{"id":2594,"date":"2015-04-27T07:20:27","date_gmt":"2015-04-27T07:20:27","guid":{"rendered":"http:\/\/biomedpharmajournal.org\/?p=2594"},"modified":"2016-12-08T08:34:26","modified_gmt":"2016-12-08T08:34:26","slug":"recurrent-aphthous-stomatitis-a-review","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol6no1\/recurrent-aphthous-stomatitis-a-review\/","title":{"rendered":"Recurrent Aphthous Stomatitis: A Review"},"content":{"rendered":"

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

Recurrent aphthous stomatitis (RAS) is defined as the presence of recurring ulcers confined to the oral mucosa in patients with no other signs or symptoms of underlying disease.The types of oral ulcers are diverse, with a multitude of associated causes including: physical or chemical trauma, infection from microorganisms, medical conditions or medications, cancerous and nonspecific processes. Once formed, the ulcer may be maintained by inflammation and\/or secondary infection. The causes of oral ulcers are diverse which includes a multitude of factors (1)<\/sup>. (Table-1)<\/p>\n

Table 1: Principal causes of oral ulcers.<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Solitary ulcer<\/strong><\/p>\n

\u00a0<\/strong><\/td>\n

Trauma<\/p>\n

 <\/td>\n<\/tr>\n

\u00a0<\/strong><\/td>\nSquamous cell carcinoma<\/p>\n

 <\/td>\n<\/tr>\n

\u00a0<\/strong><\/td>\nInfections (e.g. syphilis, tuberculosis)<\/p>\n

 <\/td>\n<\/tr>\n

Recurrent bouts of one or more ulcers healing spontaneously<\/strong><\/td>\nRecurrent aphthous stomatitis (RAS)<\/p>\n

 <\/td>\n<\/tr>\n

\u00a0<\/strong><\/td>\nBehcet\u2019s disease<\/td>\n<\/tr>\n
\u00a0<\/strong><\/td>\n\u2018Aphthous-like\u2019 ulcers due to systemic disease or drug therapy.<\/td>\n<\/tr>\n
\u00a0<\/strong><\/td>\nRecurrent erythema multiforme<\/td>\n<\/tr>\n
Single bout of ulceration, preceded by vesicles and affecting multiple oral sites<\/strong><\/td>\nViral infections (e.g. herpangina and primary herpetic stomatitis)<\/td>\n<\/tr>\n
\u00a0<\/strong><\/td>\nErythema multiforme<\/td>\n<\/tr>\n
Persistent oral ulceration affecting different sites<\/strong><\/td>\nMucocutaneous disease (e.g. oral lichen planus)<\/td>\n<\/tr>\n
\u00a0<\/strong><\/td>\nImmunobullous disease (e.g. oral pemphigus)<\/td>\n<\/tr>\n
\u00a0<\/strong><\/td>\nGastrointestinal disease (e.g. Crohn\u2019s disease)<\/td>\n<\/tr>\n
\u00a0<\/strong><\/td>\nHaematological (e.g. leukaemia)<\/td>\n<\/tr>\n
\u00a0<\/strong><\/td>\nDrug therapy (e.g. nicorandil)<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 <\/p>\n

RAS is the most common type of ulcerative disease of the oral mucosa, and it affects approximately 20% of the general population. Prevalence of RAS varies among different socioeconomic groups and its incidence is strongly affected by family history (2)<\/sup>. Age of presentation is between the second and third decades of life in otherwise healthy individuals. RAS is the most common type of recurrent oral ulceration in the age group of 10 to 19 years. Similar ulcers can be seen in patients with a variety of diseases including systemic lupus erythematosis, Behcet\u2019s syndrome, iron deficiency anemia and Crohn\u2019s disease. Therefore, RAS patients must be carefully evaluated for associated symptoms to determine whether laboratory evaluation is required.<\/p>\n

The worldwide distribution, high frequency and decreased quality of life generated by RAS have resulted in a great deal of research into the etiology and efficient therapy of this disease. However, the etiology of RAS still remains unclear, and the currently available therapy remains inadequate.<\/p>\n

