Recurrent aphthous ulceration: a review of potential causes and novel treatments

Journal of Dermatological Treatment

Volumn 29, Issue 6, 2018, Pages 542-552

  Saikaly, Sami Kameel ^a,b   Saikaly, Tanya Siham ^c   Saikaly, Lara Elizabeth ^d  

^a ORLANDO REGIONAL MEDICAL CENTER   (United States)

^b UNIVERSITY OF CENTRAL FLORIDA COLLEGE OF MEDICINE   (United States)

^c Univ of Alabama School of Dentistry   (United States)

^d UNIVERSITY OF FLORIDA   (United States)

Author keywords

Aphthous; causes; treatment; ulcer

Indexed keywords

ANTIOXIDANT; MOUTHWASH; REACTIVE OXYGEN METABOLITE; TOPICAL AGENT; VITAMIN; ANTIINFLAMMATORY AGENT; IMMUNOGLOBULIN A;

ALLERGY; APHTHOUS STOMATITIS; DIET; GENETIC POLYMORPHISM; HELICOBACTER PYLORI; HEMATOLOGICAL PARAMETERS; HUMAN; IMMUNOLOGY; LOW LEVEL LASER THERAPY; MOUTH FLORA; MOUTH INJURY; MOUTH MUCOSA; NONHUMAN; NUTRITION; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; STRESS; SYSTEMATIC REVIEW; SYSTEMIC DISEASE; SYSTEMIC THERAPY; TOPICAL TREATMENT; VITAMIN DEFICIENCY; VITAMIN SUPPLEMENTATION; MENTAL STRESS; METABOLISM; MICROBIOLOGY; PATHOGENICITY;

ANTI-INFLAMMATORY AGENTS; HELICOBACTER PYLORI; HUMANS; IMMUNOGLOBULIN A; LASER THERAPY; MOUTH MUCOSA; REACTIVE OXYGEN SPECIES; STOMATITIS, APHTHOUS; STRESS, PSYCHOLOGICAL; VITAMINS;

EID: 85041013605     PISSN: 09546634     EISSN: 14711753     Source Type: Journal    
DOI: 10.1080/09546634.2017.1422079     Document Type: Review

References (136)

