DÄ internationalArchive40/2014The Treatment of Chronic Recurrent Oral Aphthous Ulcers

Review article

The Treatment of Chronic Recurrent Oral Aphthous Ulcers

Dtsch Arztebl Int 2014; 111(40): 665-73; DOI: 10.3238/arztebl.2014.0665

Altenburg, A; El-Haj, N; Micheli, C; Puttkammer, M; Abdel-Naser, M; Zouboulis, C C

Background: Chronic recurrent oral aphthous ulcers are the most common type of inflammatory efflorescence of the oral mucosa, with a prevalence of 2% to 10% in Caucasian populations. To treat them properly, physicians should know their clinical appearance and course, conditioning factors, underlying causes, and differential diagnosis.

Method: This review is based on pertinent articles that were retrieved by a selective search in PubMed and in the Cochrane Central Register of Controlled Trials.

Results: Hard, acidic, and salty foods and toothpastes containing sodium lauryl sulfate should be avoided, along with alcohol and carbonated drinks. In Germany, the only drugs that have been approved to treat oral aphthous ulcers are corticosteroids, topical antiseptic/anti-inflammatory agents such as triclosan and diclofenac, and local anesthetics such as lidocaine. Antiseptic agents and local anesthetics should be tried first; if these are ineffective, topical corticosteroids should be used. In severe cases, local measures can be combined with systemic drugs, e.g., colchicine, pentoxifylline, or prednisolone. The efficacy of systemic treatment is debated. Other immunosuppressive agents should be given systemically only for refractory or particularly severe oral aphthous ulcers due to Adamantiades-Behçet disease.

Conclusion: The treatment of chronic recurrent oral aphthous ulcers is symptomatic, mainly with topically applied agents. It is tailored to the severity of the problem in the individual case, i.e., the frequency of ulcers, the intensity of pain, and the responsiveness of the lesions to treatment. Effective treatment relieves pain, lessens functional impairment, and lowers the frequency and severity of recurrences.

LNSLNS

Oral aphthous ulcers typically present as painful, sharply circumscribed fibrin-covered mucosal defects with a hyperemic border.

Chronic recurrent oral aphthous ulcers occur in three different clinical morphological variants and with two different time courses. Small ulcers of the minor-type (Mikulicz) are less than 1 cm in diameter (usually 2–5 mm) and heal spontaneously in 4–14 days. They account for 80–90% of all recurrent oral aphthous ulcers (1, e1). Scarring occurs in around 8% of cases (1, e2) (Figure 1a). Large ulcers of the major-type (Sutton ulcers) are usually 1–3 cm in diameter, deeply indurated and can last for 10 days to 6 weeks or occasionally even longer (1, e3) (Figure 1b). They account for around 10% of recurrent benign oral ulcers. About 64% of Sutton ulcers heal with scarring. Herpetiform aphthous ulcers are very small (1–2 mm) grouped lesions (1, e4) (Figure 1c). They account for around 5% of recurrent oral aphthous ulcers, are extremely painful and persist for 7–10 days. As many as a 100 ulcers can be present; they may coalesce into larger erosive plagues and about 32% heal with scarring. The three morphologic variants can occasionally appear simultaneously (2).

(a) Minor-type oral aphthous ulcers, (b) major-type oral aphthous ulcer, (c) herpetiform oral aphthous ulcers
(a) Minor-type oral aphthous ulcers, (b) major-type oral aphthous ulcer, (c) herpetiform oral aphthous ulcers
Figure 1
(a) Minor-type oral aphthous ulcers, (b) major-type oral aphthous ulcer, (c) herpetiform oral aphthous ulcers

Another classification is based on the time course. The simple chronic recurrent oral aphthous ulcers present with a limited number of small, quickly healing, minimally painful ulcers limited to the oral mucosa and recurring with 3–6 episodes annually. In complex aphthosis, there are a few or many slowly healing intensely painful ulcers on the oral and perhaps genital mucosa (3). The latter may also be perigenital, affecting the scrotum, vulva, anus, perineum and inguinal region. Complex aphthosis features frequently appearing ulcers with either short lesion-free periods or even repeatedly recurrent ulcers, severe pain and even systemic effects such as interference with eating and the resultant problems of inadequate nutrition (3).

Algorithm for the treatment of chronic recurrent oral aphthous ulcers to reduce the duration of illness and the size of the ulcers
Algorithm for the treatment of chronic recurrent oral aphthous ulcers to reduce the duration of illness and the size of the ulcers
Figure 2
Algorithm for the treatment of chronic recurrent oral aphthous ulcers to reduce the duration of illness and the size of the ulcers

Methods

A selective literature search concentrating on randomized controlled therapeutic trials was performed to prepare this review. The literature search employed PubMed and the Cochrane Central Register of Controlled Trials. Letters to the editor and meeting reports were ignored. Because of the small number of published controlled studies, both studies without control groups and studies whose results correlate with our clinical experience were in exceptional cases included.

Epidemiology

Chronic recurrent oral aphthous ulcers are the most common inflammatory disease of the oral mucosa with a prevalence of 2–10% in Caucasian populations; women are more frequently affected (2, 4). A study evaluating 40 693 school children in the USA showed a point prevalence of 1.23% and a lifetime prevalence of 36.5% (5).

Pathogenesis

The etiology of chronic recurrent oral aphthous ulcers is still unclear. A variety of underlying disorders may predispose patients to develop oral aphthous ulcers; they include iron deficiency anemia, neutropenia, and folic acid or vitamin B12 deficiency, as well as a selective vitamin B12 resorption defect (e5e7). Appropriate replacement therapy has reduced the severity of the disease as documented in case reports (e8) (evidence level [EL] 4). Local mucosal injuries are also possible trigger factors (6, e9). In addition, genetic factors may be important; the family history is positive in up to 40% of patients (7). No consistent association with an HLA haplotype has been shown (e10).

Differential diagnosis

Oral aphthous ulcers are clearly defined in a nosologic sense, but often hard to distinguish clinically from a broad group of similar (aphthoid) erosions and ulcers. The differential diagnosis includes a variety of diseases which can imitate the clinical picture of oral aphthous ulcers (Box).

Important differential diagnostic considerations for oral aphthous ulcers
Important differential diagnostic considerations for oral aphthous ulcers
Box
Important differential diagnostic considerations for oral aphthous ulcers

Adamantiades-Behçet disease (ABD) is a chronic recurrent systemic vasculitis (e11) in which oral and genital ulcers are major diagnostic criteria. Some include ABD among the autoinflammatory diseases. In ABD, 98.5% of patients have recurrent oral aphthous ulcers; this is the most common manifestation of the disorder (8). Recurrent genital aphthous ulcers are seen in 64.7% (8). In 84.5% of patients, the first manifestation is oral ulcers, while 3.5% start with genital ulcers, which are the second most frequent symptom (8). About 10% of the patients with complex aphthosis in Western Europe and North America develop ABD; the likelihood is higher in the eastern Mediterranean region, Middle East and Asia (9). In order to make the diagnosis, clinical diagnostic criteria are applied, such as those of the International Study Group for Behçet’s Disease (e12), or the new International Criteria for Behçet’s Disease (9) (eBox) which are based on epidemiological data.