Discussion<\/strong><\/p>\n

The exact cause of many aphthous ulcers is unknown, diagnosis is entirely based on history and clinical criteria and no laboratory procedures exist to confirm the diagnosis. Although RAS may be a marker of an underlying systemic illness such as coeliac disease, or may present as one of the features of Behcet’s disease, in most cases no additional body systems are affected, and patients remain otherwise fit and well.<\/p>\n

Lack of sleep,\u00a0illness, physical trauma, stress,\u00a0hormonal\u00a0changes, sudden\u00a0weight loss,\u00a0food allergies,\u00a0immune system\u00a0reactions\u00a0and deficiencies in\u00a0vitamin B12,\u00a0iron,\u00a0folic acid\u00a0and citrus\u00a0fruits may contribute to their development (3-5)<\/sup>.<\/p>\n

Trauma to the mouth is the most common trigger.\u00a0Physical trauma, such as that caused by toothbrush\u00a0abrasions, laceration with sharp or abrasive foods such as\u00a0toast, potato chips or other objects, accidental biting (particularly common with sharp\u00a0canine\u00a0teeth), after losing teeth, or\u00a0dental braces\u00a0can cause aphthous ulcers by breaking the mucous membrane. \u00a0<\/sup><\/p>\n

Oral aphthous ulcers are also commonly seen in celiac disease\u00a0and\u00a0Crohn’s disease.\u00a0There is no indication that aphthous ulcers are related to\u00a0menstruation, pregnancy and menopause, however, smokers appear to be affected less often. \u00a0<\/strong><\/p>\n

Systemic Conditions And Apthous-Like Lesions<\/strong><\/p>\n

Principal systemic conditions associated with \u2018aphthous-like\u2019 ulcers. These frequently start in adulthood with no previous history of oral ulceration. These conditions may mimic aphthous ulcers which may pose a diagnostic problem (4)<\/sup>.\u00a0 (Table-2)<\/p>\n

Table 2: Systemic conditions and aphthous like lesions (table-2).<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n
Behcet\u2019s disease<\/p>\n

 <\/td>\n<\/tr>\n

Nutritional deficiencies<\/p>\n

 <\/td>\n<\/tr>\n

Gastrointestinal disorders<\/p>\n

\u00b7\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Crohn\u2019s disease<\/p>\n

\u00b7\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 ulcerative colitis<\/td>\n<\/tr>\n

Cyclical neutropenia<\/p>\n

 <\/td>\n<\/tr>\n

HIV infection<\/p>\n

 <\/td>\n<\/tr>\n

MAGIC syndrome<\/p>\n

 <\/td>\n<\/tr>\n

FAPA syndrome<\/p>\n

 <\/td>\n<\/tr>\n

Drug reactions<\/p>\n

 <\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 <\/p>\n

Clinical Presentation<\/strong><\/p>\n

Aphthous ulcers usually begin with a tingling or burning sensation at the site of the future aphthous ulcer. In a few days, they often progress to form a red spot or bump, followed by an open ulcer.<\/p>\n

The aphthous ulcer appears as a white or yellow oval with an inflamed red border. Sometimes a white circle or halo around the lesion can be observed. The gray-, white-, or yellow-colored area within the red boundary is due to the formation of layers of\u00a0fibrin, a\u00a0protein\u00a0involved in the\u00a0clotting\u00a0of blood. The ulcer, which itself is often extremely painful, especially when agitated, may be accompanied by a painful swelling of the\u00a0lymph nodes\u00a0below the jaw, which can be mistaken for\u00a0toothache, another symptom is\u00a0fever. A sore on the gums may be accompanied by discomfort or pain in the teeth.<\/p>\n

Minor ulceration<\/strong><\/p>\n

“Minor aphthous ulcers” indicate that the lesion size is between 3\u00a0mm (0.1\u00a0in)-10\u00a0mm (0.4\u00a0in). The appearance of the lesion is that of an\u00a0erythematous\u00a0halo with yellowish or grayish color. Extreme pain is the obvious characteristic of the lesion. When the ulcer is white or grayish, the ulcer will be extremely painful and the affected lip may swell. They may last about 1 week.<\/p>\n

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

Major aphthous ulcers\u00a0have the same appearance as minor ulcerations, but are greater than 10\u00a0mm in diameter and are extremely painful. They usually take more than a month to heal, and frequently leave a\u00a0scar. These typically develop after\u00a0puberty\u00a0with frequent recurrences. They occur on movable non-keratinizing\u00a0oral surfaces, but the ulcer borders may extend onto keratinized surfaces. They may last about 10 to 14 days.<\/p>\n

