Aphthous Stomatitis Clinical Presentation
- Author: Ginat W Mirowski, MD, DMD; Chief Editor: William D James, MD more...
Recurrent aphthous ulcers consist of one or multiple round-to-ovoid, shallow, punched-out–appearing, painful oral ulcers that recur at intervals of a few days to a few months. To evaluate oral ulcers as recurrent aphthous ulcers, ascertain the following information:
Nature of the lesions (number, size, duration, recurrence): The prodromal stage (when present) may begin with a pricking or burning sensation on the mucosa. The ulcers develop within 24-48 hours. Pain lasts 3-4 days or until a thicker fibrinous cover develops or early epithelialization occurs. Healing is complete in 7-14 days.
Age of the patient at onset
Cutaneous or mucosal changes
Symptoms of other organ system involvement
Current medications, including herbal medications and vitamins
Host factors associated with recurrent aphthous ulcer (see Causes): With regard to genetic factors, a family history is evident in some cases. Hematinic deficiency may play a role. Iron, folic acid, or vitamin B-6 and B-12 deficiencies are possible. [15, 16] Immune dysregulation may play possibly play a role. Physical or emotional stress is often reported by patients as associated with recurrent outbreaks.  This stress appears to affect onset but not duration or severity of episodes. 
Environmental factors associated with recurrent aphthous ulcer: Local, chemical, or physical trauma may initiate ulcer development in patients who are susceptible (pathergy). Allergy or sensitivity to chemicals or food additives may stimulate an outbreak. The role of microbial infection is debated.
HIV infection (associated with lesions)  : Aphthouslike oral ulcerations involving all 3 types of recurrent aphthous ulcers are observed. Approximately 66% of patients who are HIV positive have herpetiform and major recurrent aphthous ulcers. Unlike in healthy individuals, these ulcerations may be present on both keratinized and nonkeratinized surfaces, making it even more critical to rule out opportunistic infections. Ulcerations must be distinguished from those caused by HIV medications and fungal, viral, or bacterial infections. Tissue biopsy for pathologic evaluation and for culture is indicated.
Behçet syndrome (associated with lesions) [20, 21, 22, 23, 24, 25] : This complex, multisystemic inflammatory disorder of unknown cause is characterized by recurrent oral aphthae and at least 2 of the following findings: genital aphthae, synovitis, cutaneous pustular vasculitis, posterior uveitis, or meningoencephalitis. Oral aphthae of Behçet syndrome are clinically similar to those in recurrent aphthous ulcers but are accompanied by ocular and genital lesions. The incidence is highest in Japan, Southeast Asia, the Middle East, and southern Europe and in persons aged 30-40 years. Behçet syndrome is strongly associated with HLA-B51. Studies also demonstrate an association between IL-18 gene polymorphisms and Behçet syndrome, which was not observed in patients with aphthous stomatitis. 
Gluten-sensitive enteropathy (also known as celiac sprue) [27, 28, 29] : Oral lesions occur in most cases of gluten-sensitive enteropathy (GSE) and can often precede abdominal symptoms. Less than 5% of patients with recurrent aphthous ulcers have GSE, also known as celiac disease, or other minor mucosal abnormalities of the small intestine. However, celiac disease is not universally agreed to be causative; thus, the need for patients with aphthosis to be screened for celiac disease is unclear. [30, 31] Bowel symptoms may not be present, but patients may have folate deficiency, and they sometimes have reticulin antibodies.
Xerostomia or dry mouth: This may be a precipitating or aggravating factor in many patients since saliva is a lubricating agent with antimicrobial properties. 
No specific laboratory tests are available. It is important to exclude other disorders by medical history and a comprehensive laboratory evaluation when indicated.
Regardless of the clinical form of recurrent aphthous ulcer, ulcers are confined to the nonkeratinized mucosa of the mouth, sparing the dorsum of the tongue, the attached gingiva, and the hard palate mucosae, which are keratinized unless the patient is HIV positive. Although patients may have submandibular lymphadenopathy, fever is rare. Most patients are otherwise well. Different gradations and their findings are as follows:
Recurrent aphthous ulcer minor (see image below): Recurrent aphthous ulcer minor is characterized by discrete shallow ulcers smaller than 1 cm in diameter. The ulcers are covered by a yellow-gray pseudomembrane (fibrinous exudate) and are surrounded by an erythematous halo.
Recurrent aphthous ulcer major (see image below): Recurrent aphthous ulcer major is characterized by oval ulcers that are larger (>1 cm in diameter; often 2-3 cm) and deeper than those observed in recurrent aphthous ulcer minor. The ulcers may coalesce and often have an irregular border.
Herpetiform recurrent aphthous ulcer (see image below): Herpetiform recurrent aphthous ulcer is characterized by crops of smaller ulcers; tens of ulcerations may be present in clusters. The ulcers can coalesce to produce a widespread area of irregular ulceration.
