CLINICS 2009;64(3):193-8

CLINICAL SCIENCE

Systemic treatment in severe cases of

recurrent aphthous stomatitis: an open
trial

Maria Angela Martins Mimura,I Silvio Kenji Hirota,I Norberto Nobuo Sugaya,I
José Antonio Sanches Jr,II Dante Antonio MigliariI

doi: 10.1590/S1807-59322009000300008

Mimura MAM, Hirota SK, Sugaya NN, Sanches Jr. JA, Migliari DA. Systemic treatment in severe cases of recurrent aphthous
stomatitis: an open trial. Clinics. 2009;64(3):193-8.

PURPOSE: This study aimed to evaluate the efficacy of the systemic drugs thalidomide, dapsone, colchicine, and pentoxifylline
in the treatment of severe manifestations of RAS.
METHODS: An open, 4-year clinical trial was carried out for 21 consecutive patients with severe RAS. Initially, patients were
given a 2-week course of prednisone to bring them to a baseline status. Simultaneously, one of the four test drugs was assigned to
each patient to be taken for a period of 6 months. During the course of the trial, patients were switched to one of the other three
drugs whenever side effects or a lack of satisfactory results occurred, and the 6-month limit of the treatment was then reset.
RESULTS: The most efficient and best-tolerated drug was thalidomide, which was administered to a total of eight patients and
resulted in complete remission in seven (87.5%). Dapsone was prescribed for a total of nine patients, of whom eight (89%) showed
improvement in their symptoms, while five showed complete remission. Colchicine was administered to a total of ten patients,
with benefits observed in nine (90%), of whom four showed complete remission. Pentoxyfilline was administered to a total of five
patients, with benefits observed in three (60%), of whom one patient showed complete remission.
CONCLUSION: The therapeutic methods used in this trial provided significant symptom relief. Patients experienced relapses of
the lesions; however, this occurred after withdrawal of their medication during the follow-up period.

KEYWORDS: Aphthous stomatitis; Thalidomide; Colchicine; Pentoxyfilline; Dapsone.

INTRODUCTION individuals. There is some evidence that the disease has

a higher prevalence in younger adults, decreasing in both
Recurrent aphthous stomatitis (RAS) is a common oral incidence and severity with age.2-5 The cause of RAS remains
inflammatory disease characterized by painful recurrent unknown, but there is growing evidence for an immunogenic
ulcerations of the oral mucosa.1-3 RAS shows no predilection basis for its development.3,6,7
for sex, and it seems to be more common among white RAS occurs in three clinical presentations: minor, major,
and herpetiform. Minor RAS is the most common form, and
it is characterized by shallow, well-defined ulcers of less
I
Department of Stomatology, School of Dentistry, University of São Paulo than 1 cm in diameter surrounded by an erythematous halo.
- São Paulo/SP, Brazil.
II
Division of Dermatology, Hospital das Clínicas, Faculdade de Medicina da
These ulcers heal in 7–14 days without scarring. Major RAS
Universidade de São Paulo - São Paulo/SP, Brazil. is less common, but more severe than the minor form. The
Tel.: 55 11 3091.7883
Email: nnsugaya@usp.br
ulcers are larger and deeper, with a raised irregular border,
Received for publication on September 12, 2008 and they frequently exceed 1 cm in size. Major RAS can
Accepted for publication on November 21, 2008 last for weeks to months, and usually heals with scarring.

