Acute Immune-Mediated Lesions of the Oral Cavity

Although acute immune-mediated lesions of the oral cavity (AIML) can have an onset over several months, they often demonstrate rapid onset and can be self-limited. Despite the self-limiting nature of some disorders, patients with AIML can have significant pain and multisystem involvement. It is vital for the oral health care provider to arrive at the proper diagnosis with distinction from overlapping conditions, as the oral manifestations may be harbingers of more serious systemic complications.

Key points

  • Acute immune-mediated lesions of the oral cavity (AIML) of the oral mucosa arise suddenly and often are self-limited. They may be associated with systemic, multisystem inflammatory disease.

  • Thorough clinical examination with medical, dental, and family history is vital in the diagnosis and classification of many of these conditions.

  • The oral health care provider plays a pivotal role in the management of AIML, especially because oral manifestations may be the presenting sign for underlying systemic disease.

  • Although all AIML have the potential to be recurring and/or relapsing, recurrences of some AIML are preventable with early diagnosis and proper management.

Aphthous stomatitis

Recurrent Aphthous Stomatitis

Recurrent aphthous stomatitis (RAS) or canker sores is a disease of unknown cause characterized by recurrent painful ulcers of the unattached oral mucous membranes. The lesions typically begin in childhood or adolescence and are characterized as single or multiple round or ovoid ulcerations with inflammatory halos. RAS is one of the most common diseases of the oral mucosa with a reported worldwide prevalence of 10% to 15%. A single triggering agent has not been identified, and investigators theorize that an altered local immune response to a variety of factors may induce aphthae. Approximately 80% of individuals with RAS report his or her first ulceration before the age of 30 years. Commonly reported predisposing factors include stress, trauma, allergies, nutritional deficiencies, genetic predisposition, and hematologic abnormalities. Patients with frequent recurrences should be evaluated for systemic disorders ( Table 1 ) that result in identical-appearing ulcerations termed aphthous-like ulcerations.

Table 1
Systemic disorders associated with aphthous-like ulcerations
Cause Example
Rheumatic diseases Behçet’s disease
Reactive arthritis
Sweet’s syndrome
PFAPA syndrome
MAGIC syndrome
Gastrointestinal diseases Celiac disease
Inflammatory bowel disease (ulcerative colitis; Crohn’s disease)
Nutritional diseases Iron; folate; zinc; B1; B2; B6; B12
Drug reaction NSAIDs, beta-blockers
Immunocompromised states HIV infection
Hematologic disorders Cyclic neutropenia; leukemia

Abbreviations: HIV, Human immunodeficiency virus; MAGIC syndrome, mouth and genital ulcers with inflamed cartilage syndrome; NSAID, non-steroidal anti-inflammatory drug; PFAPA, periodic fever, aphthous stomatitis, pharyngitis, adenitis.

The three clinical variants of aphthous stomatitis (AS) are minor AS, major AS, and herpetiform AS. Minor AS, or Mikulicz aphthae, represent approximately 80% of patients with RAS and often begin in childhood. Lesions present on nonkeratinized oral mucosa and are typically less than 1 cm in diameter ( Fig. 1 ). Minor AS may be painful, but they heal spontaneously within 7 to 14 days without scarring. Major AS or Sutton disease occurs in approximately 10% of patients with RAS and is characterized by ulcerations that are larger and deeper ( Fig. 2 ). The onset of major AS is often after puberty. Major aphthae may take several weeks to heal and can result in mucosal scarring that can rarely lead to restricted mouth opening. Herpetiform AS occurs in approximately 10% of patients with RAS and demonstrates the greatest number of ulcerations and most frequent recurrences. Herpetiform AS typically occurs during adulthood and is most common in women. Individual pinhead-sized (1 to 3 mm) ulcerations ( Fig. 3 ) can coalesce into larger, irregular ulcerations ( Fig. 4 ). The multiple small ulcerations resemble lesions associated with an intraoral herpes simplex infection, hence the designation herpetiform AS; however, the etiology of herpetiform AS is unknown and unrelated to herpes simplex virus (HSV).

Fig. 1
Minor aphthous ulceration: a small, recurrent, and painful lesion of the labial mucosa.
( Courtesy of Mark Mintline, DDS, Pomona, CA.)

Fig. 2
Major aphthous ulceration: a large, deep ulceration of the pterygomandibular raphe was slow to heal and led to scarring (not pictured).
( Courtesy of Mark Mintline, DDS, Pomona, CA.)