1. Scully C. Clinical practice. Aphthous ulceration. N Engl J Med. 2006;355:165–172
2. Bratel J, Hakeberg M. Anamnestic findings from patients with recurrent aphthous stomatitis. Swed Dent J. 2014;38:143–149
3. Schemel-Suarez M, Lopez-Lopez J, Chimenos-Kustner E. [Oral ulcers: differential diagnosis and treatment]. Med Clin (Barc). 2015;145:499–503
4. Cui RZ, Bruce AJ, Rogers RS. Recurrent aphthous stomatitis. Clin Dermatol. 2016;34:475–481
5. Tarakji B, Gazal G, Al-Maweri SA, et al. Guideline for the diagnosis and treatment of recurrent aphthous stomatitis for dental practitioners. J Int Oral Health. 2015;7:74–80
6. Akintoye SO, Greenberg MS. Recurrent aphthous stomatitis. Dent Clin North Am. 2014;58:281–297
7. Stanley HR. Aphthous lesions. Oral Surg Oral Med Oral Pathol. 1972;33:407–416
8. Rivera C, Droguett D, Arenas-Marquez MJ. Oral mucosal lesions in a Chilean elderly population: a retrospective study with a systematic review from thirteen countries. J Clin Exp Dent. 2017;9:e276–e283
9. Tappuni AR, Kovacevic T, Shirlaw PJ, et al. Clinical assessment of disease severity in recurrent aphthous stomatitis. J Oral Pathol Med. 2013;42:635–641
10. Marty M, Bailleul-Forestier I, Vaysse F. Recurrent aphthous stomatitis as a marker of celiac disease in children. Pediatr Dermatol. 2016;33:241
11. Tan CX, Brand HS, de Boer NK, et al. Gastrointestinal diseases and their oro-dental manifestations: part 1: Crohn’s disease. Br Dent J. 2016;221:794–799
12. Cansu DU, Kasifoglu T, Korkmaz C. Do clinical findings of Behcet’s disease vary by gender? A single-center experience from 329 patients. Eur J Rheumatol. 2016;3:157–160
13. Patton LL. Oral lesions associated with human immunodeficiency virus disease. Dent Clin North Am. 2013;57:673–698
14. Subramaniam P, Kumar K. Oral mucosal lesions and immune status in HIV-infected Indian children. J Oral Pathol Med. 2015;44:296–299
15. Vanoni F, Theodoropoulou K, Hofer M. PFAPA syndrome: a review on treatment and outcome. Pediatr Rheumatol Online J. 2016;14:38
16. Jin J, Li R, Jiang C, et al. Transcriptome analysis reveals dynamic changes in coxsackievirus A16 infected HEK 293T cells. BMC Genomics. 2017;18:933
17. Gupta N, Levitt JO. Unique clinical presentations of pityriasis rosea: aphthous ulcers, vesicles and inverse distribution of lesions. Dermatol Online J. 2017;23:11
18. Bayraktar K, Gurer G. Pulmonary tuberculosis presenting with oral aphthae. Eur J Rheumatol. 2015;2:117–119
19. Baccaglini L, Theriaque DW, Shuster JJ, et al. Validation of anamnestic diagnostic criteria for recurrent aphthous stomatitis. J Oral Pathol Med. 2013;42:290–294
20. Al-Samadi A, Drozd A, Salem A, et al. Epithelial cell apoptosis in recurrent aphthous ulcers. J Dent Res. 2015;94:928–935
21. Zad M, Flowers SA, Bankvall M, et al. Salivary mucin MUC7 oligosaccharides in patients with recurrent aphthous stomatitis. Clin Oral Investig. 2015;19:2147–2152
22. Barile MF, Graykowski EA, Driscoll EJ, et al. L form of bacteria isolated from recurrent aphthous stomatitis lesions. Oral Surg Oral Med Oral Pathol. 1963;16:1395–1402
23. Seoudi N, Bergmeier LA, Drobniewski F, et al. The oral mucosal and salivary microbial community of Behçet’s syndrome and recurrent aphthous stomatitis. J Oral Microbiol. 2015;7:27150
24. Bankvall M, Sjoberg F, Gale G, et al. The oral microbiota of patients with recurrent aphthous stomatitis. J Oral Microbiol. 2014;6:25739
25. Hijazi K, Lowe T, Meharg C, et al. Mucosal microbiome in patients with recurrent aphthous stomatitis. J Dent Res. 2015;94:87S–94s
26. Kim YJ, Choi YS, Baek KJ, et al. Mucosal and salivary microbiota associated with recurrent aphthous stomatitis. BMC Microbiol. 2016;16:57