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

This is the most severe form. It occurs more frequently in females, and onset is often in\u00a0adulthood. It is characterized by small, numerous, 1\u20133\u00a0mm lesions that form clusters. They typically heal in less than a month without scarring.\u00a0Palliative treatment is almost always necessary.<\/p>\n

Classification<\/p>\n

To help determine management strategies, Crispian Scully divided RAS in three clinical presentations: type A, type B and type C (5)<\/sup>. (Table-3)<\/p>\n

Table 3: Classification of RAS (table-3).<\/strong><\/p>\n\n\n\n\n\n\n
TYPE<\/strong><\/td>\nFEATURES<\/strong><\/td>\nTREATMENT<\/strong><\/td>\n<\/tr>\n
Type A<\/strong><\/td>\nRAS episodes lasting for only a few days, occurring only a few times a year<\/td>\n*Medication may not be indicated<\/p>\n

*Topical anesthetics to relieve pain<\/td>\n<\/tr>\n

Type B<\/strong><\/td>\n*Frequent and painful RAS, lasting between three and 10 days.<\/p>\n

*The patient might have changed diet and oral hygiene habits because of the pain<\/td>\n

*Medication is needed in this type of RAS<\/p>\n

*Treated by topical corticosteroids or systemic corticosteroids<\/td>\n<\/tr>\n

Type C<\/strong><\/td>\nPainful, chronic courses of RAS in which by the time one ulcer heals, another develops.<\/td>\nBest treated by topical corticosteroids, systemic corticosteroids, azathioprine or other immunosuppressants such as dapsone, pentoxifylline and sometimes thalidomide<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

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

Management<\/strong><\/p>\n

The treatment of recurrent aphthous stomatitis (RAS) still remains nonspecific and is based primarily on empirical data. The goals of therapy include the management of pain and functional impairment by suppressing inflammatory responses, as well as reducing the frequency of recurrences or avoiding the onset of new aphthae. Non therapeutic treatment includes proper maintenance of oral hygiene, trauma prevention, avoidance of certain foods\/drinks, use of straws, relaxation techniques. Therapeutic options for RAS include topical and systemic corticosteroids, topical antibiotics, immunomodulators and others. Numerous randomized control trials have been reported discussing their efficacy in the treatment of RAS (Table-4).<\/p>\n

Table 4: Randomized control trials for RAS (table-4).<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n
Study<\/strong><\/p>\n

\u00a0<\/strong><\/td>\n

Subjects<\/strong><\/p>\n

\u00a0<\/strong><\/td>\n

Treatment <\/strong><\/td>\nResults<\/strong><\/td>\nAdverse effects<\/strong><\/td>\n<\/tr>\n
Binnie et al, 1997 (6)<\/sup><\/strong><\/p>\n

\u00a0<\/strong><\/td>\n

1133 healthy subjects with history of minor RAS and mean age of 27.5<\/td>\n5% Amlexanox oral paste<\/p>\n

 <\/td>\n

Better healing, pain relief<\/p>\n

 <\/td>\n

No adverse reactions<\/p>\n

reported<\/td>\n<\/tr>\n

Khandwala et al, 1997 (7)<\/sup><\/strong><\/td>\n1335 healthy subjects with history of minor RAS and Mean age of 28.6<\/td>\n\u00a05% Amlexanox oral<\/p>\n

paste<\/p>\n

 <\/td>\n

Decreased healing time<\/p>\n

 <\/p>\n

 <\/td>\n

No adverse reactions<\/p>\n

reported<\/td>\n<\/tr>\n

Ylikontiola et al,1997 (8)<\/sup><\/strong><\/p>\n

\u00a0<\/strong><\/td>\n

31 healthy subjects with history of minor RAS and Mean age of 38<\/td>\n150 mg doxymycine<\/p>\n

0.9% NaCl<\/p>\n

1 drop cryo<\/td>\n

Decreased pain<\/p>\n

 <\/p>\n

 <\/td>\n

No adverse reactions<\/p>\n

reported<\/td>\n<\/tr>\n

Kerr et al, 2003 (9)<\/sup><\/strong><\/td>\n110 healthy subjects with history of minor RAS<\/td>\nTopical 50mg penicillin G potassium troches\u00a0 applied 4 times a day for 4 days<\/p>\n