193
Systemic treatment in severe RAS CLINICS 2009;64(3):193-8
Mimura MAM et al.

Herpetiform RAS is the rarest form of the disease, and it later development, were not included in the study. Patients
manifests as clusters of 10–100 small ulcers of 1–3 mm in whose oral ulcerations could be associated with a drug
diameter, which tend to coalesce into large ulcers and follow reaction were also excluded.
a clinical course similar to that of minor RAS (healing Diagnosis of RAS. Diagnosis was made based on
without scarring).1,8-10 the clinical presentation of lesions, as described in the
A diagnosis of RAS is almost invariably established on Introduction. Histological and direct immunofluorescence
the basis of the patient’s clinical history and presentation examination was available when the clinical diagnosis
of the lesions.1,2 Although histological examination is not was uncertain and was used mainly for differentiation
in itself sufficient for a definitive diagnosis of RAS, it from vesiculobullous diseases. A blood-cell count with
can aid in the differential diagnosis by eliminating other determination of hemoglobin concentration, coupled with
diseases that may resemble RAS clinically, including measurements of glucose-6-phosphate dehydrogenase
erosive oral lichen planus, vesiculobullous diseases, (G6PD), glycemia, and liver enzyme levels was performed
and oral cancer. Herpetiform RAS can be distinguished before the trial and twice a month during treatment for all
from intra-oral herpetic lesions via exfoliative cytology patients.
techniques and clinical features (e.g., herpetic, recurrent Patients. During the period between 2002 and 2005,
oral lesions usually affect keratinized oral mucosa, the 32 consecutive patients were referred to the Clinic of Oral
gingival or hard palate areas, and are preceded by vesicles). Diagnosis, Division of Dermatology, University of São
A detailed clinical history is also important in each case of Paulo, and subsequently diagnosed as having severe clinical
RAS to exclude other diseases that can present aphthous- manifestations of RAS. Later, five of the patients were
like lesions but cannot be differentiated from RAS based found to have one of the aforementioned systemic diseases
on histology. These include Behcet’s syndrome, Crohn’s (one patient with HIV infection, one with leukemia, two
disease, human immunodeficiency virus (HIV) infection, with anemia, and one with Behcet’s syndrome), and thus
and neutropenia.1,10-13 their data was excluded from the study. The remaining 27
There have been many attempts over the years to find patients were enrolled in the treatment protocol. This study
an effective treatment for RAS. Since the etiology of RAS was approved by the hospital’s Committee on Ethics, and
remains unknown, its treatment consists of therapeutic informed consent was obtained from all participants.
measures to suppress the symptoms rather than bringing Treatment protocol. Before entering the study, patients
about a definitive cure. The therapeutic choice depends on were informed about the trial, the medications and their
the severity of the disease, including the frequency of ulcer possible side effects. A clinical history concerning the ulcer
recurrence, the number of ulcers present, their location and type, size, number, recurrence, healing time, and symptoms
duration, and the level of associated orofacial pain. Patients were recorded for each patient. Initially, patients were given
with light-to-moderate symptoms and infrequent ulcers may systemic prednisone for a 2-week period, starting with
only require palliative therapy for pain.8 Cases of severe 0.5 mg/kg/day as a single dose in the morning, which was
RAS, those with painful ulcers, and those that show a high reduced after 1 week to half the initial dose. Simultaneously,
frequency of recurrence usually require systemic therapy. one of the four test drugs – namely thalidomide, dapsone,
The use of immunosuppressive and anti-inflammatory drugs colchicine, or pentoxifylline – was assigned to each patient,
has demonstrated varying degrees of success in severe cases keeping the proportion of assignments as equal as possible
of RAS. Drugs commonly used include corticosteroids, under the conditions that thalidomide was not prescribed
dapsone, colchicine, thalidomide, pentoxifylline, low-dose for fertile women, while dapsone was not prescribed for
interferon-α, and levamisole.14-17 patients with low levels of G6PD and pentoxifylline was
The purpose of the present investigation was to evaluate only prescribed for patients who could afford it, since it was
the clinical response to systemic drugs in the treatment of the only drug that could not be supplied free of charge by
patients with severe RAS. the hospital. After withdrawing the prednisone, the assigned
drug was maintained for 6 months, unless adverse side
METHODS effects or unsatisfactory results occurred. In either of these
cases, the patient was switched to one of the other three
Patient selection. Patients were selected for this drugs following the same safety criteria described above.
study based on a severe clinical course of RAS, i.e., with The drugs and dosages employed are shown in table 1.
multiple episodes of ulcers monthly. Patients with any Evaluation and follow-up. Patients were evaluated at 15-
hematologic disease, Behcet’s syndrome, Crohn’s disease, day intervals during the period of medication usage. At each
HIV infection or Reiter’s syndrome, either initially or as a visit, data regarding clinical status (benefits or side effects)

194
CLINICS 2009;64(3):193-8 Systemic treatment in severe RAS
Mimura MAM et al.

Table 1 - Therapeutic schedule Table 2 - Characteristics of the patients (n = 21)

