{"id":2603,"date":"2015-04-27T07:05:04","date_gmt":"2015-04-27T07:05:04","guid":{"rendered":"http:\/\/biomedpharmajournal.org\/?p=2603"},"modified":"2020-04-26T06:51:48","modified_gmt":"2020-04-26T06:51:48","slug":"recurrent-aphthous-stomatitis-a-review-2","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol6no1\/recurrent-aphthous-stomatitis-a-review-2\/","title":{"rendered":"Recurrent Aphthous Stomatitis – A Review"},"content":{"rendered":"

Introduction<\/strong><\/p>\n

Oral ulcers are diverse with a wide variety causes. Among the oral ulcers, Recurrent aphthous stomatitis(RAS) \u00a0is the most common form of ulceration .It is a disease characterized by episodic appearance of oral ulcers \u00a0in which etiology and pathophysiology remains unclear. The word aphthous \u00a0was originated\u00a0\u00a0 with \u00a0Hippocrates in 460-370BC in reference\u00a0 to disorders of mouth (Terri.S.I. et al<\/em>. 2002). It is a widespread disorder affecting at least 5% to 66% of examined adult patient groups. Frequently the affected groups find difficulty in eating and speaking (Srinivas Rao et.al<\/em> 2010). The cause is multitude in number with many precipitating factors. There are three clinical presentations of RAS they are major, minor and herpetiform.<\/p>\n

Etiology<\/strong><\/p>\n

The exact etiology of RAS is unidentified. On a survey, 10-20% of patients with RAS \u00a0had deficiencies of iron, folic acid or vitamin B12 . 2-3% of patients were related to celiac disease and haematinic deficiency. Numerous investigations and investigators, studies have been unsuccessful to find the exact etiology and pathophysiology of RAS. They are various systemic diseases which are associated with RAS such as cyclic neutropenia,\u00a0 agranulocytosis, Behcet\u2019s syndrome is related with RAS, which has been documentated. \u00a0<\/u>RAS is also associated with other syndrome such as SWEET\u2019s syndrome, MAGIC syndrome and PFPA syndrome. Some predictable factors which are accountable for recurrent aphthous\u00a0 stomatitis \u00a0are heredity, immune dysregulation,certain foods, stress, hormonal disturbances, local trauma, infections, drugs, smoking habits, and poor oral hygiene.( Serap Koybasi et al <\/em>2006)<\/p>\n

Role of Micro Organism in Aphthous Ulcer<\/strong><\/p>\n

Helicobacter Pylori<\/strong><\/p>\n

They are many micro organism studied in the pathogenesis of RAS. Helicobacter Pylori has been recently attracted the concentration of many investigators. In 1983, the germ was isolated for the first time from a human gastric biopsy specimen. The bacterium was isolated from dental plaque in 1989 (Mansour \u00a0et al <\/em>2005).\u00a0H.pylori<\/em> is a gram negative bacterium commonly found in gastric mucosa. It has been found in saliva, sub-gingival region and also detected in dental plaque. Many facts have suggested that oral cavity is a reservoir of the organism. Oral cavity is a possible route of transmission to other sites (Anak Iamaroon et al<\/em>, 2003). So the secondary source of infection was considered as oral cavity.<\/p>\n

Oral Streptococci<\/sub><\/strong><\/p>\n

Streptococci are one of the microbial agents which are measured in the pathogenesis of RAS. It is recommended that L form of \u03b1- hemolytic streptococci were strongly implicated in RAS.The causative organism of the disease is Streptococcus sanguis. \u00a0Some studies have recommended that there is cross reactivity found between streptococcal 65-kDa heat shock protein and 60-k-Da human mitochondrial hsp.<\/u> Accordingly, RAS could be a T-cell-mediated response to antigens of S. sanguis to facilitate cross-react with the mitochondrial hsp and provoke oral mucosal damage Streptococcus mitis was another causative agent of RAS which was later identified. (Lehner T et al<\/em>, 1991).<\/p>\n

Virus<\/strong><\/p>\n

There are been many suggestive factors for virus as an etiologic agent in RAS. But still there exist questionable evidence towards viral etiology. Epstein-Barr virus has been studied in patients with RAS. Thus virus was associated with epithelial cells of pre Ulcerative RAS (Sun A et al<\/em>, 1998 )<\/p>\n

