Guidelines for Diagnosis and Management of Aphthous Stomatitis

Transcription

1 REVIEW ARTICLE Guidelines for Diagnosis and Management of Aphthous Stomatitis Felice Femiano, MD, PhD, Alessandro Lanza, DD, Curzio Buonaiuto, MD, Fernando Gombos, MD, Monica Nunziata, DD, Silvia Piccolo, DD, and Nicola Cirillo, DD Abstract: Aphthous ulcers are the most common oral mucosal lesions in the general population. These often are recurrent and periodic lesions that cause clinically significant morbidity. Many suggestions have been proposed but the etiology of recurrent aphthous stomatitis (RAS) is unknown. Several precipitating factors for aphthous ulcers appear to operate in subjects with genetic predisposition. An autoimmune or hypersensitivity mechanism is widely considered possible. Sometimes aphthous ulcers can be the sign of systemic diseases, so it is essential to establish a correct diagnosis to determine suitable therapy. Before initiating medications for aphthous lesions, clinicians should determine whether well-recognized causes are contributing to the disease and these factors should be corrected. Various treatment modalities are used, but no therapy is definitive. Topical medications, such as antimicrobial mouth-washes and topical corticosteroids (dexamethasone, triamcinolone, fluocinonide, or clobetasol), can achieve the primary goal to reduce pain and to improve healing time but do not improve recurrence or remission rates. Systemic medications can be tried if topical therapy is ineffective. Key Words: aphthae, oral ulcer, stomatitis, RAS (Pediatr Infect Dis J 2007;26: ) The term aphthous originated with Hippocrates as far back as BC in reference to disorders of the mouth. In general usage, the word aphthae refers to the presence of an otherwise undefined ulcer. 1 Aphthous ulcers are a common disease of the oral mucosa affecting 20% of the general population. The term aphthous stomatitis has been used interchangeably with aphthous ulcers, but at present, the term aphthous stomatitis is preferred. 2 A higher prevalence has been found in the higher socioeconomic groups, in females, and among individuals with stress, such as students at the time of examinations. 3 Aphthous lesions are rarely documented as a single episode in the clinical history of patients; generally, the ulcers have a periodic course and are described as recurrent aphthous stomatitis or RAS. The onset of RAS usually occurs Accepted for publication March 23, From the Stomatology Department, II University of Medicines and Surgery, Naples, Italy. Address for correspondence: Dr. Felice Femiano, Via Francesco Girardi 2, S. Antimo, NA 80029, Italy. femiano@libero.it. Copyright 2007 by Lippincott Williams & Wilkins ISSN: /07/ DOI: /INF.0b013e f9 during childhood, particularly in adolescences, with the ulcers showing a tendency to diminish in severity and frequency with age. The onset of aphthous lesions in later years suggests these lesions may have an underlying systemic cause. 4 The ulcers are painful, clearly defined, shallow, round or oval, with a necrotic center covered by yellowish-tan pseudomembranes and surrounded by an erythematous halo. The ulcerations may lead to difficulty in speaking, eating, and swallowing, thus may negatively affect patients quality of life. 5 There is often a genetic basis for RAS. The probability of developing aphthous lesions is approximately 90% in subjects with both parents affected, whereas it is reduced to 20% when neither parent has RAS. There is also a greater severity and an earlier onset of aphthous lesions in people with a positive family history for RAS tan in those without a family history. The probability of a sibling developing RAS may be influenced by the parents RAS status and there is a high correlation of RAS in monozygotic but not dizygotic twins. 6,7 CLASSIFICATION Aphthous stomatitis is divided, on morphologic criterion, into 3 clinical presentations. It is unclear whether these presentations are manifestations of a specific disease or they represent other oral disorders characterized by recurrent ulcer. The clinical presentations of RAS include minor, major, and herpetiform aphthae. 