International criteria for the diagnosis of Adamantiades-Behçet disease (2014)
International criteria for the diagnosis of Adamantiades-Behçet disease (2014)
eBox
International criteria for the diagnosis of Adamantiades-Behçet disease (2014)

Overview of therapy

The studies that we evaluated generally reached an EL 2A because of a variety of limitations including small patient number, reliance on self-reported information, unclear information on randomization, incomplete or lacking blinding, or inadequate information on the nature of the placebo.

Effects on the overall quality of life of the patients was not evaluated in the studies. Undesired effects of topical medications were either mild or not mentioned. In studies on systemic drugs, the undesired effects were not always discussed.

With the exception of the corticosteroids, topical antiseptics and topical anesthetics, all tested substances are used off-label for oral aphthous ulcers in Germany. Rebamipide, clofazimine and camel thorn distillate are not available in Germany.

Dietary and general measures

There are no reliable studies addressing the role of diet in managing aphthous ulcers. Substances that a majority of patients report frequently trigger ulcers should be avoided, especially if the patient in question has noticed an association. In general one should avoid hard, acidic and salty substances such as fruit juices, citrus fruits, tomatoes, and spices like pepper, paprika and curry, as well as alcoholic and carbonated beverages. Avoiding dental care products with sodium lauryl sulfate (SLS) is also desirable. Using a SLS-free toothpaste significantly reduced the healing period and pain of oral aphthous ulcers (10) (EL 1B).

Topical therapy

Topical anesthetics

Topical anesthetics often provide satisfactory pain relief (6). Options include lidocaine as 1% cream (randomized placebo-controlled study; EL2A [11]), 2% gel or spray; polidocanol as paste; and benzocaine lozenges. There is a pump spray that combines tetracaine 0.5% and polidocanol 0.1%. A mouth wash containing benzocaine and cetylpyridinium chloride is also available.

Antiseptics and anti-inflammatory agents

A mouth wash containing 0.15% triclosan in ethanol and zinc sulfate reduced the number of new aphthous ulcers in 43% of cases, the pain intensity in 45% and extended the ulcer-free interval (12) (Table 1) (EL 1B). Diclofenac 3% in a 2.5% hyaluronic acid gel was superior to a lidocaine 3% gel in reducing pain after 2–6 hours (13) (Table 2) (EL 2A).

Therapeutic options to reduce the frequency of recurrence and/or the number of oral aphthous ulcers
Therapeutic options to reduce the frequency of recurrence and/or the number of oral aphthous ulcers
Table 1
Therapeutic options to reduce the frequency of recurrence and/or the number of oral aphthous ulcers
Therapeutic options to reduce pain
Therapeutic options to reduce pain
Table 2
Therapeutic options to reduce pain

Chlorhexidine mouthwash and chamomile extract both reduced the frequency, increased healing speed, and decreased the severity of aphthous ulcers in non-randomized studies (6, 14) (EL 2B). Chlorhexidine gels and sprays are also available. A useful adjuvant therapy is dexpanthenol in a variety of forms (spray, solution and tablets).

Cauterization

Topical application of hydrogen peroxide 0.5% solution or silver nitrate 1–2% solution significantly reduced the pain severity after one day, but did not increase the speed of healing (15) (EL2A).Treatment with a CO2 (16) or Nd:YAG laser (17, e13) brought immediate pain relief which lasted for 4–7 days (Table 2) (EL 2A).

Topical tetracycline treatment

Using a mouthwash containing chlortetracycline 2.5% increased the number of ulcer-free or pain-free days significantly, by 40% compared to a placebo (18) (Table 1) (EL 2A). In regards to pain reduction, a minocycline 0.2% mouthwash was superior to a tetracycline 0.25% mouthwash (19, e13) (Table 2) (EL 2A).

Tetracycline hydrochloride powder 250 mg can be combined with 10 mL of tap water by the patient immediately before use to avoid stabilization problems. Because of the acid pH value, there may be temporary mucosal burning generally followed by clinical improvement. A stable mixture can also be prepared by neutralizing the tetracycline hydrochloride to create a basic product (6).

Both a standardized formulation—as well as the less-stable freshly prepared solution—can produce rapid healing in some patients, even in those with large ulcers resistant to topical corticosteroids.

Topical corticosteroids

If combined treatment with topical anesthetics and anti-inflammatory agents is not effective, then topical corticosteroids should be employed. In Germany, a registered oral paste containing prednisolone is commonly used, which is applied 1–2 times daily (20). The combination of topical anesthetics (for example, lidocaine gel) during the day with an oral paste containing triamcinolone in the evening is also effective (21). Studies indicate that triamcinolone oral paste is superior to phenytoin syrup (22) (Table 3) (EL 2A). Although both were equally effective in reducing pain, dexamethasone oral paste produced more rapid healing than triamcinolone oral paste (23) (Table 3) (EL 2A).

Topical therapeutic options to reduce the duration of illness and size of oral aphthous ulcers
Topical therapeutic options to reduce the duration of illness and size of oral aphthous ulcers
Table 3
Topical therapeutic options to reduce the duration of illness and size of oral aphthous ulcers

When topical corticosteroids are used regularly, one should be alert to the possibility of increased numbers of oral yeast infections (24). Especially painful, deep ulcers can be treated with intralesional triamcinolone suspension 0.1–0.5 mL per lesion (21).

Additional topical therapies

A double-blind, placebo-controlled study showed that 5-aminosalicylic acid 5% cream achieved pain reduction and more rapid healing of oral aphthous ulcers (25) (Table 3) (EL 2A). Amlexanox 5% paste or 2 mg tablets, when used in the prodromal stage, led to a reduction in the number and size of oral aphthous ulcers, as well as reduction in pain (26, 27) (Table 3) (EL 2A).

An association between smoking and a reduction in the frequency of recurrences of oral aphthous ulcers has been observed. The number of lesions and the intervals between recurrences appear to be reduced during periods when the patient is smoking versus abstaining from tobacco (28, e14). Experimental evidence indicates that nicotine has an anti-inflammatory effect on keratinocytes (6, 14). Nicotine patches apparently cannot achieve the effects of tobacco smoke (own unpublished data). In a preliminary study with 3 patients, complete remission of recurrent oral aphthous ulcers was achieved with nicotine gum (e15) (EL 4). Neither cyclosporine (70 mg/g oral paste) nor interferon-α-2c gel was effective in treating oral aphthous ulcers (14).

Systemic therapy

A current review of the Cochrane Collaboration analyzed 25 studies (22 of which were placebo-controlled) on systemic therapy of oral aphthous ulcers and found no convincing evidence of efficacy (29) (eTables 1, 2),

Colchicine

Colchicine (0.5–2 mg daily) is helpful for the majority of patients with chronic recurrent oral aphthous ulcers. An off-label trial is recommended for 6 weeks with 1–2 mg daily—followed by long-term therapy depending on how severe the ulcers are and how well-tolerated the medication is (20). In a large open study of Fontes at al. (30), colchicine produced clear improvement in 63% of cases over a period of 3 months and in 37% over many years. 22% of the patients were free of disease, while 41% had at least a 50% reduction in number and duration of aphthous ulcers. In 37% the improvement was maintained for 5 years. In additional controlled studies, colchicine 1–2 mg daily led to significantly fewer oral and genital aphthous ulcers in patients with ABD (e16, e17) (EL 2A). The aphthous ulcers frequently recurred when the treatment was stopped (20). Contraceptive measures after the conclusion of therapy are recommended for 3 months in women and 6 months in men. Up to 45% of patients experienced gastrointestinal symptoms.

