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Table of Contents
REVIEW ARTICLE
Year : 2017  |  Volume : 14  |  Issue : 4  |  Page : 202-206

Recurrent aphthous ulcers — Still a challenging clinical entity


1 Department of Otorhinolaryngology, IMS and SUM Hospital, Siksha “O” Anusandhan University, Bhubaneswar, Odisha, India
2 Department of Otorhinolaryngology, Apollo Hospital, Bhubaneswar, Odisha, India
3 Directorate of Medical Research, IMS and SUM Hospital, Siksha “O” Anusandhan University, Bhubaneswar, Odisha, India

Date of Web Publication5-Feb-2018

Correspondence Address:
Santosh Kumar Swain
Department of Otorhinolaryngology, IMS and SUM Hospital, Kalinga Nagar, Bhubaneswar 3, Odisha
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/am.am_40_17

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  Abstract 

Recurrent aphthous ulcer (RAU) is a clinical condition characterized by painful ulcer with different size affecting the mucosa of the oral cavity. Its etiology and pathogenesis are not clearly known and the diagnosis is based on the clinical picture. These lesions may be classified into minor, major, and herpetiformis. The aphthous ulcers in the oral cavity affect speech and feeding, leading to poor quality of life. Relevant literature was searched from PubMed, Science Direct, Cochrane Central Register of Controlled Trials, and Scopus last 20 years using the keywords “RAU.” The RAU is a common clinical entity. The diagnosis of RAU is mainly based on clinical ground and must be differentiated from other causes of oral ulceration. The treatment is often unsatisfactory as topical application of corticosteroids and other treatment modalities minimizes the severity of the ulceration but not stop chance of recurrence.

Keywords: Behcet's disease, corticosteroids, immunocompromised patients, oral ulcer, recurrent aphthous ulcer


How to cite this article:
Swain SK, Gupta S, Sahu MC. Recurrent aphthous ulcers — Still a challenging clinical entity. Apollo Med 2017;14:202-6

How to cite this URL:
Swain SK, Gupta S, Sahu MC. Recurrent aphthous ulcers — Still a challenging clinical entity. Apollo Med [serial online] 2017 [cited 2018 Nov 14];14:202-6. Available from: http://www.apollomedicine.org/text.asp?2017/14/4/202/224735


  Introduction Top


The term “aphthous” in medicine is derived from a Greek word “aphtha” which means ulceration. Recurrent aphthous ulcer (RAU) is seen worldwide and characterized by multiple, recurrent, small ovoid, or round ulcers with circumscribed margins, erythematous haloes, and gray or yellow floors.[1] RAU is an inflammatory condition of unknown etiology showing painful multiple or single recurrent ulcerations in the oral mucosa. RAU is the most common ulcerative lesion in the oral cavity mucosa in the United States.[2] It is seen commonly found in childhood or adolescent age group. RAU or Canker sores is commonly seen in the oral cavity, characterized by recurrent episodes of a single or multiple and painful ulcers covered by fibrin and surrounded by erythematous rim locating in the nonkeratinizing mucosa of the oral cavity. RAU is seen in 5%–25% of the general population and it is more than 50% among students at the time of examination.[3] Although RAUs are self-limited, this lesion causes pain and discomfort and interferes in eating, speaking, and swallowing which leads to poor quality of life. Early and effective treatment of RAUs ulcer minimizes the discomfort in speaking and painful swallowing.