3 Minor aphthae represent the most common variety accounting for 80 85% of RAS. These ulcers vary between 3 and 10 mm. Minor ulcers typically involve movable and nonkeratinized oral mucosa, principally the mucosa of the cheek, lip, floor of mouth, ventral and lateral surface of tongue. The prodromal stage of ulceration is variable, but there is usually a sensation described as burning or prickling for a short period before the ulcers appear. During an attack of minor aphthae, single lesions or up to 5 concurrent ulcers may occur. Each lesion lasts days and heals without scarring. The variability in times of recovery can depend on the area affected or on whether superinfection occurred. 8,9 Major aphthae, formerly known as periadenitis mucosa necrotica recurrentis or Sutton disease, represent about 10% of RAS. Major ulcers have an irregular border and a size exceeding 10 mm. These lesions are deeper and larger and they last longer than minor aphthae. As a result of the long periods involved, there is a greater tendency for the production of a heaped-up margin which, when a single ulcer is seen, may lead to the suspicion that the lesion is malig- 728 The Pediatric Infectious Disease Journal Volume 26, Number 8, August 2007

2 The Pediatric Infectious Disease Journal Volume 26, Number 8, August 2007 Management of Aphthous Stomatitis nant. 5,10 They persist longer than minor aphthae and can last for weeks or months and often leave a scar after healing. These lesions cause substantial pain associated with fever, dysphagia, and malaise. They have a predilection for the posterior part of the month, particularly the soft palate and pharyngeal wall or tonsillar fauces. Major aphthae can be associated with human immunodeficiency virus (HIV) infection; clinicians should consider HIV testing when aphthae are large and slow to heal. 11 Herpetiform aphthae are the least common type comprising about 10% of occurrences. This variety is characterized by multiple recurrent crops of 10 or more (as many as a hundred ulcers may be present at the same time) small ulcers of 2 3 mm in diameter, although they may fuse producing large irregular ulcers. This tendency to coalesce is similar to what is seen in viral infections, thus, the term herpetiform and the subsequent confusion. The herpetiform type, like the other forms of RAS, occurs usually on mobile mucosa and not on attached mucosa like a true herpes infection. The age of onset of herpetiform aphthae is later than the other types with initial episode usually presenting in the second or third decade of life. 12 Currently classification of aphthous lesions is based on severity and they are associated with systemic factors. Simple aphthosis is described when ulcer recurrences are few and not associated with systemic factors and occur only 2 4 times each year. Complex aphthosis is a disorder in which patients develop recurrent oral and genital aphthous ulcers or when there is a continuous disease activity with new lesions developing as older lesions heal, or when ulcers are associate with systemic diseases These complex ulcers can mimic aphthous lesions occurring in RAS and for this reason they are named aphthous-like lesions. Diseases associated with aphthae include Behcet disease, Crohn disease, ulcerative colitis, malabsorption syndromes, gluten-sensitive enteropathy, nutritional deficiencies, PFAPA syndrome (periodic fever, aphthae, pharyngitis and adenitis), Sweet syndrome, HIV infection, and cyclic neutropenia. 9 IMMUNOPATHOGENESIS Although the clinical characteristics of RAS are well defined, the precise etiology remains unclear, and therefore the term idiopathic is widely used. RAS may be the common manifestation of a group of disorders of different etiology, rather than a single entity. 16 Immune mechanisms appear to play an essential role for onset of oral ulceration. 17 A genetic background is found for some RAS patients and those having positive family history for oral ulcerations have shown an increased frequency of HLA types A2, A11, B12, and DR2. At present, no unifying theories on the immunopathogenesis of RAS exist. Immune dysregulation may play a role. 18 A strong correlation was observed in the inheritance of an allele of interleukin-1 (IL-1 51). In addition, the allele of IL was strongly associated with RAS, this being greatest with a/a homozygosity. Such strong associations with these genotypes of IL-1 and IL-6 suggest that RAS may indeed have some sort of genetic basis. It may be that an unopposed or excessive production of IL-1 or IL-6 (eg, response to local trauma) may be instrumental in the development of RAS. 17,19 The HLA class I and II antigens occur on basal epithelial and then perilesional cells in all layers of the epithelium in the early phases of ulceration presumably mediated by interferon gamma (IFN- ). 