If aphthous ulcers fail to respond to colchicine monotherapy, combination approaches are possible. In patients with ABD, treatment with colchicine and benzathine penicillin was superior to colchicine alone in producing a slight improvement in the frequency of ulcers and a clear reduction in their healing time (more than 50%) (e18) (eTable 1) (EL 2A).

Systemic therapeutic options to reduce duration of illness and size of aphthous ulcers
Systemic therapeutic options to reduce duration of illness and size of aphthous ulcers
eTable 1
Systemic therapeutic options to reduce duration of illness and size of aphthous ulcers

In our experience the off-label use of colchicine for chronic recurrent aphthous ulcers is generally approved and reimbursed by insurance companies.

Pentoxifylline

In case reports and older non-controlled studies, both pentoxifylline and oxypentoxifylline; 300 mg 1–3 times daily or 400 mg t.i.d. achieved good response rates (in children 36–50%) (6). In a more recent controlled study, pentoxifylline (400 mg t.i.d.) was only able to reduce the size of oral aphthous ulcers (p = 0.05) (31) (eTable1) (EL 2A).

Systemic corticosteroids

Systemic corticosteroids should be considered if colchicine and pentoxifylline do not produce improvement (20). Prednisolone or prednisone equivalents (10–30 mg daily) can be used on a short-term basis (up to one month) during a flare of the disease to speed healing. In a small controlled study, prednisolone 5 mg daily for 3 months was comparable to colchicine 0.5 mg daily. It produced a clear reduction in pain, as well as in number and size of oral aphthous ulcers (32) (eTables 1 and 2) (EL 2A). Prednisone (25 mg daily tapered over 2 months) was more effective than the leukotriene inhibitor montelukast in managing oral aphthous ulcers (33) (eTable1) (EL 2A).

Sucralfate

Sucralfate is used as an antacid in treating gastric and duodenal ulcers. Sucralfate suspension produced more rapid healing and reduced pain of both oral and genital aphthous ulcers (34, e19) (Table 3, eTable 1) (EL 2A).

Dapsone

Dapsone significantly reduced the number and size of oral and genital aphthous ulcers in ABD (e20) (eTable 1) (EL 2A).

Antimetabolites: azathioprine and methotrexate

In a placebo-controlled study, azathioprine reduced the frequency and severity of orogenital aphthous ulcers in ABD; it is approved for this indication in Germany (35) (eTable 1) (EL 1B). In a case series, methotrexate 7.5–20 mg in a single weekly dose was helpful for severe orogenital aphthous ulcers (4) (EL 4).

Cyclosporine

There is information on over 350 patients with ABD treated with variable doses of cyclosporine (1–10 mg/ kg body weight daily) for divergent periods of time (1–77 months) (36). In a controlled study up to 70% of patients experienced improvement in oral aphthous ulcers (37) (eTable 2) (EL 2A).There were more side effects in the cyclosporine group than in the colchicine control group. 92% of the women and 32% of men developed hirsutism, fever, fatigue, and gastrointestinal symptoms, all of which improved when the dose was reduced. In contrast to colchicine, cyclosporine led to increased creatinine and blood urea nitrogen levels. Cyclosporine is approved in Germany for treating uveitis associated with ABD.

Thalidomide

Thalidomide is considered effective against orogenital aphthous ulcers. In older open or retrospective studies, initial doses of 100–300 mg daily were tapered to 50 mg daily or the medication was discontinued after 3 months, in order to avoid a sensory neuropathy (e21, e22). Thalidomide in a dose of 100 mg daily for an average interval of 5 months was well tolerated by 8 patients with chronic recurrent oral aphthous ulcers (21). Thalidomide should only be used in exceptional cases. Because of its teratogenicity, it is absolutely contraindicated in pregnancy (e23). When it is discontinued, recurrences may develop rapidly (e22, e25). In Germany thalidomide is only approved for treating multiple myeloma.

Interferon-α

Interferon-α can achieve complete or partial remission (reduction in pain, duration and frequency) of recurrent orogenital aphthous ulcers in ABD within 1–4 months (14, 38, e26) (eTable 2) (EL 2A). A low-dose (3 million IU 3 times weekly) maintenance therapy is recommended after 6 months for ABD patients (14). Combination therapy with corticosteroids, colchicine, or benzathine penicillin is possible (e27).

Systemic therapeutic options to reduce frequency of attacks or number of aphthous ulcers
Systemic therapeutic options to reduce frequency of attacks or number of aphthous ulcers
eTable 2
Systemic therapeutic options to reduce frequency of attacks or number of aphthous ulcers

Other systemic agents

In a controlled study, sub-antimicrobial doses of doxycycline (40 mg daily) prolonged the interval between aphthous ulcers (e28) (Table1) (EL 2A). Zinc sulfate 300 mg daily reduced the number and size of aphthous ulcers in comparison to placebo (e29) (eTable1) (EL 2A). In patients with pre-menstrual flares of oral aphthous ulcers, once yearly subcutaneous injections of testosterone helped in some cases (39). Estrogen-dominant oral contraceptives can also be employed (14, 21) (EL 4). An effect is first to be expected after 3 to 6 months.

Summary

Until the etiology of chronic recurrent oral aphthous ulcers is determined, all therapeutic measures are aimed at symptomatic relief. Topical measures should be preferred as first-line therapy because of their low risk for systemic side effects (Figure 2).

Systemic measures should only be considered in addition to topical treatment in patients with a severe course and complex aphthosis; options include sucralfate, colchicine, pentoxifylline or prednisolone and combinations thereof. Systemic therapy with other immunosuppressive agents should be reserved for refractory or especially severe aphthous ulcers in patients with ABD.

Conflict of interest statement
The authors declare that no conflict of interest exists.

Manuscript received on 14 January 2014, revised version accepted on
18 June 2014.

Translated from the original German by Walter H. C. Burgdorf, MD.