27. Lehner T, Lavery E, Smith R, et al. Association between the 65-kilodalton heat shock protein, Streptococcus sanguis, and the corresponding antibodies in Behçet’s syndrome. Infect Immun. 1991;59:1434–1441
28. Seoudi N, Bergmeier LA, Hagi-Pavli E, et al. The seroprevalence and salivary shedding of herpesviruses in Behçet’s syndrome and recurrent aphthous stomatitis. J Oral Microbiol. 2015;7:27156
29. Eguia A, Marcos-Arias C, Eraso E, et al. [Presence of Candida in recurrent aphthous stomatitis]. Rev Iberoam Micol. 2013;30:271–272
30. Gomes CC, Gomez RS, Zina LG, et al. Recurrent aphthous stomatitis and Helicobacter pylori. Med Oral Patol Oral Cir Bucal. 2016;21:e187–e191
31. Li L, Gu H, Zhang G. Association between recurrent aphthous stomatitis and Helicobacter pylori infection: a meta-analysis. Clin Oral Investig. 2014;18:1553–1560
32. Gulseren D, Karaduman A, Kutsal D, et al. The relationship between recurrent aphthous stomatitis, and periodontal disease and Helicobacter pylori infection. Clin Oral Investig. 2016;20:2055–2060
33. Tas DA, Yakar T, Sakalli H, et al. Impact of Helicobacter pylori on the clinical course of recurrent aphthous stomatitis. J Oral Pathol Med. 2013;42:89–94
34. Besu I, Jankovic L, Konic-Ristic A, et al. The role of specific cow’s milk proteins in the etiology of recurrent aphthous ulcers. J Oral Pathol Med. 2013;42:82–88
35. Chainani-Wu N, Nayudu A. Resolution of recurrent aphthous ulcers after discontinuation of cow’s milk protein intake. J Am Dent Assoc. 2017;148:614–617
36. Gulseren D, Hapa A, Ersoy-Evans S, et al. Is there a role of food additives in recurrent aphthous stomatitis? A prospective study with patch testing. Int J Dermatol. 2017;56:302–306
37. de Groot A. Contact allergy to (ingredients of) toothpastes. Dermatitis. 2017;28:95–114
38. Aynali G, Ozkan M, Aynali A, et al. [The evaluation of serum vitamin B12, folic acid and hemoglobin levels in patients with recurrent minor aphthous stomatitis]. Kulak Burun Bogaz Ihtis Derg. 2013;23:148–152
39. Khan NF, Saeed M, Chaudhary S, et al. Haematological parameters and recurrent aphthous stomatitis. J Coll Physicians Surg Pak. 2013;23:124–127
40. Wu YC, Wu YH, Wang YP, et al. Hematinic deficiencies and anemia statuses in recurrent aphthous stomatitis patients with or without atrophic glossitis. J Formos Med Assoc. 2016;115:1061–1068
41. Chen H, Sui Q, Chen Y, et al. Impact of haematologic deficiencies on recurrent aphthous ulceration: a meta-analysis. Br Dent J. 2015;218:E8
42. Sun A, Chen HM, Cheng SJ, et al. Significant association of deficiencies of hemoglobin, iron, vitamin B12, and folic acid and high homocysteine level with recurrent aphthous stomatitis. J Oral Pathol Med. 2015;44:300–305
43. Khabbazi A, Ghorbanihaghjo A, Fanood F, et al. A comparative study of vitamin D serum levels in patients with recurrent aphthous stomatitis. Egypt Rheumatol. 2015;37:133–137
44. Khademi H, Khozeimeh F, Tavangar A, et al. The serum and salivary level of malondialdehyde, vitamins A, E, and C in patient with recurrent aphthous stomatitis. Adv Biomed Res. 2014;3:246
45. Bao ZX, Yang XW, Shi J, et al. Serum zinc levels in 368 patients with oral mucosal diseases: a preliminary study. Med Oral Patol Oral Cir Bucal. 2016;21:e335–e340
46. Ozler GS. Zinc deficiency in patients with recurrent aphthous stomatitis: a pilot study. J Laryngol Otol. 2014;128:531–533
47. Ozturk P, Belge Kurutas E, Ataseven A. Copper/zinc and copper/selenium ratios, and oxidative stress as biochemical markers in recurrent aphthous stomatitis. J Trace Elem Med Biol. 2013;27:312–316
48. Savage NW, Seymour GJ, Kruger BJ. Expression of class I and class II major histocompatibility complex antigens on epithelial cells in recurrent aphthous stomatitis. J Oral Pathol. 1986;15:191–195