 <\/td>\n

Better\u00a0 healing and pain relief<\/p>\n

 <\/td>\n

No allergic reactions reported<\/td>\n<\/tr>\n
Alidaee et al, 2005 (10)<\/sup><\/strong><\/p>\n

\u00a0<\/strong><\/td>\n

97 healthy subjects with history of minor RAS and Mean age of 26<\/td>\n\u00a0Silver nitrate sticks gently painted on ulcer\u00a0 leading to chemical cauterization<\/td>\nSignificant reduction of pain<\/p>\n

 <\/td>\n

Must be done by trained professional<\/td>\n<\/tr>\n
Murray et al,2005 (11)<\/sup><\/strong><\/p>\n

\u00a0<\/strong><\/td>\n

46 healthy subjects with history of minor RAS and associated prodromal symptoms.<\/p>\n

Mean age of 37<\/td>\n

\u00a00.5cm of 5% Amlexanox<\/p>\n

paste applied 4 times a day to check the prevention of ulcer and healing<\/td>\n

Decreased ulcer size and extent of pain<\/p>\n

Decreased healing time<\/td>\n

Mild and transient\u00a0 side effects<\/p>\n

 <\/td>\n<\/tr>\n

Martin H Thornhill et al,<\/strong><\/p>\n

2007 (12)<\/sup><\/strong><\/td>\n

26 subjects\u00a0<\/sup>were randomized to placebo or treatment<\/td>\nPentoxifylline 400 mg 3 times daily, or matching placebo<\/td>\nless pain smaller and fewer ulcers<\/td>\nDizziness, headaches,\u00a0 <\/sup>stomach upset,\u00a0 increased heart rate, and nausea<\/td>\n<\/tr>\n
Porter SR et al,<\/strong><\/p>\n

2009 (13)<\/sup><\/strong><\/td>\n

63 healthy subjects with history of minor RAS and Mean age of 25<\/td>\nHybenX versus an occlusive covering device<\/p>\n

(Salicept oral patches; Carrington Laboratories)<\/p>\n

(HybenX\u00a0 is normally\u00a0 used as plaque biofilm\u00a0 remover)<\/td>\n

HybenX safely and effectively reduced the painful symptoms<\/td>\nNausea<\/td>\n<\/tr>\n
Volkov I et al,<\/strong><\/p>\n

2009 (14)<\/sup><\/strong><\/td>\n

58 healthy subjects with history of minor RAS<\/td>\nSublingual dose of 1000 mcg of vitamin B(12)<\/td>\nDuration of outbreaks, the number of ulcers, and the level of pain were reduced significantly<\/td>\nNo known signi\ufb01cant toxic effects<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

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

Topical Therapy<\/strong><\/p>\n

Medication prescribed to treat RAS should relate to the severity of the disease. In mild cases, with two or three small lesions, use of topical coating agents such as Orabase or Zilactin is appropriate. Pain relief can be obtained with the use of a topical anesthetic agent, such as benzocaine in Orabase.<\/p>\n

In more severe cases, the use of a high potency topical steroid preparation, such as fluocinonide, betamethasone or clobetasol, placed directly on the lesion shortens healing time and the size of the ulcer.<\/p>\n

Other topical preparations that have been shown to decrease the healing time of minor RAS lesions include amlexanox paste and topical tetracycline.<\/p>\n

Systemic Therapy<\/strong><\/p>\n

Systemic therapy for RAS is usually advised to patients with chronic lesions and multiple painful lesions. Vitamin B12 is a simple, effective, and low-risk therapy to prevent recurrent aphthous stomatitis (15)<\/sup>. Zinc deficiency\u00a0has been reported in people with recurrent aphthous ulcers.\u00a0Zinc supplementation had reported positive results in these individuals (16)<\/sup>.<\/p>\n