Corresponding author
Prof. Dr. med. Dr. h.c. Christos C. Zouboulis
Klinik für Dermatologie,
Venerologie und Allergologie/Immunologisches Zentrum
Städtisches Klinikum Dessau
Auenweg 38, 06847 Dessau, Germany
christos.zouboulis@klinikum-dessau.de

@For eReferences please refer to:
www.aerzteblatt-international.de/ref4014

eBox, eTables:
www.aerzteblatt-international.de/14m0665

1.
Altenburg A, Krahl D, Zouboulis CC: Nicht-infektiöse exulzerierende Mundschleimhauterkrankungen. J Dtsch Dermatol Ges 2008; 7: 242–57. CrossRef CrossRef MEDLINE
2.
Bork K, Burgdorf W, Hoede N: Mundschleimhaut und Lippenkrankheiten. 3rd edition. Stuttgart: Schattauer 2008; 49–58.
3.
Rogers RS 3rd: Complex aphthosis. Adv Exp Med Biol 2003; 528: 311–6. CrossRef MEDLINE
4.
Hornstein OP: Aphthen und aphthoide Läsionen der Mundschleimhaut. HNO 1998; 46: 102–11. CrossRef MEDLINE
5.
Kleinman DV, Swango PA, Pindborg JJ: Epidemiology of oral mucosal lesions in United States schoolchildren: 1986–87. Community Dent Oral Epidemiol 1994; 22: 243–53. CrossRef MEDLINE
6.
Altenburg A, Abdel-Naser MB, Abdallah M, Seeber H, Zouboulis CC: Practical aspects of management of recurrent aphthous stomatitis. J Eur Acad Dermatol Venereol 2007; 21: 1019–26. CrossRef MEDLINE
7.
Chavan M, Jain H, Diwan N, Khedkar S, Shete A, Durkar S:
Recurrent aphthous stomatitis: a review. J Oral Pathol Med 2012; 41: 577–83. CrossRef MEDLINE
8.
Altenburg A, Mahr A, Maldini C, et al.: Epidemiologie und Klinik des Morbus Adamantiades-Behçet in Deutschland: Aktuelle Daten. Ophthalmologe 2012; 109: 531–41. CrossRef MEDLINE
9.
International Team for the Revision of the International Criteria for Behçet’s Disease (ITR-ICBD): The International Criteria for Behçet’s Disease (ICBD): a collaborative study of 27 countries on the
sensitivity and specificity of the new criteria. J Eur Acad Dermatol Venereol 2014; 28: 338–47. CrossRef MEDLINE
10.
Shim Y, Choi JH, Ahn HJ, Kwon JS: Effect of sodium lauryl sulfate on recurrent aphthous stomatitis: a randomized controlled clinical trial. Oral Dis 2012; 18: 655–60. CrossRef MEDLINE
11.
Descroix V, Coudert AE, Vigé A, et al.: Efficacy of topical 1 %
lidocaine in the symptomatic treatment of pain associated with oral mucosal trauma or minor oral aphthous ulcer: a randomized, double-blind, placebo-controlled, parallel-group, single-dose study. J Orofac Pain 2011; 25: 327–32. MEDLINE
12.
Skaare AB, Herlofson BB, Barkvoll P: Mouthrinses containing triclosan reduce the incidence of recurrent aphthous ulcers (RAU). J Clin Periodontol 1996; 23: 778–81. CrossRef MEDLINE
13.
Saxen MA, Ambrosius WT, al Rehemtula KF, Russell AL, Eckert GJ: Sustained relief of oral aphthous ulcer pain from topical diclofenac in hyaluronan: a randomized, double-blind clinical trial. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997; 84: 356–61. CrossRef MEDLINE
14.
Bonitsis NG, Altenburg A, Krause L, Stache T, Zouboulis CC: Current concepts in the treatment of Adamantadies-Behçet’s disease. Drugs Future 2009; 34: 749–63.
15.
Alidaee MR, Taheri A, Mansoori P, Ghodsi SZ: Silver nitrate cautery in aphthous stomatitis: a randomized controlled trial. Br J Dermatol 2005; 153: 521–5. CrossRef MEDLINE
16.
Zand N, Ataie-Fashtami L, Djavid GE, et al.: Relieving pain in minor aphthous stomatitis by a single session of non-thermal carbon dioxide laser irradiation. Lasers Med Sci 2009; 24: 515–20. CrossRef MEDLINE
17.
Arabaci T, Kara C, Ciçek Y: Relationship between periodontal parameters and Behçet’s disease and evaluation of different treatments for oral recurrent aphthous stomatitis. J Periodontal Res 2009; 44: 718–25. CrossRef MEDLINE
18.
Henricsson V, Axéll T: Treatment of recurrent aphthous ulcers with aureomycin mouth rinse or Zendium dentifrice. Acta Odontol Scand 1985; 43: 47–52. CrossRef MEDLINE
19.
Gorsky M, Epstein J, Rabenstein S, Elishoov H, Yarom N: Topical minocycline and tetracycline rinses in treatment of recurrent aphthous stomatitis: a randomized cross-over study. Dermatol Online J 2007; 13: 1. MEDLINE
20.
Altenburg A, Zouboulis CC: Current concepts in the treatment of recurrent aphthous stomatitis. Skin Therapy Lett 2008; 13(7): 1–4. MEDLINE
21.
Zouboulis CC: Adamantiades-Behçet’s disease. In: Katsambas AD, Lotti TM, eds.: European Handbook of Dermatological Treatments. 2nd edition. Berlin: Springer 2003; 16–26. CrossRef
22.
Fani MM, Ebrahimi H, Pourshahidi S, et al.: Comparing the effect of phenytoin syrup and triamcinolone acetonide ointment on aphthous ulcers in patients with Behçet´s syndrome. Iran Red Crescent Med J 2012; 14: 75–8. MEDLINE PubMed Central
23.
Al-Na’mah ZM, Carson R, Thanoon IA: Dexamucobase: a novel treatment for oral aphthous ulceration. Quintessence Int 2009; 40: 399–404. MEDLINE
24.
Vincent SD, Lilly GE: Clinical, historic, and therpeutic features of aphthous stomatitis. Literature review and open clinical trial employing steroids. Oral Surg Oral Med Oral Pathol 1992; 74: 79–86. CrossRef
25.
Collier PM, Neill SM, Copeman PW: Topical 5-aminosalicylic acid: a treatment for aphthous ulcers. Br J Dermatol 1992; 126: 185–8. CrossRef MEDLINE
26.
Greer RO Jr, Lindenmuth JE, Juarez T, Khandwala A: A double-blind study of topically applied 5 % amlexanox in the treatment of aphthous ulcers. J Oral Maxillofac Surg 1993; 51: 243–8. CrossRef
27.
Liu J, Zeng X, Chen Q, et al.: An evaluation on the efficacy and safety of amlexanox oral adhesive tablets in the treatment of recurrent minor aphthous ulceration in a Chinese cohort: a randomized, double-blind, vehicle-controlled, unparallel multicenter clinical trial. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006; 102: 475–81. CrossRef MEDLINE
28.
Marakoglu K, Sezer RE, Toker HC, Marakoglu I: The recurrent aphthous stomatitis frequency in the smoking cessation people. Clin Oral Investig 2007; 11: 149–53. CrossRef MEDLINE
29.
Brocklehurst P, Tickle M, Glenny A-M, et al.: Systemic interventions for recurrent aphthous stomatitis (mouth ulcers). Cochrane Database of Systematic Reviews 2012; 9: CD005411. MEDLINE