49. Gunhan O, Gunal A, Avci A, et al. Oral epithelial barrier function and the role of nuclear factor kappa-beta pathway in the pathogenesis of aphthous ulceration. Turk J Gastroenterol. 2013;24:508–514
50. Kalpana R, Thubashini M, Sundharam BS. Detection of salivary interleukin-2 in recurrent aphthous stomatitis. J Oral Maxillofac Pathol. 2014;18:361–364
51. Shilpashree HS, Sarapur S. Evaluation of salivary immunoglobulin a levels in tobacco smokers and patients with recurrent aphthous ulcers. J Nat Sci Biol Med. 2012;3:177–181
52. Mohamed S, Janakiram C. Recurrent aphthous ulcers among tobacco users-hospital based study. J Clin Diagn Res. 2014;8:Zc64–lc66
53. Almoznino G, Zini A, Mizrahi Y, et al. Elevated serum IgE in recurrent aphthous stomatitis and associations with disease characteristics. Oral Dis. 2014;20:386–394
54. Cicek D, Dagli AF, Aydin S, et al. Does hepcidin play a role in the pathogenesis of aphthae in Behcet’s disease and recurrent aphthous stomatitis? J Eur Acad Dermatol Venereol. 2014;28:1500–1506
55. Gallo CB, Borra RC, Rodini CO, et al. CC chemokine ligand 3 and receptors 1 and 5 gene expression in recurrent aphthous stomatitis. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;114:93–98
56. Pinto Rodrigues JF, Fujiyama Oshima CT, Ribeiro Paiotti AP, et al. Expression of apoptosis regulatory proteins p53, bcl-2 and bax in recurrent aphthous ulceration. J Eur Acad Dermatol Venereol. 2012;26:1247–1251
57. Ma R, Chen H, Zhou T, et al. Effect of bedtime on recurrent aphthous stomatitis in college students. Oral Surg Oral Med Oral Pathol Oral Radiol. 2015;119:196–201
58. Zadik Y, Levin L, Shmuly T, et al. Recurrent aphthous stomatitis: stress, trait anger and anxiety of patients. J Calif Dent Assoc. 2012;40:879–883
59. Keenan AV, Spivakovksy S. Stress associated with onset of recurrent aphthous stomatitis. Evid Based Dent. 2013;14:25
60. Al-Omiri MK, Karasneh J, Alhijawi MM, et al. Recurrent aphthous stomatitis (RAS): a preliminary within-subject study of quality of life, oral health impacts and personality profiles. J Oral Pathol Med. 2015;44:278–283
61. Karthikeyan P, Aswath N. Stress as an etiologic co-factor in recurrent aphthous ulcers and oral lichen planus. J Oral Sci. 2016;58:237–240
62. Nadendla LK, Meduri V, Paramkusam G, et al. Relationship of salivary cortisol and anxiety in recurrent aphthous stomatitis. Indian J Endocrinol Metab. 2015;19:56–59
63. Gupta I, Shetti A, Keluskar V, et al. Assessment of serum enzymatic antioxidant levels in patients with recurrent aphthous stomatitis: a case control study. Enzyme Res. 2014;2014:340819
64. Akoglu G, Metin A, Kilinc F, et al. Total serum oxidant/antioxidant status and arylesterase activity in recurrent aphthous stomatitis. Ann Dermatol. 2013;25:273–277
65. Babaee N, Hosseinkazemi H, Pouramir M, et al. Salivary oxidant/antioxidant status and hematological parameters in patients with recurrent aphthous stomatitis. Caspian J Intern Med. 2016;7:13–18
66. Bagan J, Saez G, Tormos C, et al. Oxidative stress and recurrent aphthous stomatitis. Clin Oral Investig. 2014;18:1919–1923
67. Zhang Z, Li S, Fang H. Enzymatic antioxidants status in patients with recurrent aphthous stomatitis. J Oral Pathol Med. 2017;46:817–820
68. Takci Z, Karadag AS, Ertugrul DT, et al. Elevated insulin resistance in patients with recurrent aphthous stomatitis. Clin Oral Investig. 2015;19:1193–1197
69. Ekiz O, Balta I, Sen BB, et al. Mean platelet volume in recurrent aphthous stomatitis and Behçet disease. Angiology. 2014;65:161–165
70. Terzi S, Dursun E, Ozgur A, et al. Status of neutrophils, lymphocytes and platelets in patients with recurrent aphthous stomatitis: a retrospective study. Iran J Otorhinolaryngol. 2016;28:421–424