Drugs Dosage Characteristics Male Female Total

Prednisone 0.5 mg/kg/day for 7 days Age range (mean) years 10–58 (29.9) 13–78 (41.9) 10–78 (35.5)
Byyny [33] half of the dose for 7 days
Caucasian 9 10 19
Thalidomide 100 mg/day
Non-caucasian 0 2 2
Bonnetblanc et al.[29]
Familial history of RAS 4 7 11
Dapsone 25 mg/day for 3 days
Ahmed et al.[30] 50 mg/day for 3 days Lesions per cycle
75 mg/day for 3 days 1 0 0 0
100 mg/day maintenance dose 2 to 3 2 4 6
>3 7 8 15
Colchicine 0.5 mg/day for 7 days
Ruah et al.[11] 1.0 mg/day for 7 days Healing time
1.5 mg/day maintenance dose 7 to 10 days 4 10 14
11 to 20 days 0 0 0
Pentoxifylline 400 mg 3 times a day
21 to 30 days 5 2 7
Pizarro et al.[22]
Type of ulcer
Major 5 1 6
Minor 4 11 15
were recorded, as well as compliance with the treatment.
Herpetiform 0 0 0
Any time that a drug had to be replaced with an alternative
Systemic diseases
drug, the 6-month time limit for using the medication was Yes 0 3 3
reset. The criteria for drug efficacy were mainly based on No 9 9 18
the potential to prevent relapses and/or reduce symptoms, Medications
numbers of ulcers, and healing time. Drug efficacy was Anti-hypertensives 0 2 2
Cardiac drugs 0 1 1
classified as excellent, moderate, mild, or no response as Thyroid drugs 0 1 1
follows: excellent – patient with no relapses; moderate – n = number of patients
patient showing relapses but with decreasing frequency, less
lesions per cycle, and alleviated symptoms; mild – relief of to exclude other diseases. Both exams provided non-
symptoms only; no response – no improvement observed or specific findings: the histological features consisted
reported. After withdrawal of the medication, patients were predominantly of lymphocytes and neutrophils, and the
followed for a period ranging from 6 to 12 months. results of the immunofluorescence technique were non-
reactive in all cases. Three female patients presented
RESULTS with systemic diseases: two were hypertensive and one
had hypothyroidism. Only one patient was a smoker. The
Of the 27 patients, six stopped showing up for treatment, characteristics of the patients are shown in table 2.
and the data for these individuals were not used. Therefore, Initial drug assignments are shown in table 3. Eleven
this study was effectively conducted for 21 patients (nine patients were switched to alternative drugs. At the end
male and 12 female, mean age of 35.5 years). Six presented of this trial, the percentage of each drug evaluated was
with major-type RAS, while 15 presented with minor types. higher than at its initial assignment, as shown in table 4,
No patients presented with herpetiform-type RAS. which summarizes the efficacy of all drugs tested. The
Biopsy for histological and direct immunofluorescence most efficient and best-tolerated drug was thalidomide,
examination was performed for four patients in order since patients who used this drug showed an excellent

Table 3 - Drug assignments (n = 21)

Drugs Initial Switched to

Assignments
Thalidomide Dapsone Colchicine Pentoxifylline
Thalidomide 7 – 1 1 –
Dapsone 8 – – 3 –
Colchicine 5 1 – – 4
Pentoxifylline 1 – – 1 –
n = number of patients

195
Systemic treatment in severe RAS CLINICS 2009;64(3):193-8
Mimura MAM et al.

Table 4 - Efficacy of the drugs prescribed in the trial

Drugs Initial assignments Total assignments Evaluation

(n = 21) throughout trial
Excellent Moderate Mild No Response
Thalidomide 7 8 7 0 0 1
Dapsone 8 9 5 3 0 1
Colchicine 5 10 4 4 1 1
Pentoxifylline 1 5 1 2 0 2
n = number of patients

Table 5 - Side effects associated with the drugs

Thalidomide Dapsone Colchicine Pentoxifylline

Assignments 8 9 10 5
Period of administration 3 to 6 months 1 to 6 months 2 to 6 months 1 to 6 months
(mean) (4.8 months) (4.2 months) (4.8 months) (3.0 months)
Severe side effects 0 3 (33.3%) 0 0
Moderate side effects 0 3 (33.3%) 0 1 (83.3%)
Mild side effects 1 (12.5%) 0 3 (30%) 0
No side effects 7 (87.5%) 3 (33.3%) 7 (70%) 4 (16.7%)