20,21 Cell-mediated and immune complex mechanisms are probably involved in RAS pathogenesis. The involvement of cell-mediated mechanisms is corroborated by an increase in RAS patients compared with that in healthy controls, of gamma delta T cells, which may be involved in antibodydependent cell-mediated cytotoxicity. These cells produce tumor necrosis factor (TNF- ), which can be responsible for keratinocyte vacuolation. 22 Although there are cell-mediated immune changes within RAS, a B lymphocyte-mediated mechanism involving antibodydependent cell-mediated cytotoxicity and, possibly, formation of immune complexes have also been observed. Although circulating immune complexes have not reliably been demonstrated in RAS, immune deposits occur in lesional biopsy specimens, especially in the stratum spinosum, and there can be evidence of leucocytoclastic or immune complex vasculitis leading to the nonspecific deposition of immunoglobulins and complement. 23,24 TNF-, a major inflammatory mediator, induces initiation of the inflammatory process by its effect on endothelial cell adhesion and a chemotactic action on neutrophils. Studies have shown that RAS can be prevented by treatments that inhibit the synthesis of endogenous TNF- such as thalidomide and pentoxifylline. 11,25 27 In the preulcerative stage, many neutrophils have been shown to surround small vessels. This infiltrate of neutrophils represents the effect of a vasculitis by immune complex and could be responsible of appearance of ulcer lesion for tissue necrosis through a vascular obstruction and activation of lysosomial enzymes. 28,29 Cross-reactivity between a streptococcal kd heat shock protein and the oral mucosa, demonstrated in RAS patients, might play a pathogenetic role. RAS thus may be a T-cell mediated response to antigens of Streptococcus sanguis, which cross-react with the mitochondrial heat shock protein and induce oral mucosal damage. Different cytokines can contribute to the pathogenesis of oral lesions in RAS such as IL (interleukin)-2, IL-6 and IL Elevated IL-2 and TNF-, and lower concentrations of IL-10 have been reported in lesional mucosa of RAS patients. IL-10 usually stimulates epithelial proliferation in a healing process; therefore, its low levels in RAS patients may delay epithelization and prolong the duration of the ulcers. 26,29 A markedly increased plasma IL-2 has been recorded in the active stage of RAS. Also, natural killer cells activated by IL-2 may play a role in disease pathogenesis. An increased activity of these cells has been noted in active lesions, diminishing during periods of remission. Salivary prostaglandin E2 and epidermal growth factor may potentially aid mucosal healing. Both are reduced in the early stages of RAS ulcer and then rise in the healing phase. 30 Patients with RAS may be subject to uncontrolled or excessive release of locally active inflammatory mediators, 2007 Lippincott Williams & Wilkins 729

3 Femiano et al The Pediatric Infectious Disease Journal Volume 26, Number 8, August 2007 perhaps in response to local trauma. Amounts of IL-2, IFN-, and TNF- mrna are raised in lesional tissue of RAS, whereas concentrations of IL-10 mrna are reduced in the normal mucosa of RAS patients when compared with that of control subjects. Local amounts of IFN- are higher in the mucosa of RAS patients than in controls; whereas in contrast IL-10 values remain low in the former but not the latter. Local production of TNF- is higher in RAS lesions than traumatic ulcers and unstimulated peripheral blood leukocytes of patients with RAS produce greater amounts of TNF- than healthy controls. 