For patients with major aphthae or severe cases of multiple minor aphthae who do not respond to topical therapy the use of systemic therapy should be considered. Pentoxifylline (PTX) can be used systemically to control ulcers that do not respond to topical medication. PTX is a methylxanthine compound related to caffeine and theophylline. It is used chiefly to treat peripheral vascular disease because it increases the flexibility of red blood cells and enhances blood flow to ischemic limbs. It also increases neutrophil chemotaxis and motility, and decreases the clumping of neutrophils. And it has anti-inflammatory properties by decreasing the production of cytokines and by decreasing the effect of the cytokines on leukocytes. Several reports suggest that PTX is effective in preventing aphthous ulcers (17)<\/sup>.<\/p>\n

Levamisole is a safe drug. When compared with the placebo, levamisole is not effective in the prophylactic treatment of recurrent aphthous stomatitis. The placebo effect is important in diseases where emotional factors affect recurrence or expression of symptoms (18)<\/sup>.<\/p>\n

Dapsone(100mg\/day) can be used for oral and genital aphthae, however, rapid relapses can occur after discontinuation of treatment(17)<\/sup>.<\/p>\n

Colchicine is another systemic medication that has been used with success in treating ulcers that are unresponsive to topical medication. Colchicine is an anti-inflammatory agent that limits leukocyte activity by binding to tubulin, a cellular microtubular protein, and, therefore, inhibiting protein polymerization(19)<\/sup>.\u00a0It also inhibits lysosomal degranulation and increases the level of cyclic AMP, which decreases both the chemotactic and the phagocytic activity of neutrophils.<\/p>\n

Alkylating Agents like chlorambucil on orogenital ulcerations in ABD demonstrated a good response when administered at an initial dose of 0.1mg\/kg, followed by a low maintenance dose of 2mg\/day.<\/p>\n

Thalidomide has been shown to reduce the incidence and severity of RAS. The drug was first marketed in Europe in the 1950s as a non-addictive sedative agent, but it was withdrawn from the market nearly 40 years ago after the discovery of its teratogenicity. Several reports have been published reporting positive results when treating severe recurrent ulcers with thalidomide. Thalidomide has many serious adverse effects, including teratogenicity, peripheral neuropathy, and other minor adverse effects, such as dizziness and somnolence. To minimize the risk of teratogenicity, the System for Thalidomide Education Prescribing Safety (S.T.E.P.S.) program has been instituted to control and monitor the use of thalidomide(17)<\/sup>.<\/p>\n

Application of 5-aminosalicylic acid 5% cream (applying a small amount to cover the aphthae 3 times\/day), or a toothpaste containing amyloglucosidase and glucose oxidase can reduce pain and lessen the duration of oral aphthae (17)<\/sup>.<\/p>\n

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

RAS is a common oral mucosal disorder with uncertain etiopathogenesis. The diagnosis of this condition is made on clinical grounds alone. Several factors such as trauma, diet and stress are known to trigger the disease. The most important factor in the treatment of RAS is to identify underlying precipitating factors and try to eliminate them. Given its painful presentation and inflammatory nature, RAS responds quite well to the use of topical or systemic anti-inflammatory drugs, particularly corticosteroids. Since the advent of high potency topical steroids, most patients with RAS can be managed this way. Topical steroids, when used for a short period, have a very safe profile and should be the first line of treatment for recurrent oral stomatitis. Medications such as immunomodulators and other agents like thalidomide should be used with care. The use of these high end medications should be reserved for treating major, multiple and recurring ulcers.<\/p>\n