30.
Fontes V, Machet L, Huttenberger B, Lorette G, Vaillant L: Aphtose buccale récidivante: traitement par colchicine (Étude ouverte de 54 cas). Ann Dermatol Venereol 2002; 129: 1365–9. MEDLINE
31.
Thornhill MH, Baccaglini L, Theaker E, Pemberton MN: A randomized, double-blind, placebo-controlled trial of pentoxifylline for the treatment of recurrent aphthous stomatitis. Arch Dermatol 2007; 143: 463–70. CrossRef MEDLINE
32.
Pakfetrat A, Mansourian A, Momen-Heravi F, et al.: Comparison of colchicine versus prednisolone in recurrent aphthous stomatitis: A double-blind randomized clinical trial. Clin Invest Med 2010; 33: E189–95. MEDLINE
33.
Femiano F, Buonaiuto C, Gombos F, Lanza A, Cirillo N: Pilot study on recurrent aphthous stomatitis (RAS): a randomized placebo-controlled trial for the comparative therapeutic effects of systemic prednisone and systemic montelukast in subjects unresponsive to topical therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010; 109: 402–7. CrossRef MEDLINE
34.
Alpsoy E, Er H, Durusoy C, Yilmaz E: The use of sucralfate suspension in the treatment of oral and genital ulceration of Behçet disease: a randomized, placebo-controlled, double-blind study. Arch Dermatol 1999; 135: 529–32. CrossRef MEDLINE
35.
Yazici H, Pazarli H, Barnes CG, et al.: A controlled trial of azathioprine in Behçet’s syndrome. N Engl J Med 1990; 322: 281–5. CrossRef MEDLINE
36.
Zouboulis CC: Morbus Adamantiades-Behçet. In: Mrowietz U, eds.: Ciclosporin in der Dermatologie. Stuttgart: Thieme 2003; 38–51.
37.
Masuda K, Nakajima A, Urayama A, Nakae K, Kogure M, Inaba G: Double-masked trial of cyclosporine versus colchicine and long-term open study of cyclosporin in Behçet’s disease. Lancet 1989; 1: 1093–6. CrossRef MEDLINE
38.
Zouboulis CC, Orfanos CE: Treatment of Adamantiades-Behçet’s disease with systemic interferon alfa. Arch Dermatol 1998; 134: 1010–6. CrossRef MEDLINE
39.
Misra R, Anderson DC: Treatment of recurrent premenstrual orogenital aphthae with implants of low dose of testosterone. BMJ 1989; 299: 834. CrossRef MEDLINE PubMed Central
e1.
Schroeder HE, Müller-Glauser W, Sallay K: Stereologic analysis of leukocyte infiltration in oral ulcers of developing Mikulicz aphthae. Oral Surg Oral Med Oral Pathol 1983; 56: 629–40. MEDLINE
e2.
Altenburg A, Papoutsis N, Orawa H, Martus P, Krause L, Zouboulis CC: Epidemiologie und Klinik des Morbus Adamantiades-Behçet in Deutschland – Aktuelle pathogenetische Konzepte und therapeutische Möglichkeiten. J Dtsch Dermatol Ges 2006; 4: 49–64.
e3.
Bruce AJ, Rogers RSW 3rd: Acute oral ulcers. Dermatol Clin 2003; 21: 49–61.
e4.
Fox EC: The problem or oral ulcerations in general practice with special reference to herpetic herpetiform lesions. J R Coll Gen Pract 1970; 19: 191–200. MEDLINE
e5.
Lopez-Jornet P, Camacho-Alonso F, Martos N: Hematological study of patients with aphthous stomatitis. Int J Dermatol 2014; 53: 159–63. MEDLINE
e6.
Chen Y, Fang L, Yang X: Cyclic neutropenia presenting as recurrent oral ulcers and periodontitis. J Clin Pediatr Dent 2013; 37: 307–8. MEDLINE
e7.
Koybasi S, Parlak AH, Serin E, Yilmaz F, Serin D: Recurrent aphthous stomatitis: investigation of possible etiologic factors. Am J Otolaryngol 2006; 27: 229–32. MEDLINE
e8.
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: 844–5. MEDLINE PubMed Central
e9.
Wray D, Graykowski EA, Notkins AL: Role of mucosal injury in initiating recurrent aphthous stomatitis. Br Med J (Clin Res Ed) 1981; 283: 1569–70. MEDLINE PubMed Central
e10.
Jurge S, Kuffer R, Scully C, Porter SR: Mucosal disease series. Number VI. Recurrent aphthous stomatitis. Oral Dis 2006; 12: 1–21. CrossRef MEDLINE
e11.
Jennette JC: 2012 revised International Chapel Hill Consensus Conference nomenclature of vasculitides. Arthritis Rheum 2013; 65: 1–11. MEDLINE
e12.
International Study Group for Behçet’s Disease: Criteria for diagnosis of Behçet’s disease. Lancet 1990; 335: 1078–80. MEDLINE
e13.
Gorsky M, Epstein J, Raviv A, Yaniv R, Truelove E: Topical minocycline for managing symptoms of recurrent aphthous stomatitis. Spec Care Dentist 2008; 28: 27–31. MEDLINE
e14.
Rivera-Hidalgo F, Shulman JD, Beach MM: The association of tobacco and other factors with recurrent aphthous stomatitis in an US adult population. Oral Dis 2004; 10: 335–45. MEDLINE
e15.
Bittoun R: Recurrent aphthous ulcers and nicotine. Med J Aust 1991; 154: 471–2. MEDLINE
e16.
Davatchi F, Sadeghi Abdollahi B, et al.: Colchicine versus placebo in Behçet’s disease: randomized, double-blind, controlled crossover trial. Mod Rheumatol 2009; 19: 542–9. CrossRef MEDLINE
e17.
Yurdakul S, Mat C, Tüzün Y, et al.: Double-blind trial of colchicine in Behçet’s syndrome. Arthritis Rheum 2001; 44: 2686–92. CrossRef MEDLINE
e18.
Calgüneri M, Kiraz S, Ertenli I, Benekli M, Karaarslan Y, Celik I: The effect of prophylactic penicillin treatment on the course of arthritis episodes in patients with Behçet’s disease. A randomized clinical trial. Arthritis Rheum 1996; 39: 2062–5. MEDLINE
e19.
Rattan J, Schneider M, Arber N, Gorsky M, Dayan D: Sucralfate suspension as a treatment of recurrent aphthous stomatitis.
J Intern Med 1994; 236: 341–3. MEDLINE
e20.
Sharquie KE, Najim RA, Abu-Raghif AR: Dapsone in Behçet’s disease: a double-blind, placebo-controlled, cross-over study. J Dermatol 2002; 29: 267–79. MEDLINE
e21.
Bonnetblanc JM, Royer C, Bedane C: Thalidomide and recurrent aphthous stomatitis: A follow-up study. Dermatology 1996; 193: 321–3. MEDLINE
e22.
Grinspan D: Significant response of oral aphthosis to thalidomide treatment. J Am Acad Dermatol 1985; 12: 85–90. MEDLINE
e23.
Grinspan D, Blanco GF, Aguero S: Treatment of aphthae with thalidomide. J Am Acad Dermatol 1989; 20: 1060–3. MEDLINE
e24.
Hamuryudan V, Mat C, Saip S, et al.: Thalidomide in the treatment of the mucocutaneous lesions of the Behçet syndrome. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998; 128: 443–50. CrossRef MEDLINE
e25.
Calabrese L, Fleischer AB: Thalidomide: current and potential clinical applications. Am J Med 2000; 108: 487–95. MEDLINE