27,29 Precipitating factors can act on genetic predisposition to cause simple aphthous lesions. Most patients appear to be otherwise well, but a minority has etiologic factors that can be identified by the history. These factors may include the following: toothpastes containing sodium-lauryl-sulfate, trauma, stress, cessation of smoking, hormonal state, and food hypersensitivity. Patients affected by RAS usually are nonsmokers. Some patients reveal an onset of RAS after smoking cessation and disappearance on reinitiation of smoking. This is likely to be due to the positive effect of nicotine on keratinization of oral mucosa. 16,31 Emotional and environmental stress may precede 60% of firsttime aphthous ulcer cases and involve approximately 20% of recurrent episodes. Food allergy such as that for chocolate, cheese, wheat flour, tomatoes, peanuts and strawberries might be responsible for the onset of oral ulcers. In a small percent of patients removing indicted food can lead to recovery from disease. A minority of women with RAS have cyclical oral ulceration related to the luteal phase of the menstrual cycle, presumed to be progestogen-driven defective oral mucosal epithelial turnover. 32 It has been suggested in some studies that sodium-lauryl-sulfate, a detergent in some oral healthcare products may give rise to ulceration akin to that of RAS. 16 A small number of aphthous ulcers are associated with other disease processes or disorders. These ulcers, also called aphthous-like ulcers, can mimic classic aphthae and their onset generally coincides with underlying disease. The onset, length, and severity of aphthous-like ulcers is determined by the conditions or defects that have caused them. The correction of responsible factors may cause healing and prevent relapses. Several kinds of drugs can cause aphthous-like lesions. In some predisposed patients, aphthous-like lesions appear after use of nonsteroidal anti-inflammatory drugs, activator of ATP-sensitive potassium (nicorandil), ace inhibitor, and antiarrhythmics drugs The pathogenesis of these oral adverse reactions related to the intake of medications is not well-understood, and the prevalence is not known. Aphthae usually commence in the second decade of life as recurrent oral ulcerations and usually wane during the fourth decade. In contrast, drug-induced ulcerations present mostly in older age groups and not always as a recurrent pattern. The interruption and the substitution of the responsible drug coincides with resolution of oral ulcers. Immunodeficiency diseases, myelodysplastic syndromes, cyclical neutropenia (RAS appearing on a regular 3-week cycle may indicate a neutropenia), immunodeficiency in HIV-positive patients with CD4 T lymphocyte counts less than 100 cells per milliliter can cause large aphtha-like ulcers. 11, Recurrent aphthous-like ulcers are seen as oral manifestations of hematinic deficiencies of vitamin B1, B2, B6, B12, of folic acid or iron. Correction of the deficiency can improve oral ulcers in some patients. Recurrent aphthous-like ulcers are seen in patients affected by celiac disease or gluten-sensitive enterophathy. These RAS like lesions remit on a gluten-free diet. Behcet syndrome is characterized by classic oral RAS and recurrent ulcers that affect the genital areas, eyes, and are associated with a range of systemic complications including joints, neurologic system, and skin; for these reasons Behcet syndrome belongs to the complex aphthosis subtype. Patients with inflammatory bowel disease, in particular Crohn disease and ulcerative colitis, may present with recurrent oral ulcer lesions like aphtha. 18,39 41 Among the conditions that may mimic classic aphthae, it is necessary to remember some syndromes such as PFAPA syndrome also known as Marshall syndrome (periodic fever, aphthae, pharyngitis, and adenitis) and Sweet syndrome, also known as acute febrile neutrophilic dermatosis characterized by fever, neutrophil leukocytosis, well demarcated cutaneous, plum-colored papules or plaques, recurrent oral ulcers and, in 50% of patients, an associated malignancy (eg, acute myeloid leukemia). Oral ulcers can be found in Reiter syndrome associated with uveitis, conjunctivitis, and HLA B27-positive arthritis, following nongonococcal urethritis or bacillary dysentery. MANAGEMENT The diagnosis of RAS is invariably based on the history and clinical findings. It is essential, however, to consider a possible systemic cause, especially when adult patients suddenly develop what appears to be RAS. 8 Ulcers are selflimiting and they can be recurrent, but because the etiology is unknown, definitive treatment is difficult to determine. Treatment of RAS depends on the number of lesions, size and duration, and particularly on the frequency of recurrences. The choice of a specific treatment modality should be based on the patient s needs and balancing the potential side effects of drugs with the benefits. 