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

    \n
  1. L. Sutton:Pariadenitis mucosa necrotica recurrens.\u00a0Journal of Cutaneous and Genito-Urinary Diseases, New-York, 1911, 29: 65-71.<\/li>\n
  2. Camila de Barros Gallo,I Maria Angela Martins Mimura,II Norberto Nobuo SugayaI, Psychological stress and recurrent aphthous stomatitis CLINICS 2009;64(6):645-8.<\/li>\n
  3. Ship JA, Chavez EM, Doerr PA, Henson BS. Recurrent aphthous stomatitis. Quintessence Int. 2000;31:95-112.<\/li>\n
  4. Casiglia JM. Recurrent aphthous stomatitis: etiology, diagnosis, and treatment. Gen Dent 2002;50:157-66.<\/li>\n
  5. Scully C, Gorsky M, Lozada-Nur F. The diagnosis and management of recurrent aphthous stomatitis: a consensus approach. J Am Dent Assoc. 2003;134:200-7.<\/li>\n
  6. Binnie WH, Curro FA. Amlexanox oral paste: a novel treatment that accelerates the healing of apthous ulcers. Compend Contin Educ Dent 1997; 18(11): 1116-8, 1120-2, 1124 passim.<\/li>\n
  7. Atul Khandwala et Al.1996 \u201c5% Amlexanox\u00a0 new treatment for recurrent minor aphthous ulcers\u201d. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997; 83: 222-30.<\/li>\n
  8. Ylikontiola, L., T. Sorsa, R. Hayrinen-Immonen and T. Salo, 1997.\u00a0Doxymycine-cyanoacrylate treatment of recurrent aphthous ulcers. Oral. Surg. Oral. Med. Oral. Pathol. Oral. Radiol. Endod., 83: 329-333.<\/li>\n
  9. Kerr R. the efficacy and safety of 50 mg Penicillin G potassium troches for recurrent aphthous ulcers. Oral Surg Oral Med Oral Radiol Endod 2003; 96: 685-694 .<\/li>\n
  10. Alidaee, M. R., A. Taheri, et al. (2005). “Silver nitrate cautery in aphthous stomatitis: a randomized controlled trial.” Br J Dermatol 153(3): 521-525.<\/li>\n
  11. Murray B, McGuinness N, Biagioni P, et al. A comparative study of the efficiency of Aptheal in the management of recurrent minor apthous ulceration. J Oral Pathol Med 2005; 34(7): 413-9.<\/li>\n
  12. Martin H. Thornhill, MBBS, PhD; Lorena Baccaglini, DDS, PhD; Elizabeth Theaker, BDS, MPhil; Michael N. Pemberton, MBBS. A Randomized, Double-blind, Placebo-Controlled Trial of Pentoxifylline for the Treatment of Recurrent Aphthous Stomatitis. Arch Dermatol.\u00a02007; 143(4):463-470.<\/li>\n
  13. S R Porter,\u00a0K Al-Johani,\u00a0S Fedele,\u00a0D R Moles. Randomised controlled trial of the efficacy of HybenX in the symptomatic treatment of recurrent aphthous stomatitis. Oral Diseases 04\/2009; 15(2):155-61.<\/li>\n
  14. Volkov I, Rudoy I, Freud T, et al. Effectiveness of vitamin B12<\/sub>\u00a0in treating recurrent aphthous stomatitis: a randomized, double-blind, placebo-controlled trial.\u00a0J Am Board Fam Med\u00a02009;\u00a022:\u00a09\u201316.<\/li>\n
  15. Carrozzo M. Vitamin B12 for the treatment of recurrent aphthous stomatitis. Evid Based Dent.2009;10(4):114-5.<\/li>\n
  16. Orbak R, Cicek Y, Tezel A, Dogru Y (2003). “Effects of zinc treatment in patients with recurrent aphthous stomatitis“.<\/em>Dent Mater J. 2003 Mar;22(1):21-9.<\/li>\n
  17. Altenburg A, Zouboulis CC.Current concepts in the treatment of recurrent aphthous stomatitis. Skin Therapy Lett.\u00a02008 Sep; 13(7):1-4.<\/li>\n
  18. Weckx LL,\u00a0Hirata CH,\u00a0Abreu MA,\u00a0Fillizolla VC,\u00a0Silva OM. Levamisole does not prevent lesions of recurrent aphthous stomatitis: a double-blind placebo-controlled clinical trial, Rev Assoc Med Bras.\u00a02009 Mar-Apr; 55(2):132-8.<\/li>\n
  19. Fontes V, Machet L, Huttenberger B, et al. Recurrent aphhous stomatitis: treatment with colchicine. An open trial of 54 cases. Ann Dermatol Venereol 129(12):1365-9 (2002 Dec).<\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

    Introduction Recurrent aphthous stomatitis (RAS) is defined as the presence […]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[16],"tags":[],"class_list":["post-2594","post","type-post","status-publish","format-standard","hentry","category-vol6no1"],"_links":{"self":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts\/2594","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/comments?post=2594"}],"version-history":[{"count":9,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts\/2594\/revisions"}],"predecessor-version":[{"id":10578,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts\/2594\/revisions\/10578"}],"wp:attachment":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/media?parent=2594"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/categories?post=2594"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/tags?post=2594"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}