Immunologic Factors<\/strong><\/p>\n

Much of the research, for the past 30 years focused on the cause of RAS on detecting the abnormality in the immunologic response. Deposition of immune complexes within the oral epithelium induces multiple immune reactions to cause damage. There is a strong association between abnormal propotions of CD4+ and CD8+ cells and RAS severity, elevated levels of interferon gamma, interleukin 2 and tumor necrosing factor \u03b1, and alteration of CD4+:CD8+ ratio in RAS lesions.<\/p>\n

Biopsy tissues of RAS staining with immune histochemistry techniques revealed numerous inflammatory cells with unpredictable ratio of CD4+:CD8+: T lymphocytes. During pre-ulcerative and healing stages CD4+ cells were numerous, but during ulcerative state CD8+ cells tend to be numerous (Mahesh Chavan et al<\/em> 2012)<\/p>\n

Nutritional Deficiency<\/strong><\/p>\n

Loads of data advocate that nutritional deficiency as a cause for RAS. Patients with low serum levels of iron, folate, zinc, or vitamins B1, B2, B6, and B12 has been allied with a small subset of 5% to 10% of RAS patients (Nolan A et al 1991). Malabsorption syndrome and gluten sensitivity are associated with RAS. Calcium and vitamin C deficiency has been proposed in patients with RAS recently (Ogura M et al<\/em> , 2001)<\/p>\n

Precipitating Factors<\/strong><\/p>\n

Many factors have been proposed. They are<\/p>\n

Local factors<\/strong><\/p>\n

Trauma is one of the major contributing agents for RAS. RAS is predisposed by trauma. It is predisposed by inducing edema, cellular inflammation. Generally not all trauma lead to RAS,.\u00a0 But denture wearers who are usually three times more vulnerable to ulceration (Stone OJ et al 1991) 28<\/sup>. Compositions of saliva also play an essential role in RAS. Modification in salivary composition such as changes in Ph, affect the properties of saliva. Tumour necrosis factor-\u03b1, salivary nitric oxide are other salivary components that are positively associated with RAS (McCartan et al<\/em> 1996)<\/p>\n

Stress is one of another contributing factor for RAS. I t has been estimated that stress may induce trauma to soft tissue with many functional habits such as lip biting, thumb sucking. This trauma may prompt to ulceration (Preeti.L et al<\/em>\u00a0 2011)<\/p>\n

Allergic factors<\/strong><\/p>\n

Allergy has been assumed as one of the cause for RAS. RAS is associated with several kinds of food stuffs. Foods stuffs such as chocolate, cheese and tomatoes can precipitate the attack of RAS are recognized in some patients (Wardhana, E.A. et al<\/em> 2010)<\/p>\n

Drugs<\/strong><\/p>\n

Many drugs such as, captopril, \u00a0angiotension converting enzyme inhibitor, , NSAIDS such as diclofenac sodium,\u00a0 gold salts, propionic acid have been projected as causative agents for RAS (. Zain R.B. et al<\/em>\u00a0 1999)<\/p>\n

Endocrine Conditions<\/strong><\/p>\n

For many years, it was recommended that a affiliation exist between development of aphthous ulcer and occurrence of menstrual period. Cyclic RAS is observed in the luteal phase of the menstrual cycle for several women.<\/p>\n

Systemic Diseases With Recurrent Aphthous Stomatitis<\/strong><\/p>\n

Bechet\u2019s syndrome<\/strong><\/p>\n

Behcet\u2019s disease is well thought-out as a chronic inflammatory disease of unknown etiology. But now considered as a systemic vasculitis of uncertain aetiology. (Gabriel Riera Matute et al, 2011)<\/p>\n

This syndrome is characterized by recurrent oral (aphthous) ulcers, genital ulcers, and skin lesions. \u00a0Experimental observations suggest that aphthous ulcers are seen in patients with Behcet\u2019s syndrome. They emerge to be allied with increased tissue oedema and appear to have an extremely erythematous border. The aphthae in Bechet\u2019s disease habitually occur in the soft palate and oropharynx.\u00a0\u00a0 Ulcers have also been seen on the hard palate, which is the most abnormal site for RAS in patients without Behcet\u2019s disease (Kovacova E, et al<\/em> 2005)<\/p>\n