5,18,34 Once a diagnosis of RAS is reached, the clinician must decide whether to provide more than palliative care. 9 As part of informed consent, the patient should receive instruction about the condition, treatment options, and the expected outcome from each of the various treatment plans offered. Patients with frequent or severe outbreaks of aphthae should be counseled, regarding the advisability of a medical screening for various forms of anemia, gastrointestinal disease, food allergies, and other diseases potentially affecting the immune system. It may also be wise to rule out Behcet s disease through questioning about the presence of lesions of the genital mucosa. Suggested supportive care includes rest, increased fluid intake, adequate nutritional intake, multivitamin and mineral therapy, and reassurance that aphthae are not communicable. 45 It is common practice to assess the full blood-cell count, red-cell folate, serum ferritin (or equivalents), glucose, vitamin B12, and IgE. If there is any suspicion of celiac 2007 Lippincott Williams & Wilkins

4 The Pediatric Infectious Disease Journal Volume 26, Number 8, August 2007 Management of Aphthous Stomatitis disease, either due to the patient s history or evidence of malabsorption on routine testing, then serologic testing for antiendomysial antibody and other appropriate investigations should be undertaken: it is debatable whether all RAS patients should undergo screening for celiac disease. Some patients present with infrequent small ulcers and do not require any treatment. In some subjects, the severity and frequency of episodes decrease with the passing of years, whereas in others, severity and frequency worsen. For this reason, the therapy for oral ulcer cannot be standardized but it is different for each patient. There is no curative treatment available for aphthous ulcers, but symptomatic improvement is possible. 46 Goals in the management of RAS reflect that it is generally mild and self-limiting, and that, currently, there is no treatment widely believed to be curative. Treatments that reduce pain during attacks or reduce ulcer number and size, promote healing of existing ulceration, frequency of recurrent attacks with minimal adverse side effects are considered successful. Treatments used for this generally benign disease should not be associated with more morbidity that the disease itself. 47 The first step towards effective management of RAS is to identify and appropriately treat any modifiable predisposing factor before introducing therapy. It is warranted to reassure RAS patients on the benign nature of this ulcer, reduce stress, eliminate trauma or bad habit (eg, cheek bite); any iron or vitamin deficiency should be corrected once the cause of that deficiency has been established. If an obvious relationship to certain foods is established, these should be excluded from the diet. Possible causal drugs should be excluded. 48 In case aphthous ulcers are the expression of systemic disease, treatment should be first directed to the underlying conditions. The treatment choice of RAS should consider severity of pain, time required to heal, ulcer number for each episode, frequency of episodes, and ability to tolerate the treatment of each patients. The American Academy of Oral Medicine has recommended topical treatments for RAS. Topical medications include anesthetics, antihistamines, antimicrobials, and anti-inflammatory agents. Evidence of successful use of these agents for aphthous ulcers is primarily anecdotal For correct control of recurrent aphthae, the clinician would have to perform an exhaustive medical history to recognize precipitating factors eliminating bad habit, changing oral hygiene habit, and correcting or to modify diet, and then to consider the therapy suggesting topical use of corticosteroids in mouthwash or in oral gel (dexamethasone, fluocinonide, and triamcinolone). These treatments work best if started at prodrome when the reaction is beginning. For severe RAS cases, one can resort to use of a high-potency steroid like clobetasol in ointment and to systemic therapy with corticosteroids, disodium cromoglycate, azathioprine, pentoxifylline, colchicine, or sometimes thalidomide REFERENCES 1. Ship JA. Recurrent aphthous stomatitis an update. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;81: Shulman JD. Prevalence of oral mucosal lesions in children and youths in the USA. Int J Paediatr Dent. 2005;15: Akintoye SO, Greenberg MS. Recurrent aphthous stomatitis. Dent Clin North Am. 2005;49: Natah SS, Konttinen YT, Enattah NS, Ashammakhi N, Sharkey KA, Hayrinen-Immonen R. Recurrent aphthous ulcers today: a review of the growing knowledge. Int J Oral Maxillofac Surg. 2004;33: Porter S, Scully C. Aphthous ulcers (recurrent). Clin Evid. 2005;13: Scully C. Clinical practice. Aphthous ulceration. N Engl J Med. 2006; 13:355: Rioboo-Crespo Mdel R, Planells-del Pozo P, Rioboo-Garcia R. Epidemiology of the most common oral mucosal diseases in children. Med Oral Patol Oral Cir Bucal. 2005;10: Pastore L, De Benedittis M, Petruzzi M, et al. Importance of oral signs in the diagnosis of atypical forms of celiac disease. Recenti Prog Med. 2004;95: Scully C, Gorsky M, Lozada-Nur F. The diagnosis and management of recurrent aphthous stomatitis: a consensus approach. J Am Dent Assoc. 2003;134: Scully C. Mucosal diseases series. Oral Dis. 2005;11: Shetty K. Thalidomide in the management of recurrent aphthous ulcerations in patients who are HIV-positive: a review and case reports. Spec Care Dentist. 2005;25: Sciubba JJ. Herpes simplex and aphthous ulcerations: presentation, diagnosis and management an update. Gen Dent. 2003;51: Letsinger JA, McCarty MA, Jorizzo JL. Complex aphthosis: a large case series with evaluation algorithm and therapeutic ladder from topicals to thalidomide. J Am Acad Dermatol. 2005;52: Rogers RS. Complex aphthosis. Adv Exp Med Biol. 2003;528: McCarty MA, Garton RA, Jorizzo JL. Complex aphthosis and Behcet s disease. Dermatol Clin. 2003;21: Coli P, Jontell M, Hakeberg M. The effect of a dentifrice in the prevention of recurrent aphthous stomatitis. Oral Health Prev Dent. 2004;2: Boras VV, Lukac J, Brailo V, Picek P, Kordic D, Zilic IA. Salivary interleukin-6 and tumor necrosis factor- in patients with recurrent aphthous ulceration. J Oral Pathol Med. 2006;35: Volkov I, Rudoy I, Abu-Rabia U, Masalha T, Masalha R. Case report: recurrent aphthous stomatitis responds to vitamin B12 treatment. Can Fam Physician. 2005;51: Sun A, Chang YF, Chia JS, Chiang CP. Serum interleukin-8 level is a more sensitive marker than serum interleukin-6 level in monitoring the disease activity of recurrent aphthous ulcerations. J Oral Pathol Med. 2004;33: Aridogan BC, Yildirim M, Baysal V, Inaloz HS, Baz K, Kaya S. Serum Levels of IL-4, IL-10, IL-12, IL-13 and IFN- in Behcet s disease. J Dermatol. 2003;30: Jang HS, Jo JH, Kim BS, et al. A case of severe tongue ulceration and laryngeal inflammation induced by low-dose nicorandil therapy. Br J Dermatol. 2004;151: Borra RC, Andrade PM, Silva ID, et al. The Th1/Th2 immune-type response of the recurrent aphthous ulceration analyzed by cdna microarray. J Oral Pathol Med. 2004;33: Ben Slama L. Aphthae and aphthosis. Rev Stomatol Chir Maxillofac. 2003;104: Lewkowicz N, Lewkowicz P, Banasik M, Kurnatowska A, Tchorzewski H. Predominance of Type 1 cytokines and decreased number of CD4( ) CD25( high) T regulatory cells in peripheral blood of patients with recurrent aphthous ulcerations. Immunol Lett. 2005;99: Broides A, Yerushalmi B, Levy R, et al. Imerslund-Grasbeck syndrome associated with recurrent aphthous stomatitis and defective neutrophil function. J Pediatr Hematol Oncol. 2006;28: Guimaraes AL, de Sa AR, Victoria JM, et al. Association of interleukin 1- polymorphism with recurrent aphthous stomatitis in Brazilian individuals. Oral Dis. 2006;12: Sun A, Wang JT, Chia JS, Chiang CP. Levamisole can modulate the serum tumor necrosis factor- level in patients with recurrent aphthous ulcerations. J Oral Pathol Med. 2006;35: Saulsbury FT, Wispelwey B. Tumor necrosis factor receptor-associated periodic syndrome in a young adult who had features of periodic fever, aphthous stomatitis, pharyngitis, and adenitis as a child. J Pediatr. 2005;146: Lippincott Williams & Wilkins 731