Although the clinical characteristics of recurrent aphthous ulcer are well defined, the precise etiology and the pathogenesis of recurrent aphthous ulcer remain unclear. Many possibilities have been investigated. Recurrent aphthous ulcer is a multifactorial condition, and it is likely that immune-mediated destruction of the epithelium is the common factor in recurrent aphthous ulcer pathogenesis. Host risk factors associated with recurrent aphthous ulcer are described below.
A family history of recurrent aphthous ulcers is evident in some patients. A familial connection includes a young age of onset and symptoms of increased severity. Recurrent aphthous ulcer is highly correlated in identical twins.[33, 34]
Associations between specific HLA haplotypes (eg, HLA- B51) and recurrent aphthous ulcer have been investigated. No consistent association has been demonstrated. However, in two Iranian studies, polymorphisms in an inflammasome-related gene, NLRP3, and in the promoter region for the IL6 gene were found to be significantly associated with recurrent aphthous in a small cohort of patients.[35, 36] Still, host susceptibility is clearly variable, with a polygenic inheritance pattern, and penetrance likely depends on other factors.
In several studies, hematinic (iron, folic acid, vitamins B-6 and B-12) deficiencies were twice as common in patients with recurrent aphthous ulcers as in control subjects. As many as 20% of patients with recurrent aphthous ulcer have a hematinic deficiency, with some studies also reporting notable elevations of blood homocysteine. Lower dietary intake of folate and vitamin B-12 is more common among persons with aphthous ulcers and treatment with 1000 mcg/d has shown benefit in individuals regardless of serum B-12 levels.[39, 40] A small group of adolescents were shown to have reduced incidence and pain from recurrent aphthous stomatitis when given 2000 mg/d of ascorbic acid. Vitamin D deficiency is also more prevalent in patients with recurrent aphthous stomatitis, although there is no correlation between vitamin D levels and a patient’s clinical course, including number of ulcers, duration of ulcers, or frequency of ulcer development.
Thus, serologic workup is warranted. Hemoglobin and RBC indices are not sufficient in all cases.
At present, no unifying theory of the immunopathogenesis of recurrent aphthous ulcer exists, but immune dysregulation may play a significant role. Cytotoxic action of lymphocytes and monocytes on the oral epithelium seems to cause the ulceration, but the trigger remains unclear. Upon histologic analysis, recurrent aphthous ulcer consists of mucosal ulcerations with mixed inflammatory cell infiltrates. T-helper cells predominate in the preulcerative and healing phases, whereas T-suppressor cells predominate in the ulcerative phase.
Other findings associated with immune dysregulation include the following:
Reduced response of patients' lymphocytes to mitogens
Circulating immune complexes
Alterations in the activity of natural killer cells in various stages of disease 
Increased adherence of neutrophils
Reduced quantities and functionality of regulatory T cells in lesional tissue
Increased expression of pro-inflammatory Th1 genes 
Release of tumor necrosis factor-alpha (TNF-alpha) 
Significant involvement of mast cells in the pathogenesis of recurrent aphthous ulcer
Reduced cellular expression of heat shock protein 27 and interleukin 10 in aphthous lesions [46, 47]
Elevated levels of salivary and serum cortisol, as well as increased anxiety 
Increased Toll-like receptor activity 
Oxidative stress (altered levels and balance of glutathione and malondialdehyde) [50, 51]
Increased levels of autoimmune thyroid-related problems and antithyroid antibodies, although the significance is unclear 
Immunogenetic factors, including single nucleotide polymorphisms in immune modulatory genes [35, 36]
Researchers disagree about the role of microbes in the development of recurrent aphthous ulcers. Emphasis has been on a microbial agent as a primary pathogen or an antigenic stimulus. Numerous studies have failed to provide strong evidence to support the role of herpes simplex virus, human herpesvirus, varicella-zoster virus, or cytomegalovirus in the development of aphthous ulcers.[53, 54]
Recurrent aphthous ulcer formation may be a T-cell–mediated response to antigens of Streptococcus sanguis that cross-react with the mitochondrial heat shock proteins and induce oral mucosa damage. Helicobacter pylori has been detected in lesional tissue of oral ulcers, and a 2014 meta-analysis found H pylori infection was associated with an increased risk of recurrent aphthous stomatitis. Still, the frequency of serum immunoglobulin G antibodies to H pylori is not increased in recurrent aphthous ulcers, and the organisms have never proven causative.[56, 57, 58, 59, 60]
Imbalances in the oral mucosal microbiome have been identified in patients with recurrent aphthous stomatitis. Although no phylum-level differences were appreciated between nonulcerated sites in these patients and healthy controls, patients with recurrent aphthous stomatitis did exhibit an increased abundance of Bacteroidales species. Further investigation is required to understand if these microbiome imbalances play a causative role in aphthous stomatitis and how diet and oral hygiene influence the oral mucosal microbiome.
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