these elements truly affects RAS aetiology. Because there is no surefire cure for RAS, it is frequently treated with antibiotics, steroids, immunomodulators, and other drugs.¹³

Behcet disease

Unknown reasons contribute to this multisystemic autoimmune disease. The three primary symptoms that describe it most frequently are oral ulcers, vaginal ulcers, and eye irritation. Often, the first sign of Behcet syndrome is the mucocutaneous lesions. They enable a better prognosis, and their recognition substantially aids early diagnosis. The oral lesions are oral mucosal ulcers which have the same appearance as typical oral aphthae. They come back in waves and hurt. The lips, buccal mucosa, soft palate, and tongue are the areas they occur. Allegedly, there are no pathognomonic laboratory results. According to the International Study Group (ISG) criteria, two or more of the essential features (oral, genital, or ocular lesions) must be present to diagnose Behcet syndrome after all other clinical explanations have been ruled out. Given the high prevalence of oral aphthous lesions in the general population, a complex differential diagnosis must be made. Behcet syndrome can be treated with local and systemic corticosteroids alone or in conjunction with immunosuppressive drugs. Monocorticosteroid therapy's failure to prevent relapse warrants the use of immunosuppressive drugs.¹⁴

Mucous membrane pemphigoid

It is an immune-mediated chronic blistering disorder. Additionally, other affected areas may include skin, conjunctiva, and vaginal mucous membranes. The gingiva is the most common site of pemphigoid lesions (nearly 94% of the instances), where they result in desquamative gingivitis, a clinical disease. According to some sources, desquamative gingivitis is not a diagnostic entity unto itself. The pharynx, lips, tongue, palate, buccal mucosae, and other areas of the oral cavity can potentially develop lesions. The symptoms of these disorders include everything from bleeding to masticatory difficulty to a burning feeling. Pemphigoid blisters are less brittle than pemphigus blisters and can remain in the oral cavity for up to 48 hours. The diagnosis of mucous membrane pemphigoid is made using clinical and histological samples. The epithelium is split from the underlying connective tissue, according to a histologic study. Direct immunofluorescence is advised when there are doubtful histology samples that show linear involvement at the level of basal membrane. Lesions can be treated with topical corticosteroid gel in less severe situations, although dapsone (diaminodiphenyl sulfone) also has its uses. The most severe instances require systemic administration of treatment.¹

Rheumatoid arthritis (RA)

It is an autoimmune inflammatory illness affecting the synovial membranes of diarthrodial joints. Fever, fatigue, and systemic weight loss are among the early signs of RA. TMJ involvement affects more than 50% of RA patients. It can begin early in childhood and result in malocclusion, retrognathic mandible, bilateral or unilateral TMJ ankylosis, facial deformity, and mandibular development disruption, providing the appearance of a typical bird's face. In juvenile idiopathic arthritis, mandibular rami shortening and space reduction result in a narrow oropharyngeal airway, and hypotonicity of the oropharyngeal muscles can induce issues such as upper airway obstruction. The patient's current RA drugs must be known to the dentist. Negative side effects or interactions with other drugs are possible. Before recommending any NSAIDs, the doctor must assess the patient's current prescription regimen to avoid renal or stomach toxicity. Other gastrointestinal protective drugs, like misoprostol, may help minimise these adverse effects. Replacement therapy is essential in a patient on glucocorticoids for a long time to prevent secondary adrenal insufficiency. It is important to carefully assess the patient's health because even minor episodes of RA might be challenging for them to maintain excellent oral hygiene.¹⁵

Conclusion

The morbidity of a patient is increased due to oral lesions which can affect the patient's psychological and financial well-being as well as the health of the community. The best course of action is typically to seek medical assistance because these lesions can cause pain, irritation, and other symptoms. Immune-mediated disorders commonly present with oral manifestations, which frequently act as the pathology's earliest clinical symptoms and alarm signals. Thus, oral health providers must be aware, and a full mucosa inspection sometimes necessitates the assistance of dental and/or oral medicine specialists. Healthcare workers who collaborate well can improve patient outcomes and quality of life. The incidence of the aforementioned primarily nonspecific oral lesions is not known for sure, though.

Conflict of Interest

None