  Etiology Top


Aphthous ulcers are often recurrent and multiple lesions seen in the oral cavity mucosa particularly in buccal mucosa, labial mucosa, floor of the mouth, and tongue. The etiology of RAU remains unclear. Several etiological factors are thought to relate for causing this lesion such as trauma, immunological dysfunction, psychological stress, systemic diseases, nutritional deficiency, infections, and so on.[4] The other possible etiologies are drug use, lack of folic acid, Vitamin B12, iron, and other dietary factors, stress, hormonal changes, metabolic diseases, and infections.[5] RAU is commonly seen oral lesion affecting 5%–66% of the adult patients seen in outpatient department.[6] There are numerous aggravating factors which are identified for the RAU, but the exact etiology is still unknown. There is difficulty in establishing the exact nature of RAU due to their nonspecific histopathology and absence of any reproducible identifiable cause, i.e., endogenous or exogenous cause.[7] The extensive investigations on the patients identified a range of local, gastrointestinal, hematological, genetic nutritional, allergic, psychological, and drug reactions as trigger factors in RAU.[8] Certain factors such as interstitial collagenases (MMP-1 and MMP-8) are enzymes that cause degradation of main oral mucosa collagen Type I and Type III, leading to RAU.[9] Although the etiology of RAU is not clear, the defective immune regulation plays an important role.[10] The Vitamin D has complex role in the regulation of immune system. The deficiency of Vitamin D is an important factor in etiopathogenesis of immune-mediated disorders.[11] The relationship between regulation of immune system and pathogenesis of RAU is proven.[12] In addition to immune dysregulation, nutritional deficiencies such as Vitamins B1, B2, B6, and B12, folate, iron, and ferritin are thought to be the possible causes in RAU.[13] Abdollahi et al.[14] who documented a comprehensive review on drug-induced oral ulcer suggested that sertraline, fluoxetine, and olanzapine are the psychotropics drugs which have potential to cause aphthous ulcers. As the exact etiology of the aphthous ulcer is still not clear, many predisposing factors such as trauma, stress, immunological, and viral infections are taken into consideration. Stress and anxiety are associated with RAU. Stressful condition is thought to increase salivary cortisol [15] and enhance immunoregulatory activity by increasing leukocytes number at the site of inflammation.[16] Psychological stress in RAU might be triggering factor rather than an etiological factor.


  Pathogenesis Top


In RAU, the lesions develop over several days with different stages for forming aphthous ulcer [Table 1]. In the early phase, the patient will complain paresthesia before the development of the proper ulcer. First, a macula develops which progresses to a papule that later on becomes necrotic and ulcer formation. In RAU, the lesion typically appears as round to oval ulcer covered by a yellow-white fibromembranous slough which is surrounded by a peripheral halo of erythematous area. The severity of the pain increases till the ulcerative process ends and diminishes in the healing phase. Smaller aphthous ulcers heal in 4–7 days whereas the larger lesions such as major aphthous ulcers need longer time for healing. Smaller lesions heal without formation of any scar whereas the larger aphthous ulcers may form scar. RAU may be associated with HLA-B51 which controls heat shock proteins or cytokines.[17] It is likely that immunologically mediated mechanism is involved in the etiopathogenesis of RAU. It may be due to excessive production of interleukin 1 (IL-1) or IL-6.[18] The RAU appears characteristically at nonmasticatory soft oral mucosal surfaces of the cheek, lips, ventral and lateral surface of tongue, upper and lower nonattached area of gingivae and sulci and sometimes in soft palate. The histopathological changes seen in the preulcerative phase include infiltration of lymphocytic cells in the epithelium. The keratinocyte vacuolization and focal vasculitis lead to edema which ulcerates and is infiltrated with neutrophils, lymphocytes, and plasma cells. There is cell-mediated immune response with involvement of T-cells with generation of tumor necrosis factor alpha (TNF-α) from these cells and mast cells and macrophages.[19] TNF-α is an important inflammatory cytokine which has a chemotactic action on neutrophil, so causing acute inflammation and expression of major histocompatibility complexes. It results in the targeting of epithelial cells by CD8 T-cells.[17] Other cytokines implicated are IL-2, IL-10 or IL-1, and IL-6. The gamma delta T-lymphocytes may play role in an antibody-dependent cell-mediated cytotoxic reaction toward the oral mucosal layer for ulcer formation.[18]
Table 1: Stages of recurrent aphthous ulcer