Fig. 3
Herpetiform aphthous ulcerations: a collection of pinhead lesions present on the lateral ventral tongue.
( Courtesy of Molly Housley Smith, DMD, Lexington, KY.)

Fig. 4
Herpetiform aphthous stomatitis: multiple pinhead ulcerations of the labial vestibule coalesced into large and irregular areas of ulceration.
( Courtesy of Mark Mintline, DDS, Pomona, CA.)

Aphthous ulcerations are typically diagnosed based on their clinical appearance and a suggestive patient history. Classically, RAS lesions are recurrent, small, and round ulcerations found on nonkeratinized oral mucosa that started during childhood. The histopathology of an aphthous ulceration is nonspecific, but a biopsy may rule out other clinical mimics. All three clinical variants of AS may be further subdivided into simple and complex aphthosis to characterize healing and recurrence rates. In simple aphthosis, a few lesions are present, heal within 7 to 14 days, and rarely recur. In complex aphthosis, multiple lesions are present in a constant state of healing and development.

Effective treatment involves maintenance of the oral mucosal barrier, identification, and elimination of precipitating factors and minimizing recurrences. Most patients with mild aphthosis do not receive treatment, but ulcerations may be managed with over-the-counter anesthetics, medicaments, adhesive products, or topical corticosteroids. Ulcerations in major aphthosis are more resistant and often necessitate more potent topical corticosteroids, corticosteroid injections, or systemic corticosteroids. Patients with complex aphthosis should be evaluated to rule out possible triggers and underlying systemic disorders such as cancer, infection, and other inflammatory or autoimmune conditions.

Behçet’s disease

First described as a combination of oral and genital ulcerations ( Fig. 5 ) and “hypopyon uveitis ( Fig. 6 ),” Behçet’s disease (BD) is a rare, chronic, multisystem and relapsing inflammatory disorder of the vasculature classified as a “variable vessel vasculitis.” Although the condition is chronic, the topic is discussed under this article because of the acute onset of oral ulcerations.

Fig. 5
Oral ulcers in Behçet’s disease: ulcerations are identical to those found in aphthous stomatitis and often are small, painful, on unattached mucosa, and ovoid-to-round with an erythematous halo.
( Courtesy of William T. Driebe, MD, and Eric Grieser, MD, Gainesville, FL.)

Fig. 6
Ocular manifestations of Behçet’s disease: ( A ) inflamed conjunctival vasculature with inferior layered hypopyon ( arrows ) in the anterior chamber of the eye and ( B ) retinal photograph with vasculitis ( white arrow ) and retinitis ( black arrow ).
( Courtesy of William T. Driebe, MD, and Eric Grieser, MD, Gainesville, FL.)

Owing to the increased historical prevalence of BD in individuals from the Mediterranean, Central Asia, and Far East regions, BD has been nicknamed “Silk Road Disease.” The disease affects between 1 in 1000 and 1 in 10,000 individuals, with Turkey having the highest incidence among the endemic regions (20–420 per 100,000 people), , although other regions have seen an increase in cases due to immigration (especially to Germany, France, and the United States). Interestingly, the ocular signs, pustular lesions, and vascular lesions are more often seen in men, and erythema nodosum and genital ulcerations are more frequently encountered in women. In a large Iranian study analyzing 6,075 BD patients, 56% of patients were males, and 44% were females.

Although the exact etiology and pathogenesis remain unclear, a variety of etiologic agents have been associated with BD, including microbial triggers/poor oral health, immunological abnormalities, genetic factors, and endothelial dysfunction. Because familial cases of BD have been identified, many genetic links have been investigated, and a plethora of alleles have been implicated; HLA-B51, located on chromosome 6, is found most frequently in Japanese and Turkish patients with BD and is the best known HLA type associated with BD in general, affecting about 20% of patients. Infectious agents, such as HSV 1, Streptococcus sanguinis (found in the oral microbiome), and others have been implicated. Autoantibodies, particularly anti-endothelial cell antibodies as well as cytokines, also play important roles in this complex immune/environment interaction.

The signs and symptoms of BD are summarized in Table 2 . Recurrent oral ulcerations are the presenting symptom in approximately 70% of BD patients, and they are present in 86% to 100% of patients. The oral ulcerations present identically to AS (see Fig. 5 ); thus, evaluation for other sites of involvement is critical to proper diagnosis. The ulcerations begin as painful papules that transform into round-to-ovoid ulcerations with erythematous halos and central white/yellow pseudomembranes. The ulcers predominantly affect the nonkeratinized mucosa. Oral ulcerations do not appear to scar, whereas genital ulcerations are more commonly associated with scarring.