e26.
Alpsoy E, Durusoy C, Yilmaz E, et al.: Interferon alfa-2a in the treatment of Behçet disease: a randomized placebo-controlled and double-blind study. Arch Dermatol 2002; 138: 467–71. CrossRef MEDLINE
e27.
Demiroglu H, Ozcebe OI, Barista I, Dündar S, Eldem B: Interferon alfa-2b, colchicine, and benzathine penicillin versus colchicine and benzathine penicillin in Behçet’s disease: a randomised trial. Lancet 2000; 355: 605–9. MEDLINE
e28.
Preshaw PM, Grainger P, Bradshaw MH, Mohammad AR, Powala CV, Nolan A: Subantimicrobial dose doxycycline in the treatment of recurrent oral aphthous ulceration: a pilot study. J Oral Pathol Med 2007; 36: 236–40. MEDLINE
e29.
Sharquie KE, Najim RA, Al-Hayani RK, Al-Nuaimy AA, Maroof DM: The therapeutic and prophylactic role of oral zinc sulfate in management of recurrent aphthous stomatitis (ras) in comparison with dapsone. Saudi Med J 2008; 29: 734–8. MEDLINE
e30.
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: 117–22. MEDLINE
e31.
Pourahmad M, Rahiminejad M, Fadaei S, Kashafi H: Effects of camel thorn distillate on recurrent oral aphthous lesions. J Dtsch Dermatol Ges 2010; 8: 348–52. MEDLINE
e32.
Matsuda T, Ohno S, Hirohata S, et al.: Efficacy of rebamipide as adjunctive therapy in the treatment of recurrent oral aphthous ulcers in patients with Behçet’s disease: a randomised, double-blind, placebo-controlled study. Drugs 2003; 4: 19–28. MEDLINE
e33.
Melikoglu M, Fresko I, Mat C, et al.: Short-term trial of etanercept in Behçet’s disease: a double blind, placebo controlled study. J Rheumatol 2005; 32: 98–105. MEDLINE
e34.
de Abreu MA, Hirata CH, Pimentel DR, Weckx LL: Treatment of recurrent aphthous stomatitis with clofazimine. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009; 108: 714–21. MEDLINE
Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center: Dr. med. Altenburg, Dr. med. El-Haj, Dipl. med. Micheli, Prof. Dr. med. Abdel-Naser, Prof. Dr. med. Dr. h.c. Zouboulis
Pharmacy, Dessau Medical Center: Puttkammer
Department of Dermatology and Andrology, Faculty of Medicine, Ain Shams University, Cairo (Egypt):
Prof. Dr. med. Abdel-Naser
Important differential diagnostic considerations for oral aphthous ulcers
Important differential diagnostic considerations for oral aphthous ulcers
Box
Important differential diagnostic considerations for oral aphthous ulcers
(a) Minor-type oral aphthous ulcers, (b) major-type oral aphthous ulcer, (c) herpetiform oral aphthous ulcers
(a) Minor-type oral aphthous ulcers, (b) major-type oral aphthous ulcer, (c) herpetiform oral aphthous ulcers
Figure 1
(a) Minor-type oral aphthous ulcers, (b) major-type oral aphthous ulcer, (c) herpetiform oral aphthous ulcers
Algorithm for the treatment of chronic recurrent oral aphthous ulcers to reduce the duration of illness and the size of the ulcers
Algorithm for the treatment of chronic recurrent oral aphthous ulcers to reduce the duration of illness and the size of the ulcers
Figure 2
Algorithm for the treatment of chronic recurrent oral aphthous ulcers to reduce the duration of illness and the size of the ulcers
KeyMessages
Therapeutic options to reduce the frequency of recurrence and/or the number of oral aphthous ulcers
Therapeutic options to reduce the frequency of recurrence and/or the number of oral aphthous ulcers
Table 1
Therapeutic options to reduce the frequency of recurrence and/or the number of oral aphthous ulcers
Therapeutic options to reduce pain
Therapeutic options to reduce pain
Table 2
Therapeutic options to reduce pain
Topical therapeutic options to reduce the duration of illness and size of oral aphthous ulcers
Topical therapeutic options to reduce the duration of illness and size of oral aphthous ulcers
Table 3
Topical therapeutic options to reduce the duration of illness and size of oral aphthous ulcers
International criteria for the diagnosis of Adamantiades-Behçet disease (2014)
International criteria for the diagnosis of Adamantiades-Behçet disease (2014)
eBox
International criteria for the diagnosis of Adamantiades-Behçet disease (2014)
Systemic therapeutic options to reduce duration of illness and size of aphthous ulcers
Systemic therapeutic options to reduce duration of illness and size of aphthous ulcers
eTable 1
Systemic therapeutic options to reduce duration of illness and size of aphthous ulcers
Systemic therapeutic options to reduce frequency of attacks or number of aphthous ulcers
Systemic therapeutic options to reduce frequency of attacks or number of aphthous ulcers
eTable 2
Systemic therapeutic options to reduce frequency of attacks or number of aphthous ulcers
1.Altenburg A, Krahl D, Zouboulis CC: Nicht-infektiöse exulzerierende Mundschleimhauterkrankungen. J Dtsch Dermatol Ges 2008; 7: 242–57. CrossRef CrossRef MEDLINE
2.Bork K, Burgdorf W, Hoede N: Mundschleimhaut und Lippenkrankheiten. 3rd edition. Stuttgart: Schattauer 2008; 49–58.
3.Rogers RS 3rd: Complex aphthosis. Adv Exp Med Biol 2003; 528: 311–6. CrossRef MEDLINE
4.Hornstein OP: Aphthen und aphthoide Läsionen der Mundschleimhaut. HNO 1998; 46: 102–11. CrossRef MEDLINE
5.Kleinman DV, Swango PA, Pindborg JJ: Epidemiology of oral mucosal lesions in United States schoolchildren: 1986–87. Community Dent Oral Epidemiol 1994; 22: 243–53. CrossRef MEDLINE
6.Altenburg A, Abdel-Naser MB, Abdallah M, Seeber H, Zouboulis CC: Practical aspects of management of recurrent aphthous stomatitis. J Eur Acad Dermatol Venereol 2007; 21: 1019–26. CrossRef MEDLINE
7.Chavan M, Jain H, Diwan N, Khedkar S, Shete A, Durkar S:
Recurrent aphthous stomatitis: a review. J Oral Pathol Med 2012; 41: 577–83. CrossRef MEDLINE
8.Altenburg A, Mahr A, Maldini C, et al.: Epidemiologie und Klinik des Morbus Adamantiades-Behçet in Deutschland: Aktuelle Daten. Ophthalmologe 2012; 109: 531–41. CrossRef MEDLINE
9.International Team for the Revision of the International Criteria for Behçet’s Disease (ITR-ICBD): The International Criteria for Behçet’s Disease (ICBD): a collaborative study of 27 countries on the