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  Clinical Presentation Top


The RAU is a common clinical entity seen in the second decade of life, between 20 and 30 years of age.[20] This clinical condition is considered as RAUs as these are painful, deeper, repair slowly and may be healed with scar. Often these lesions of the oral cavity are more than 1 cm in diameter.[21] This clinical entity can be classified into three types such as minor, major [Figure 1], and herpetiformis [Table 2].[22] The minor RAU is the most common type, and the size of the ulcers are usually <5 mm in diameter, round or oval shape with gray-white pseudomembrane and erythematous halo. It is usually seen on nonkeratinized surface of oral cavity mucosa particularly at the labial buccal mucosa, floor of the mouth but rarely seen on the gingival, palate, or dorsum of the tongue. The minor [Figure 2] types of RAU heal within 10–14 days without any scaring. The major type of RAU is sometimes called as periadenitis mucosa necrotica recurrent. It may affect approximately 10% of patients affected with RAU. The size of the ulcer in major category [Figure 3] exceeds 1 cm in diameter and usually occurs on the lips, soft palate, and fauces. These ulcers stay for up to 6 weeks and usually heal with scarring. The major type of RAU is usually seen after puberty age group and even persists up to 20 years or more.[18] Herpetiform ulcers are seen in about 1%–10% of the patients affected with RAU and are characterized by small, painful, multiple, widespread, and recurrent ulcers. The number of ulcers may be up to 100 in number at a given time and each ulcer measures 2–3 mm in diameter. Despite the name as herpetiform, there is no association with herpes viruses. RAU may cause impairment in swallowing and leading to nutritional deficit and poor quality of life. The symptoms are more aggravated in immunocompromised patients. As per “Classification and Diagnostic Criteria for Oral Lesions in HIV Infection” (proposed by Ec-Clearinghouse on Oral Problems Related to HIV Infection and WHO Centre on Oral Manifestations Collaborating on the Immunodeficiency Virus in 1993), the RAU is part of the group 3 (lesions observed in HIV infection). This classification states that the incidence of major and herpetiformis types of aphthous ulcers is increased in immunocompromised patients, for example, HIV infection and particularly for children with HIV infection; this classification is modified and RAU is in the group 1 (lesions commonly associated with pediatric HIV infection).[23] Aphthous ulcers were seen in the buccal mucosa, labial mucosa, floor of the mouth, and tongue. A genetic predisposition is associated with approximately 40% of patients with RAU and these patients have a family history of aphthous ulcers in the oral cavity. These patients present with early and severe presentation of ulcerations. AIDS patients may present with different clinical conditions such as mouth ulcers. Mouth ulcers caused by herpes simplex and cytomegalovirus are most prevalent during the disease period of AIDS.[24] Thus, the diagnosis must include history taking and clinical presentations.[22] The clinical presentations such as multiple ulcers >1 cm, lesions seen in nonkeratinized mucosa, presence of scar, and history of recurrence established the diagnosis in our case. The majority of patient presenting with RAU have simple aphthosis whereas those with complex aphthosis may have association with certain clinical conditions such as Behcet's disease, anemia, inflammatory bowel disease, gluten-sensitive enteropathy, hematinic, or mineral deficiencies [Table 3].
Figure 1: Major aphthous ulcer in the oral cavity

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Figure 2: Minor aphthous ulcer in the oral cavity

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Figure 3: Major aphthous ulcer in the palate and lips

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Table 2: Types of recurrent aphthous ulcers

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Table 3: Recurrent aphthous ulcer in different systemic disorders

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  Diagnosis of Recurrent Aphthous Ulcer Top


There is no definite laboratory test available for establishing the diagnosis of RAU. The histopathological examination does not give a definite diagnosis for this lesion. The diagnosis of RAU is done by considering clinical features and history taking. There are no specific diagnostic tests for RAU. There is need to exclude some possible causes of recurrent oral ulcerations such as Behcet's disease, periodic fever adenitis pharyngitis aphthous ulcer syndrome, and HIV infection.[10] In Behcet's disease, the ulcerative lesions are seen elsewhere, usually on the mucosa such as genitals, eyes, skin, and oral mucosa. The detailed virological tests are usually not warranted unless to rule out atypical herpetic infection.