response to therapy and did not develop any significant side Each of the four drugs compared in this trial was
effects. Dapsone, despite presenting good results, had to be previously tested separately in other studies.18-26 The anti-
discontinued for most of the patients (six out of nine) due to inflammatory and immunological properties of these
its adverse side effects. Colchicine and pentoxifylline also drugs enable them to reduce or prevent the development
provided good results with few side effects; nevertheless, of RAS. Dapsone appears to inhibit the migration of
pentoxifylline was used by only five patients due to its polymorphonuclear leukocytes (PMNs) by inhibiting
financial cost. The side effects experienced were categorized lysosomal enzyme activity and interfering with the
into three types: mild – minor gastrointestinal pain and cellular response to chemotactic stimuli. 27,28 Colchicine
nausea; moderate – dizziness, fatigue, diarrhea, lethargy, and appears to depolymerize the microtubular proteins of
headache; or severe – hemolysis, jaundice, and decreased inflammatory cells, inhibiting chemotaxis, mobilization,
hemoglobin level. The mean time for use of each drug and adhesiveness, and lysosomal degranulation11. Thalidomide
the patient side effects are shown in table 5. and pentoxifylline present immunomodulatory and anti-
All patients presented relapses after discontinuing inflammatory properties, and inhibit the production of tumor
medication during the follow-up period. Recurrences necrosis factor alpha (TNFα).15,18,22,29
occurred from 2 weeks up to 9 months, but most of the A corticosteroid (prednisone) was prescribed for all
patients experienced relapses within a few weeks after the patients at the beginning of the trial in order to dampen the
medication was withdrawn. RAS bout in course. This procedure was carried out to obtain
a baseline for comparison of the results and to provide relief
DISCUSSION of symptoms for the patients. The short-term prescription
of a corticosteroid (0.5mg/kg/day/1week, followed by half
Treatment of RAS remains a great challenge. Different this dosage for another week) did not cause any significant
kinds of treatment have been attempted over the years, yet no adverse side effects and was valuable in decreasing patient
specific management has been established as being the most discomfort. This initial course with a systemic corticosteroid
appropriate.18 RAS affects patients differently and, in some was important for halting bouts of RAS and for patients’
cases, may cause severe pain and interfere with one’s day-to- compliance with the trial.
day life. The present study dealt with patients suffering from Thalidomide was the most effective drug tested in this
the severe form of RAS, and therefore received systemic trial. It was administered to a total of eight patients for a
medication. time period ranging from 3 to 6 months (mean, 4.8 months).