sensitivity and specificity of the new criteria. J Eur Acad Dermatol Venereol 2014; 28: 338–47. CrossRef MEDLINE
10.Shim Y, Choi JH, Ahn HJ, Kwon JS: Effect of sodium lauryl sulfate on recurrent aphthous stomatitis: a randomized controlled clinical trial. Oral Dis 2012; 18: 655–60. CrossRef MEDLINE
11.Descroix V, Coudert AE, Vigé A, et al.: Efficacy of topical 1 %
lidocaine in the symptomatic treatment of pain associated with oral mucosal trauma or minor oral aphthous ulcer: a randomized, double-blind, placebo-controlled, parallel-group, single-dose study. J Orofac Pain 2011; 25: 327–32. MEDLINE
12.Skaare AB, Herlofson BB, Barkvoll P: Mouthrinses containing triclosan reduce the incidence of recurrent aphthous ulcers (RAU). J Clin Periodontol 1996; 23: 778–81. CrossRef MEDLINE
13.Saxen MA, Ambrosius WT, al Rehemtula KF, Russell AL, Eckert GJ: Sustained relief of oral aphthous ulcer pain from topical diclofenac in hyaluronan: a randomized, double-blind clinical trial. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997; 84: 356–61. CrossRef MEDLINE
14.Bonitsis NG, Altenburg A, Krause L, Stache T, Zouboulis CC: Current concepts in the treatment of Adamantadies-Behçet’s disease. Drugs Future 2009; 34: 749–63.
15.Alidaee MR, Taheri A, Mansoori P, Ghodsi SZ: Silver nitrate cautery in aphthous stomatitis: a randomized controlled trial. Br J Dermatol 2005; 153: 521–5. CrossRef MEDLINE
16.Zand N, Ataie-Fashtami L, Djavid GE, et al.: Relieving pain in minor aphthous stomatitis by a single session of non-thermal carbon dioxide laser irradiation. Lasers Med Sci 2009; 24: 515–20. CrossRef MEDLINE
17.Arabaci T, Kara C, Ciçek Y: Relationship between periodontal parameters and Behçet’s disease and evaluation of different treatments for oral recurrent aphthous stomatitis. J Periodontal Res 2009; 44: 718–25. CrossRef MEDLINE
18.Henricsson V, Axéll T: Treatment of recurrent aphthous ulcers with aureomycin mouth rinse or Zendium dentifrice. Acta Odontol Scand 1985; 43: 47–52. CrossRef MEDLINE
19.Gorsky M, Epstein J, Rabenstein S, Elishoov H, Yarom N: Topical minocycline and tetracycline rinses in treatment of recurrent aphthous stomatitis: a randomized cross-over study. Dermatol Online J 2007; 13: 1. MEDLINE
20.Altenburg A, Zouboulis CC: Current concepts in the treatment of recurrent aphthous stomatitis. Skin Therapy Lett 2008; 13(7): 1–4. MEDLINE
21.Zouboulis CC: Adamantiades-Behçet’s disease. In: Katsambas AD, Lotti TM, eds.: European Handbook of Dermatological Treatments. 2nd edition. Berlin: Springer 2003; 16–26. CrossRef
22.Fani MM, Ebrahimi H, Pourshahidi S, et al.: Comparing the effect of phenytoin syrup and triamcinolone acetonide ointment on aphthous ulcers in patients with Behçet´s syndrome. Iran Red Crescent Med J 2012; 14: 75–8. MEDLINE PubMed Central
23.Al-Na’mah ZM, Carson R, Thanoon IA: Dexamucobase: a novel treatment for oral aphthous ulceration. Quintessence Int 2009; 40: 399–404. MEDLINE
24.Vincent SD, Lilly GE: Clinical, historic, and therpeutic features of aphthous stomatitis. Literature review and open clinical trial employing steroids. Oral Surg Oral Med Oral Pathol 1992; 74: 79–86. CrossRef
25.Collier PM, Neill SM, Copeman PW: Topical 5-aminosalicylic acid: a treatment for aphthous ulcers. Br J Dermatol 1992; 126: 185–8. CrossRef MEDLINE
26.Greer RO Jr, Lindenmuth JE, Juarez T, Khandwala A: A double-blind study of topically applied 5 % amlexanox in the treatment of aphthous ulcers. J Oral Maxillofac Surg 1993; 51: 243–8. CrossRef
27.Liu J, Zeng X, Chen Q, et al.: An evaluation on the efficacy and safety of amlexanox oral adhesive tablets in the treatment of recurrent minor aphthous ulceration in a Chinese cohort: a randomized, double-blind, vehicle-controlled, unparallel multicenter clinical trial. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006; 102: 475–81. CrossRef MEDLINE
28.Marakoglu K, Sezer RE, Toker HC, Marakoglu I: The recurrent aphthous stomatitis frequency in the smoking cessation people. Clin Oral Investig 2007; 11: 149–53. CrossRef MEDLINE
29.Brocklehurst P, Tickle M, Glenny A-M, et al.: Systemic interventions for recurrent aphthous stomatitis (mouth ulcers). Cochrane Database of Systematic Reviews 2012; 9: CD005411. MEDLINE
30.Fontes V, Machet L, Huttenberger B, Lorette G, Vaillant L: Aphtose buccale récidivante: traitement par colchicine (Étude ouverte de 54 cas). Ann Dermatol Venereol 2002; 129: 1365–9. MEDLINE
31.Thornhill MH, Baccaglini L, Theaker E, Pemberton MN: A randomized, double-blind, placebo-controlled trial of pentoxifylline for the treatment of recurrent aphthous stomatitis. Arch Dermatol 2007; 143: 463–70. CrossRef MEDLINE
32.Pakfetrat A, Mansourian A, Momen-Heravi F, et al.: Comparison of colchicine versus prednisolone in recurrent aphthous stomatitis: A double-blind randomized clinical trial. Clin Invest Med 2010; 33: E189–95. MEDLINE
33.Femiano F, Buonaiuto C, Gombos F, Lanza A, Cirillo N: Pilot study on recurrent aphthous stomatitis (RAS): a randomized placebo-controlled trial for the comparative therapeutic effects of systemic prednisone and systemic montelukast in subjects unresponsive to topical therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010; 109: 402–7. CrossRef MEDLINE
34.Alpsoy E, Er H, Durusoy C, Yilmaz E: The use of sucralfate suspension in the treatment of oral and genital ulceration of Behçet disease: a randomized, placebo-controlled, double-blind study. Arch Dermatol 1999; 135: 529–32. CrossRef MEDLINE
35.Yazici H, Pazarli H, Barnes CG, et al.: A controlled trial of azathioprine in Behçet’s syndrome. N Engl J Med 1990; 322: 281–5. CrossRef MEDLINE
36.Zouboulis CC: Morbus Adamantiades-Behçet. In: Mrowietz U, eds.: Ciclosporin in der Dermatologie. Stuttgart: Thieme 2003; 38–51.
37.Masuda K, Nakajima A, Urayama A, Nakae K, Kogure M, Inaba G: Double-masked trial of cyclosporine versus colchicine and long-term open study of cyclosporin in Behçet’s disease. Lancet 1989; 1: 1093–6. CrossRef MEDLINE