  Treatment Top


Management of RAU remains unsatisfactory. Most of the treatment done in aphthous ulcers are only for reducing severity of the ulceration but not meant to stop recurrence. As there are multiple causes for aphthous ulcer, the objective of the treatment is always to give symptomatic treatment of pain by different topical application of anesthetic or antiseptic agents. To enhance healing process, different anti-inflammatory and anti-allergic agents are often tried. Treatment of RAU in the oral cavity is always challenging to clinician regardless to its type. Although there are numerous treatment options [Table 4] for aphthous ulcer, there is no effective treatment option till now. Medications used in RAU are mainly meant to relieve pain and discomfort and decrease the healing period. The topical anesthetic agent is used for the patient with less frequent minor RAU or herpetiformis types. In major type of aphthous ulcer or in more frequent minor and herpetiformis types, there are numerous topical treatment options available such as topical anesthetics, sucralfate, and corticosteroids (clobetasol propionate 0.05%, dexamethasone 0.5 mg/5 ml, fluocinonide 0.05%).[24] Systemic treatment options of RAU are corticosteroids such as prednisolone, intralesional triamcinolone, and immunomodulators such as thalidomide (200 mg/day).[24] Amlexanox (C16H14N2O4) is a topical anti-allergic, anti-inflammatory drug and has been used as a 5% topical paste for the treatment of patients with RAU.[25] Treatment of RAU is done occasionally with systemic corticosteroids. The prolonged use of systemic corticosteroids is not advised due to its side effects particularly in immunocompromised patients.[26] The systemic steroids, colchicine, azathioprine, thalidomide, levamisole, cyclophosphamide, pentoxifylline, and dapsone may be reserved in case of refractory condition as these drugs have many side effects in comparison to topical medications.[27] The pentoxifylline (anti-TNF agent) in the dose of 400 mg three times daily reduced the number of RAU after 1 month of treatment. Allicin is a component derived from the garlic extracts and can be used for the treatment of RAU due to their multiple bioactivities such as anti-inflammatory, antimicrobial, antioxidant, and immunomodulatory properties.[3] Application of low powered lasers is thought to stimulate the reepithelialization of the ulcer and is helpful for healing of the RAU.[28] Despite numerous treatment options available for the RAU, no one is specific and definitive.[29] Topical and systemic use of tetracycline have been used since decades in the treatment of RAU.[30] The use of doxycycline in RAU is based on its antimicrobial nature. However, the other newer actions of doxycycline such as inhibition of prostaglandin production, inhibition of collagenases, gelatinase, and suppression of leukocyte help for the effective use in RAU.[31] Cromolyn has a modest result in the treatment of RAU.[32] It can be used as topical drops or lozenges to minimize the duration of ulceration and increase the gap between the recurrence periods. The exact mechanism of cromolyn is not known. It has a mast cell stabilizer and inhibits the release of leukotrienes and histamines from the mast cells.
Table 4: Treatment of recurrent aphthous ulcer

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  Conclusion Top


RAUs are common lesions in the oral mucosa characterized by multiple, recurrent, small, round, or ovoid ulcers with circumscribed margins, erythematous haloes, and yellow gray floors. RAUs in patients give rise to severe pain, odynophagia, and significant morbidity. Recurrent painful aphthous ulcers affect oral functions and reduce the quality of life. Early attention should be given for the diagnosis and treatment for relieving pain by maintaining proper nutrition and preventing recurrence. Considering the fact that the exact etiology of RAU is not known, the treatment is always challenging to the clinician. Although several modalities of treatment have been employed for RAU, patients have yet to be treated with an effective therapeutic option.

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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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