5 Femiano et al The Pediatric Infectious Disease Journal Volume 26, Number 8, August Bazrafshani MR, Hajeer AH, Ollier WE, Thornhill MH. Polymorphisms in the IL-10 and IL-12 gene cluster and risk of developing recurrent aphthous stomatitis. Oral Dis. 2003;9: Arbiser JL, Johnson D, Cohen C, Brown LF. High-level expression of vascular endothelial growth factor and its receptors in an aphthous ulcer. J Cutan Med Surg. 2003;7: Kalayciyan A, Orawa H, Fimmel S, et al. Nicotine and biochanin A, but not cigarette smoke, induce anti-inflammatory effects on keratinocytes and endothelial cells in patients with Behcet s disease. J Invest Dermatol. 2007;127: Veller-Fornasa C, Bezze G, Rosin S, Lazzaro M, Tarantello M, Cipriani R. Recurrent aphthous stomatitis and atopy. Acta Derm Venereol. 2003;83: Rhee SH, Kim YB, Lee ES. Comparison of Behcet s disease and recurrent aphthous ulcer according to characteristics of gastrointestinal symptoms. J Korean Med Sci. 2005;20: Aydemir S, Tekin NS, Aktunc E, Numanoglu G, Ustundag Y. Celiac disease in patients having recurrent aphthous stomatitis. Turk J Gastroenterol. 2004;15: Altinor S, Ozturkcan S, Hah MM. The effects of colchicine on neutrophil function in subjects with recurrent aphthous stomatitis. J Eur Acad Dermatol Venereol. 2003;17: Boulinguez S, Sommet A, Bedane C, Viraben R, Bonnetblanc JM. Oral nicorandil-induced lesions are not aphthous ulcers. J Oral Pathol Med. 2003;32: Lisi P, Hansel K, Assalve D. Aphthous stomatitis induced by piroxicam. J Am Acad Dermatol. 2004;50: Madrid C. Aphthous ulcerations, an undesirable little-known effect of antihypertensive agents. Rev Med Suisse. 2005;1: Burgan SZ, Sawair FA, Amarin ZO. Hematologic status in patients with recurrent aphthous stomatitis in Jordan. Saudi Med J. 2006;27: Bucci P, Carile F, Sangianantoni A, D Angio F, Santarelli A, Muzio LL. Oral aphthous ulcers and dental enamel defects in children with coeliac disease. Acta Paediatr. 2006;95: Thongprasom K, Youngnak P, Aneksuk V. Hematologic abnormalities in recurrent oral ulceration. Southeast Asian J Trop Med Public Health. 2002;33: Leong SC, Karkos PD, Apostolidou MT. Is there a role for the otolaryngologist in PFAPA syndrome? A systematic review. Int J Pediatr Otorhinolaryngol. 2006;70: Stojanov S, Hoffmann F, Kery A, et al. Cytokine profile in PFAPA syndrome suggests continuous inflammation and reduced anti-inflammatory response. Eur Cytokine Netw. 2006;17: Frye RE. Recurrent aseptic encephalitis in periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome. Pediatr Infect Dis J. 2006;25: Shetty K. Thalidomide for recurrent aphthous ulcerations. HIV Clin. 2003;15:1, Esparza Gomez G. Management of aphtous stomatitis. Med Oral. 2003; 8: Fraser J. The management of oral conditions. Practitioner. 2004;248: 330, Murray B, Biagioni PA, Lamey PJ. The efficacy of amlexanox OraDisc on the prevention of recurrent minor aphthous ulceration. J Oral Pathol Med. 2006;35: Fischman SL. Oral ulcerations. Semin Dermatol. 1994;13: Gonzalez-Moles MA, Ruiz-Avila I, Rodriguez-Archilla A, et al. Treatment of severe erosive gingival lesions by topical application of clobetasol propionate in custom trays. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2003;95: Savage NW, McCullough MJ. Topical corticosteroids in dental practice. Aust Dent J. 2005; Murray B, McGuinness N, Biagioni P, Hyland P, Lamey PJ. A comparative study of the efficacy of aphtheal in the management of recurrent minor aphthous ulceration. J Oral Pathol Med. 2005;34: Femiano F, Gombos F, Scully C. Recurrent aphthous stomatitis unresponsive to topical corticosteroids: a study of the comparative therapeutic effects of systemic prednisone and systemic sulodexide. Int J Dermatol. 2003;42: Nolan A, Baillie C, Badminton J, Rudralingham M, Seymour RA. The efficacy of topical hyaluronic acid in the management of recurrent aphthous ulceration. J Oral Pathol Med. 2006;35: Lippincott Williams & Wilkins