196
CLINICS 2009;64(3):193-8 Systemic treatment in severe RAS
Mimura MAM et al.

It worked very well in most cases, seven (87.5%) of which some discomfort (diarrhea), which was easily controlled by
resulted in complete remission of RAS; one patient presented slightly lowering their dosage.
no response. The percentage of complete remission obtained Pentoxifylline was prescribed for only five patients
for our patients was much higher than that reported by since the cost of this medication impeded its availability
other authors, namely Grinspan et al.24 (34%) and Revuz et in the present trial. Pentoxifylline was used for a period
al.20 (48%), for which the number of patients treated with ranging from 1 to 6 months (mean, 3.0 months). In two
thalidomide (40 and 73, respectively) was higher than that in patients (40%), a moderate improvement was observed
the present study. In terms of side effects, Revuz et al.20 found (shorter healing time, less severe symptoms, and a lower
a high percentage of adverse side effects with thalidomide recurrence rate), while one patient (20%) presented
use, mainly drowsiness (75%) and constipation (40%). with complete remission and two others experienced no
Similar side effects were also observed by Bonnetblanc et benefit. These results were in agreement with those of
al.29 (64%) and Grinspan et al.24 (48%). In the present study, Pizarro et al.22 and Chandrasekhar et al.15 , who obtained
only one (12.5%) patient complained of slight drowsiness excellent-to-satisfactory results with pentoxifylline in 50
during the thalidomide course. to 60% of their patients. Even better results were obtained
Dapsone was given to a total of nine patients for lengths by Wahba-Yahva23, who reported stable remission in all
of time ranging from 1 to 6 months (mean, 4.2 months). cases (six patients). Side effects were seldom reported by
Eight of these patients (89%) showed excellent-to-moderate patients in those studies. In the present study, the patients
improvement of their symptoms. This result was somewhat also presented few side effects, with only one patient
better than the results obtained by Handfield-Jones et al.19, manifesting dizziness and nausea and for whom the
who reported improvement in 50% of their patients using medication was discontinued.
the same protocol and dosage as those used in our trial Regarding the effect of the drugs in preventing RAS
(100 mg/day). These authors did not mention side effects recurrences after their withdrawal, dapsone was found
with the dapsone use. Dapsone had to be discontinued to yield the best results. Of the patients who reported
for six of our patients due to its moderate-to-severe side benefits with dapsone, three remained ulcer free without
effects. In three of these patients, anemia, hemolysis, and medication for up to 9 months. Colchicine apparently
jaundice occurred early in the course of medication, and did not protect patients against new bouts of RAS after
the patients did not receive any other systemic medication withdrawal, since recurrences occurred within 2 to 3 weeks
until they had completely recovered to a healthy clinical after drug discontinuation. Similar results were observed
condition. Other authors using dapsone for ulcerative with pentoxifylline, as just one patient remained ulcer
mucosal diseases other than RAS have reported similar side free for a 5-month period of time after drug withdrawal.
effects, although these were less severe and more delayed As for thalidomide, patients experienced no recurrences
in their onset.27,30 for a 2-week to 4-month period after its withdrawal. Of
During the course of the trial, colchicine was prescribed note, three patients who had their th alidomide prescription
to a total of ten patients for a period of time ranging from discontinued during the course of therapy due to a temporary
2 to 6 months (mean, 4.8 months). Benefits were obtained interruption in hospital supply experienced a rapid worsening
with colchicine in nine patients (90%), among which of their clinical status, which was not improved by any other
four experienced complete remission of lesions, four drug used in this trial. These patients were placed back on
demonstrated moderate improvement, and one experienced thalidomide as soon as it became available and regained the
only a mild benefit. Efficacy with the use of colchicine for clinical status they presented before the interruption. It is
treatment of RAS has also been reported by other authors21,25, also important to mention that, five of the six patients with
with improvement ranging from 63 to 71% of the cases. In major-type RAS, benefited from the treatment protocol with
one of these studies25, patients were followed for as long as thalidomide, thus reinforcing the effectiveness of this drug
4.7 years and, at the end of that period, 37% of the patients for RAS treatment.
(without medication) still maintained a better clinical status
compared with the period before treatment. Side effects with CONCLUSION
colchicine have been observed in many studies11,21,31,32, and
are mainly characterized by gastrointestinal disturbances The therapeutic methods used in this trial were able to
(e.g., diarrhea and nausea) and paresthesia of the lower provide significant relief of symptoms for as long as the drug
extremities. Ruah et al.11 reported that the continuous use of was administered. Relapses of the lesions after withdrawal of
colchicine could lead to the development of neuropathy and the medication, however, were observed during the follow-up
myopathy. In the present study, three patients complained of period. Thalidomide provided the best results in our trial, but

197
Systemic treatment in severe RAS CLINICS 2009;64(3):193-8
Mimura MAM et al.

this drug presents problems with regard to accessibility, and Pentoxifylline was moderately effective, although it was not
its use is precluded for fertile women. Dapsone produced properly tested in this trial. Colchicine demonstrated good
benefits, but also resulted in severe adverse side effects. results and was well tolerated by the patients.