PFAPA syndrome<\/strong><\/p>\n

The PFAPA, or Marshall\u2019s, syndrome was formerly reported in 1989. Several patients had a history of 3 to 6 days of fever, along with pharyngitis and aphthous stomatitis. In a percentage of patients acute episodes of fever are seen along with recurrent aphthous stomatitis. But children have uneven symptoms in free intervals. The oral lesions are described generally as small, shallow, round ulcerations. These ulcerations are present in the buccal mucosa or on the tongue surface which is bounded by erythema. The oral stomatitis in PFAPA syndrome prevalence was in the beginning reported to be as high as 70%. Recent follow-up, shows a predominance to less than 30%. (Andres Pinto, et al<\/em> 2006)20<\/sup><\/p>\n

Cyclic neutropenia<\/strong><\/p>\n

It is a \u00a0uncommon hematological disorder. Cyclic neutropenia is characterized by recurrent fevers, mouth ulcers, and infections attributable to habitually recurring severe neutropenia. Generally, the child often less than 1 year of age, who presents with recurrent fever, pharyngitis, mouth ulcers, and lymphadenopathy, \u00a0recurrent cellulitis is assumed for diagnosis. Classically, the mouth ulcers are very deep which is very painful and which often last a week or more (David C. Dale et al<\/em> 2002). Cyclic neutropenia (CN) is habitually characterized by a transient decrease in the neutrophil count, with a periodicity of around 21 days (range, 14 to 36 days) (Marcio A et al<\/em> 2000)22<\/sup>.<\/p>\n

C.Linical Presentation<\/strong><\/p>\n

Recurrent aphthous stomatitis have been classified in to three forms they are:<\/p>\n

Minor Recurrent Aphthous Stomatitis<\/strong><\/p>\n

It is the familiar presentation affecting about 80% of patients. The ulcers are oval or round, recurrent, clearly defined and usually <5mm in diameter. These ulcers are very small and very painful.\u00a0 \u00a0It is also Miculiz\u2019sapthae. It constitutes for about 80% of RAS. \u00a0It is generally seen in the nonkeratinized mucosal surface like labial mucosa. Minor ulcers often heal within 10 to 14 days without scarring.<\/p>\n

Major RAS<\/strong><\/p>\n

It is also known periadenitis mucosa necrotica\u00a0\u00a0 recurrens or Sutton disease. It is rare, form of RAS. Most frequently seen in lips, soft palate and fauces. These ulcers are larger usually greater than 5mm . The ulcer persists for six weeks in addition it\u00a0 frequently scars and often heals.<\/p>\n

Herpetiform Ulceration<\/strong><\/p>\n

Herpetiform ulceration is least common and third variety RAS.These ulcers present as multiple small clusters of pinpoint lesion. These ulcers coalesce to form large irregular ulcers. \u00a0Many ulcers may be present. Each measuring 2 to 3mm in diameter in size. It generally have a predisposition for women. These ulcers last for 7 to 10 days (Ship JA.et al<\/em> 1996)<\/p>\n

Table 1: Characteristic of different forms of recurrent aphthous stomatitis (Stephen R. Porter et al<\/em>\u00a0 2000 )<\/strong><\/p>\n\n\n\n\n
<\/td>\nMINOR<\/strong><\/td>\nMAJOR<\/strong><\/td>\nHERPETIFORM<\/strong><\/td>\nHIV-ASSOCIATED30<\/sup><\/strong><\/td>\n<\/tr>\n
Shape<\/p>\n

Number<\/p>\n

Size<\/p>\n

Location<\/td>\n

Oval<\/p>\n

1-5<\/p>\n

<0.5<\/p>\n

Non keratinized<\/p>\n

Mucosa<\/td>\n

Oval or crateriform<\/p>\n

>1-10<\/p>\n

>0.5<\/p>\n

Non keratinized<\/p>\n

Mucosa<\/td>\n

Oval<\/p>\n

10-100<\/p>\n

<0.5<\/p>\n

At any site in oral cavity<\/td>\n

1-5<\/p>\n

>1cm<\/p>\n

Non keratinized mucosa<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 <\/p>\n