Table 2
Clinical signs and symptoms of Behçet’s disease
Data from Refs. ,
Site Clinical Manifestation
Oral (86%–100%) Painful papules, ulcerations, diffuse erythema of the soft palate/oropharynx
Genital (57%–93%) Ulcerations most commonly on the scrotum in men and on the vulva for females
Skin Extragenital aphthous ulcers; erythema nodosum-like lesions; papulopustular lesions; leukocytoclastic vasculitis
Ocular (40%–60%) Bilateral panuveitis; anterior/posterior uveitis; conjunctivitis; recurrent attacks can lead to cataracts and glaucoma
Vascular Superficial thrombophlebitis; deep vein thrombosis; arterial involvement (eg, arterial aneurysm, occlusion, stenosis of the aorta, femoral, or pulmonary vessels)
Cardiac Endocarditis; pericarditis; valvular lesions; intracardiac thrombosis; myocarditis
Neurological (3%–25%) Dural sinus thrombosis; aseptic meningitis; arterial vasculitis; meningoencephalitis; peripheral nerve involvement; psychiatric problems
Gastrointestinal (3%–26%) Mucosal inflammation; ulcerations; diarrhea, abdominal pain, nausea
Musculoskeletal (45%–60%) Arthritis; arthralgia; fibromyalgia; ankylosing spondylitis
Pulmonary Vasculitis; fibrosis; infection; pleurisy; embolism

There is no one laboratory test for BD, but rather, diagnostic criteria have been proposed. Two major classification systems for diagnosis are described: by the International Study Group for Behçet’s disease (ISG) in 1990 and the International Criteria for Behçet’s Disease (ICBD) in 2014. In the ISG system, diagnosis is made on the presence of two of the following clinical signs/symptoms along with oral ulcerations: skin lesions, ocular involvement, genital ulcerations, and a pathergy test positivity. In the newest ICBD system, ocular involvement, genital ulcerations, and oral ulcerations are given two points each, whereas vascular involvement, skin lesions, and neurologic signs/symptoms are each given one point. The patient is diagnosed with BD when the total number of points equates four or more.

Patients with BD often are managed by a team of providers, which includes oral health care providers, rheumatologists, dermatologists, ophthalmologists, and gynecologists. Because poor oral health is associated with the etiology of BD, one simple step to help tame/manage oral ulcerations is regular dental checkups. In order not to exacerbate the condition, it is not recommended that patients who have active oral ulcerations undergo dental treatment. A variety of medications have been used to control the lesions, including topical and systemic corticosteroids, topical calcineurin inhibitors, anti-inflammatory agents, colchicine, azathioprine, mycophenolate mofetil, cyclosporine A, cyclophosphamide, thalidomide, methotrexate, lenalidomide, dapsone, pentoxifylline, interferon-α, anti-tumor necrosis factor (TNF)-α agents, anti-IL-1 and interleukin (IL)-6 agents. Benzydamine hydrochloride mouth rinses have been used to decrease oral pain but not healing time. Amlexanox and topical prostaglandin E2 gel also have been used to reduce ulcer size and pain as well as prevent the formation of new ulcers. Topical steroids (eg, 0.05% fluocinonide gel, 0.05% augmented betamethasone dipropionate ointment, 0.5 mg/5 mL dexamethasone solution) have been used. Of note, oral phosphodiesterase-4 inhibitor apremilast (Otezla) is the first agent approved for use in treating BD in the United States. Apremilast has been shown to reduce the pain and number of oral ulcerations, sustained over a period of 64 weeks of therapy.

Allergic contact stomatitis

Contact stomatitis (CS) is characterized by inflammation and/or pain of the oral mucosa caused by exposure to an irritant or triggering allergen. Irritants include heat, trauma, and chemicals. Irritants cause inflammation and activation of immunologic mediators without memory T-cells or antigen-specific immunoglobulins. Allergens associated with allergic CS (ACS) are numerous ( Box 1 ), and the variable clinical appearance of ACS depends on the nature, potency, concentration, and period of exposure of the allergen. Most ACS are delayed type hypersensitivity (Type IV) reactions and occur after an antigen exposure in a sensitized individual. Allergens that cause ACS may also contribute to exfoliative cheilitis and perioral dermatitis.

Nov 25, 2023 | Posted by in Oral and Maxillofacial Surgery | Comments Off on Acute Immune-Mediated Lesions of the Oral Cavity

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