REFERENCES

1. Scully C, Gorsky M, Lozada-Nur F. The diagnosis and management of 17. Barrons RW. Treatment strategies for recurrent oral aphthous ulcers.
recurrent aphthous stomatitis, a consensus approach. J Am Dent Assoc. Am J Health Syst Pharm. 2001;58:41-50.
2003;134:200-7. 18. Jurge S, Kuffer R, Scully C, Porter SR. Recurrent aphthous stomatitis.
2. Vincent SD, Lilly GE. Clinical, historic, and therapeutic features of Oral Dis. 2006;12:1-21.
aphthous stomatitis. Literature review and open clinical trial employing 19. Handfield-Jones S, Allen BR, Littlewood SM. Dapsone use with oral-
steroids. Oral Surg Oral Med Oral Pathol. 1992;74:79-86. genital ulcers. Br J Dermatol. 1985;113:501.
3. Natah SS, Konttinen YT, Enattah NS, Ashammakhi N, Shrakey KA, 20. Revuz J, Guillaume JC, Janier M, Hans P, Marchand C, Souteyrand
Häyrinen-Immonen R. Recurrent aphthous ulcers today: a review of P, et al. Crossover study of thalidomide vs placebo in severe recurrent
the growing knowledge. Int J Oral Maxillofac Surg. 2004;33:221-34. aphthous stomatitis. Arch Dermatol. 1990;126:923-7.
4. Reichart PA. Oral mucosal lesions in a representative cross-sectional 21. Katz J, Langevitz P, Shemer J, Barak S, Livneh A. Prevention of recurrent
study of aging Germans. Community Dent Oral Epidemiol. 2000;28:390- aphthous stomatitis with colchicine: An open trial. J Am Acad Dermatol.
8. 1994;31:459-61.
5. Kleinman DV, Swango PA, Niessen LC. Epidemiologic studies of oral 22. Pizarro A, Navarro A, Fonseca E, Vidaurrazaga C, Herranz P. Treatment
mucosal conditions – methodologic issues. Community Dent Oral of recurrent aphthous stomatitis with pentoxifylline. Br J. Dermatol.
Epidemiol. 1991;19:129-40. 1995;133:659-60.
6. Pedersen A, Hougen HP, Kenrad B. T-lymphocyte subsets in oral 23. Wahba-Yahav AV. Pentoxifylline in intractable recurrent aphthous
mucosa of patients with recurrent aphthous ulceration. J Oral Pathol stomatitis: an open trial. J Am Acad Dermatol. 1995;33:680-2.
Med. 1992;21:176-80. 24. Grinspan D, Blanco GF, Agüero S. Treatment of aphthae with
7. Casiglia JM. Recurrent aphthous stomatitis: Etiology, diagnosis, and thalidomide. J Am Acad Dermatol. 1989;20:1060-3.
treatment. Gen Dent. 2002;50:157-66. 25. Fontes V, Machet L, Huttenberger B, Lorette G, Vaillant L. [Recurrent
8. Porter SR, Scully C. Aphthous stomatitis – an overview of aphthous stomatitis: treatment with colchicine. An open trial of 54 cases].
aetiopathogenesis and management. Clin Exp Dermatol. 1991;16:235- Ann Dermatol Venereol. 2002;129:1365-9.
43. 26. Altinor S, Öztürkcan S, Hah MM. The effects of colchicine on neutrophil
9. Woo SB, Sonis ST. Recurrent aphthous ulcers: A review of diagnosis function in subjects with recurrent aphthous stomatitis. J Eur Acad
and treatment. J Am Dent Assoc. 1996;27:1202-13. Dermatol Venearol. 2003; 17:469-70.
10. Field EA, Allan RB. Review article: oral ulceration – aetiopathogenesis, 27. Ciarrocca KN, Greenberg MS. A retrospective study of the management
clinical diagnosis and management in the gastrointestinal clinic. Aliment of oral mucous membrane pemphigoid with dapsone. Oral Surg Oral
Pharmacol Ther. 2003;18:949-62. Med Oral Pathol Oral Radiol Endod. 1999;88:159-63.
11. Ruah CB, Stram JR, Chasin WD. Treatment of severe recurrent 28. Modschiedler K, Weller M, Wörl P, Von Den Driesch P. Dapsone and
aphthous stomatitis with colchicine. Arch Otolaryngol Head Neck Surg. colchicine inhibit adhesion of neutrophilic granulocytes to epidermal
1988;114:671-5. sections. Arch Dermatol Res. 2000;292:32-6.
12. Eversole LR. Immunopathology of oral mucosal ulcerative, 29. Bonnetblanc J-M, Royer C, Bedane C. Thalidomide and recurrent
desquamative, and bullous diseases. Selective review of the literature. aphthous stomatitis: A follow-up study. Dermatology. 1996;193:321-
Oral Surg Oral Med Oral Pathol. 1994;77:555-71. 3.
13. Ship JA, Chavez EM, Doerr PA, Henson BS, Sarmadi M. Recurrent 30. Ahmed AR, Bradley SK, Rogers III RS. Cicatricial pemphigoid. J Am
aphthous stomatitis. Quintessence Int. 2000;31:95-112. Acad Dermatol. 1991;24:987-1001.
14. Ship JA. Recurrent aphthous stomatitis: An update. Oral Surg Oral Med 31. Miyachi Y, Taniguchi S, Ozaki M, Horio T. Colchicine in the treatment
Oral Pathol Oral Radiol Endod. 1996;81:141-7. of the cutaneous manifestations of Behçet’s disease. Br J. Dermatol.
15. Chandrasekhar J, Liem AA, Cox, NH, Paterson AW. Oxypentoxifylline 1981;104:67-9.
in the management of recurrent aphthous oral ulcers. An open clinical 32. Nicolás JLL, Íñiguez JCM. Tratamiento de la estomatitis aftosa
trial. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999;87:564- recidivante: Revisón bibliográfica. Rev Clin Esp. 1998;198:234-6.
7.
16. Rodu B, Mattingly G. Oral mucosal ulcers: diagnosis and management.
J Am Dent Assoc. 1992;123:83-6.

198