Pathogenesis<\/strong><\/p>\n

The pathogenesis remains unknown. It has strong hereditary component and appears to be related to an immune reaction against the oral mucosa.The lesions of RAS are not caused by a single facto. But it occur in an environment that is permissive for development of lesions (. Kilic SS. Et al, 2004)19<\/sup>.<\/p>\n

Immunolog\u0131cal Mechanism<\/strong><\/p>\n

Recurrent aphthous ulcerations involve immunopathological mechanisms that accounts for loss of adhesion between contiguous keratinocytes or to structure within the basal lamina. They have some immunopathological features that involve T-cell\u00a0 mediated immunity. \u0130t is suggested that RAS\u00a0 is a delayed type hypersensitivity or it is cell mediated response to an antigen stimulus residing within the epithelium. (E. A. Field & R. B. Allan et al\u00a0 2003)<\/p>\n

Diagnosis<\/strong><\/p>\n

There is no particular diagnostic test. A complete and exact patient history is significant to the diagnostic process. Systemic diseases are existing with recurrent aphthous stomatitis. The diagnostic is based on clinical history and histopathology. Infrequently uses of cultures are desired to make a definitive diagnosis. Histopathology of RAS is not a diagnostic. The diagnosis is reliant upon clinical history (. C. Scully1 et al 2005)<\/p>\n

A Sequence for the diagnostic process (V Vucicevic Boras et al\u00a0 2007)<\/strong><\/p>\n\n\n\n
\"Scheme<\/td>\n\n

Scheme 1:<\/strong><\/p>\n

Click here to View Scheme<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 <\/p>\n

Differential diagnosis<\/strong>
\nSeveral medical disorders are associated which may resemble RAS.<\/p>\n

They are bechet\u2019s syndrome, MAGIC syndrome, Sweet\u2019s syndrome, PFAPA syndrome, cyclic neutropenia, HIV, Crohn\u2019s disease.( Andres Pinto, et al\u00a0 \u00a02006)<\/p>\n

Treatment<\/strong><\/p>\n

The treatment depends on frequency, size and number of ulcers. The treatment still remains non specific.( A. Altenburg, et al 2008)<\/p>\n

The goals of the therapy include the functional impairment by suppressing inflammatory response, management of pain, reducing the frequency of recurrence and avoiding the onset of new aphthae. (Khoo.sp\u00a0 et al 1999)<\/p>\n

Physical therapy<\/strong><\/p>\n

1: Surgical removal<\/p>\n

2: Laser ablation<\/p>\n

3: Dietary and genual measures<\/p>\n

4: Cauterization<\/p>\n

Table 2: Topical therapy.<\/strong><\/p>\n\n\n\n\n\n\n\n
Category<\/strong><\/td>\nEffects<\/strong><\/td>\n<\/tr>\n
Anti microbial therapy &Antiinflammatory<\/p>\n

Chlochexidene<\/p>\n

Triclosan<\/p>\n

Diclofinac<\/p>\n

Dexpanthenol<\/td>\n

Mildly inhibits inflammation<\/p>\n

Anti-inflammatory,<\/p>\n

Antiseptic analgesic effect<\/td>\n<\/tr>\n

Topical sucralfate<\/td>\nSoothing effect on lesion by adhering to mucous membrane tissue<\/td>\n<\/tr>\n
Topical steroids<\/p>\n

Triamcinolone acetonoid<\/p>\n

Prednisocone<\/td>\n

Combination therapy with a topical anesthetic is widely accepted as the optimal treatment regimen<\/td>\n<\/tr>\n
Newer findings<\/td>\n1: To apply of 5-aminosalicylic acid 5% cream<\/p>\n

2: A topical prostaglandin E2 gel<\/p>\n

3: Raw egg white may partially soften oral pain<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Systemic therapy (SB Woo et al 1996)<\/p>\n

Table 3:<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n
Colchicine<\/strong><\/td>\nTo reduce the number and duration of lesions<\/td>\n<\/tr>\n
Pentoxifylline<\/strong><\/td>\nEffective against orogenital aphthae<\/td>\n<\/tr>\n
Corticosteroids<\/strong><\/td>\nRescue treatment in patients with acute exacerbation and in those who inadequately responded to therapy with colchicine and pentoxifylline.<\/td>\n<\/tr>\n
Dapsone<\/strong><\/td>\nOral and genital aphthae<\/td>\n<\/tr>\n
Thalidomide<\/strong><\/td>\nA dose-dependent effect against orogenital ulcerations emerges within 7-10 weeks following treatment<\/td>\n<\/tr>\n
Antimetabolites<\/strong><\/p>\n