38.Zouboulis CC, Orfanos CE: Treatment of Adamantiades-Behçet’s disease with systemic interferon alfa. Arch Dermatol 1998; 134: 1010–6. CrossRef MEDLINE
39.Misra R, Anderson DC: Treatment of recurrent premenstrual orogenital aphthae with implants of low dose of testosterone. BMJ 1989; 299: 834. CrossRef MEDLINE PubMed Central
e1.Schroeder HE, Müller-Glauser W, Sallay K: Stereologic analysis of leukocyte infiltration in oral ulcers of developing Mikulicz aphthae. Oral Surg Oral Med Oral Pathol 1983; 56: 629–40. MEDLINE
e2.Altenburg A, Papoutsis N, Orawa H, Martus P, Krause L, Zouboulis CC: Epidemiologie und Klinik des Morbus Adamantiades-Behçet in Deutschland – Aktuelle pathogenetische Konzepte und therapeutische Möglichkeiten. J Dtsch Dermatol Ges 2006; 4: 49–64.
e3.Bruce AJ, Rogers RSW 3rd: Acute oral ulcers. Dermatol Clin 2003; 21: 49–61.
e4.Fox EC: The problem or oral ulcerations in general practice with special reference to herpetic herpetiform lesions. J R Coll Gen Pract 1970; 19: 191–200. MEDLINE
e5.Lopez-Jornet P, Camacho-Alonso F, Martos N: Hematological study of patients with aphthous stomatitis. Int J Dermatol 2014; 53: 159–63. MEDLINE
e6.Chen Y, Fang L, Yang X: Cyclic neutropenia presenting as recurrent oral ulcers and periodontitis. J Clin Pediatr Dent 2013; 37: 307–8. MEDLINE
e7.Koybasi S, Parlak AH, Serin E, Yilmaz F, Serin D: Recurrent aphthous stomatitis: investigation of possible etiologic factors. Am J Otolaryngol 2006; 27: 229–32. MEDLINE
e8.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: 844–5. MEDLINE PubMed Central
e9.Wray D, Graykowski EA, Notkins AL: Role of mucosal injury in initiating recurrent aphthous stomatitis. Br Med J (Clin Res Ed) 1981; 283: 1569–70. MEDLINE PubMed Central
e10.Jurge S, Kuffer R, Scully C, Porter SR: Mucosal disease series. Number VI. Recurrent aphthous stomatitis. Oral Dis 2006; 12: 1–21. CrossRef MEDLINE
e11.Jennette JC: 2012 revised International Chapel Hill Consensus Conference nomenclature of vasculitides. Arthritis Rheum 2013; 65: 1–11. MEDLINE
e12.International Study Group for Behçet’s Disease: Criteria for diagnosis of Behçet’s disease. Lancet 1990; 335: 1078–80. MEDLINE
e13.Gorsky M, Epstein J, Raviv A, Yaniv R, Truelove E: Topical minocycline for managing symptoms of recurrent aphthous stomatitis. Spec Care Dentist 2008; 28: 27–31. MEDLINE
e14.Rivera-Hidalgo F, Shulman JD, Beach MM: The association of tobacco and other factors with recurrent aphthous stomatitis in an US adult population. Oral Dis 2004; 10: 335–45. MEDLINE
e15.Bittoun R: Recurrent aphthous ulcers and nicotine. Med J Aust 1991; 154: 471–2. MEDLINE
e16.Davatchi F, Sadeghi Abdollahi B, et al.: Colchicine versus placebo in Behçet’s disease: randomized, double-blind, controlled crossover trial. Mod Rheumatol 2009; 19: 542–9. CrossRef MEDLINE
e17.Yurdakul S, Mat C, Tüzün Y, et al.: Double-blind trial of colchicine in Behçet’s syndrome. Arthritis Rheum 2001; 44: 2686–92. CrossRef MEDLINE
e18.Calgüneri M, Kiraz S, Ertenli I, Benekli M, Karaarslan Y, Celik I: The effect of prophylactic penicillin treatment on the course of arthritis episodes in patients with Behçet’s disease. A randomized clinical trial. Arthritis Rheum 1996; 39: 2062–5. MEDLINE
e19.Rattan J, Schneider M, Arber N, Gorsky M, Dayan D: Sucralfate suspension as a treatment of recurrent aphthous stomatitis.
J Intern Med 1994; 236: 341–3. MEDLINE
e20.Sharquie KE, Najim RA, Abu-Raghif AR: Dapsone in Behçet’s disease: a double-blind, placebo-controlled, cross-over study. J Dermatol 2002; 29: 267–79. MEDLINE
e21.Bonnetblanc JM, Royer C, Bedane C: Thalidomide and recurrent aphthous stomatitis: A follow-up study. Dermatology 1996; 193: 321–3. MEDLINE
e22.Grinspan D: Significant response of oral aphthosis to thalidomide treatment. J Am Acad Dermatol 1985; 12: 85–90. MEDLINE
e23.Grinspan D, Blanco GF, Aguero S: Treatment of aphthae with thalidomide. J Am Acad Dermatol 1989; 20: 1060–3. MEDLINE
e24.Hamuryudan V, Mat C, Saip S, et al.: Thalidomide in the treatment of the mucocutaneous lesions of the Behçet syndrome. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998; 128: 443–50. CrossRef MEDLINE
e25.Calabrese L, Fleischer AB: Thalidomide: current and potential clinical applications. Am J Med 2000; 108: 487–95. MEDLINE
e26.Alpsoy E, Durusoy C, Yilmaz E, et al.: Interferon alfa-2a in the treatment of Behçet disease: a randomized placebo-controlled and double-blind study. Arch Dermatol 2002; 138: 467–71. CrossRef MEDLINE
e27.Demiroglu H, Ozcebe OI, Barista I, Dündar S, Eldem B: Interferon alfa-2b, colchicine, and benzathine penicillin versus colchicine and benzathine penicillin in Behçet’s disease: a randomised trial. Lancet 2000; 355: 605–9. MEDLINE
e28.Preshaw PM, Grainger P, Bradshaw MH, Mohammad AR, Powala CV, Nolan A: Subantimicrobial dose doxycycline in the treatment of recurrent oral aphthous ulceration: a pilot study. J Oral Pathol Med 2007; 36: 236–40. MEDLINE
e29.Sharquie KE, Najim RA, Al-Hayani RK, Al-Nuaimy AA, Maroof DM: The therapeutic and prophylactic role of oral zinc sulfate in management of recurrent aphthous stomatitis (ras) in comparison with dapsone. Saudi Med J 2008; 29: 734–8. MEDLINE
e30.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: 117–22. MEDLINE
e31.Pourahmad M, Rahiminejad M, Fadaei S, Kashafi H: Effects of camel thorn distillate on recurrent oral aphthous lesions. J Dtsch Dermatol Ges 2010; 8: 348–52. MEDLINE
e32.Matsuda T, Ohno S, Hirohata S, et al.: Efficacy of rebamipide as adjunctive therapy in the treatment of recurrent oral aphthous ulcers in patients with Behçet’s disease: a randomised, double-blind, placebo-controlled study. Drugs 2003; 4: 19–28. MEDLINE
e33.Melikoglu M, Fresko I, Mat C, et al.: Short-term trial of etanercept in Behçet’s disease: a double blind, placebo controlled study. J Rheumatol 2005; 32: 98–105. MEDLINE
e34.de Abreu MA, Hirata CH, Pimentel DR, Weckx LL: Treatment of recurrent aphthous stomatitis with clofazimine. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009; 108: 714–21. MEDLINE