Azathioprine\u00a0<\/strong><\/p>\n

\u00a0<\/strong><\/p>\n

Methotrexate<\/strong><\/p>\n

\u00a0<\/strong><\/p>\n

 <\/td>\n

Reduce the frequency and extent of severe orogenital aphthosis.<\/p>\n

Effective in severe orogenital aphthosis.<\/p>\n

 <\/td>\n<\/tr>\n

Cyclosporine\u00a0 A<\/strong><\/td>\nEffective in about 50% of\u00a0 patients<\/p>\n

 <\/td>\n<\/tr>\n

Interferon-alpha<\/strong><\/td>\nIs shown to be effective within 1-4 months<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 <\/p>\n

Table 4: Adverse effects of drugs during RAS therapy (Crispian scully, et al 2003)<\/strong><\/p>\n\n\n\n\n\n\n\n\n
\u00a0\u00a0 Drugs<\/strong><\/td>\nAdverse effects<\/strong><\/td>\n<\/tr>\n
Colchicine<\/td>\nIt causes very painful gastrointestinal symptoms, fertility in male and diarrhea.<\/p>\n

 <\/td>\n<\/tr>\n

Dapsone<\/td>\nIt causes Mathemoglobinemia<\/td>\n<\/tr>\n
Levamisole<\/td>\nIt effects decrease in white blood cells<\/td>\n<\/tr>\n
Pentaxifylline<\/td>\nIt causes nausea<\/td>\n<\/tr>\n
Thalidomide<\/td>\nIt causes polyneuropathy, tetrogenicity<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Conclusion<\/strong><\/p>\n

The RAS is the common form of painful ulcerations of oral cavity. Although it is the common form of presentation the etiology and pathogenesis remains unclear. The diagnosis mainly depends on the clinical features and not on the histopathogy report. Management of RAS only provides symptomatic relief by reducing pain.<\/p>\n

References<\/strong><\/p>\n

    \n
  1. Terri.S.I. Tilliss, John Mc Dowell, \u201c<\/em><\/strong>Differential Diagnosis: Is It Herpes or Aphthous?\u201d\u00a0Volume 3 Number 1 February 15, 2002<\/li>\n
  2. Srinivas Rao Recurrent Aphthous Stomatitis: A Review J Orofac Sci, 2(3)2010<\/li>\n
  3. Serap Koybasi, Ali Haydar Parlak, Erdinc Serin, , Fahrettin Yilmaz, , Didem Serin, Recurrent aphthous stomatitis: investigation of possible etiologic factors American Journal of Otolaryngology\u2013Head and Neck Medicine and Surgery 27 (2006) 229\u2013 232<\/li>\n
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  5. Anak Iamaroon\u00a7, Siriporn Chaimano\u00a7, Sukanya Linpisarn\u2020, Surawut Pongsiriwet\u00a7 and Kannikar Phornphutkul Detection of Helicobacter pylori <\/em>in recurrent aphthous ulceration by nested PCR Journal of Oral Science, Vol. 45, No. 2, 107-110, 2003<\/li>\n
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  9. Nolan A, McIntosh WB, Allam BF, Lamey PJ. Recurrent aphthous ulceration: vitamin B1, B2 and B6 status and response to replacement therapy. J Oral Pathol Med 1991; 20: 389\u201391<\/li>\n
  10. Stone OJ. Aphthous stomatitis (canker sores): a consequence of high oral submucosal viscosity (the role of extracellular matrix and the possible role of lectins). Med Hypotheses 1991; 36: 341\u20134.<\/li>\n
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  18. Marcio A. da Fonseca, DDS, MS, Fernanda Fontes, DDS, MS Early tooth loss due to cyclic neutropenia: long-term follow-up of one patient Special Care In Dentistry, Vol20 No 5 2000<\/li>\n
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  29. Crispian scully, Francina Lozada nur, The diagnosis and management of Recurrent aphthous stomatitis, JADA volume 134 february 2003<\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

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