71. Dan S, Jinwei Z, Qiang Z, et al. Exploring the molecular mechanism and biomarker of recurrent aphthous stomatitis based on gene expression microarray. Clin Lab. 2017;63:249–253
72. Karakus N, Yigit S, Kalkan G, et al. High association of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism with recurrent aphthous stomatitis. Arch Dermatol Res. 2013;305:513–517
73. Karasneh JA, Bani-Hani ME, Alkhateeb AM, et al. Association of MMP but not TIMP-1 gene polymorphisms with recurrent aphthous stomatitis. Oral Dis. 2014;20:693–699
74. Karakus N, Yigit S, Rustemoglu A, et al. Effects of interleukin (IL)-6 gene polymorphisms on recurrent aphthous stomatitis. Arch Dermatol Res. 2014;306:173–180
75. Najafi S, Yousefi H, Mohammadzadeh M, et al. Association study of interleukin-1 family and interleukin-6 gene single nucleotide polymorphisms in recurrent aphthous stomatitis. Int J Immunogenet. 2015;42:428–431
76. Najafi S, Firooze Moqadam I, Bidoki AZ, et al. Interleukin-10 gene polymorphisms in recurrent aphthous stomatitis. Immunol Invest. 2014;43:405–409
77. Karasneh J, Bani-Hani M, Alkhateeb A, et al. TLR2, TLR4 and CD86 gene polymorphisms in recurrent aphthous stomatitis. J Oral Pathol Med. 2015;44:857–863
78. Bidoki AZ, Harsini S, Sadr M, et al. NLRP3 gene polymorphisms in Iranian patients with recurrent aphthous stomatitis. J Oral Pathol Med. 2016;45:136–140
79. Samimi M, Lauferon F, Huttenberger B, et al. [Persistent aphthous mouth ulcers associated with tocilizumab: two cases]. Ann Dermatol Venereol. 2013;140:120–124
80. Sheikh-Taha M, Ghosn S, Zeitoun A. Oral aphthous ulcers associated with orlistat. Am J Health Syst Pharm. 2012;69:1462–1464
81. Biasotto M, Perinetti G, Serroni I, et al. Oral manifestation upon short time cocaine abuse. A case report. Minerva Stomatol. 2012;61:295–298
82. Schwartz BG, Rezkalla S, Kloner RA. Cardiovascular effects of cocaine. Circulation. 2010;122:2558–2569
83. Sereflican M, Sereflican B, Dagistan E, et al. Subclinical atherosclerosis in patients with recurrent aphthous stomatitis. Oral Dis. 2016;22:573–577
84. Demmer RT, Squillaro A, Papapanou PN, et al. Periodontal infection, systemic inflammation, and insulin resistance: results from the continuous National Health and Nutrition Examination Survey (NHANES) 1999–2004. Diabetes Care. 2012;35:2235–2242
85. Kim SK, Choe JY, Park SH, et al. Increased insulin resistance and serum resistin in Korean patients with Behcet’s disease. Arch Med Res. 2010;41:269–274
86. Cakir E. Is there any relationship between recurrent oral aphthous stomatitis and prediabetes? Med Hypotheses. 2013;81:512–513
87. Present SI, Check JH. Hypofunction of the sympathetic nervous system as a possible etiologic cause of recurrent aphthous stomatitis. Compend Contin Educ Dent. 2016;37:381–385
88. Liu C, Zhou Z, Liu G, et al. Efficacy and safety of dexamethasone ointment on recurrent aphthous ulceration. Am J Med. 2012;125:292–301
89. Coudert AE, Ostertag A, Baaroun V, et al. Phase III, randomized, double-blind, placebo-controlled trial of topical 2 % lidocaine for the prevention and treatment of oral mucosal pain in children. Clin Oral Investig. 2014;18:1189–1194
90. Vijayabala GS, Kalappanavar AN, Annigeri RG, et al. Single application of topical doxycycline hyclate in the management of recurrent aphthous stomatitis. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;116:440–446
91. Soylu Ozler G. Silver nitrate cauterization: a treatment option for aphthous stomatitis. J Craniomaxillofac Surg. 2014;42:e281–e283
92. El-Haddad SA, Asiri FY, Al-Qahtani HH, et al. Efficacy of honey in comparison to topical corticosteroid for treatment of recurrent minor aphthous ulceration: a randomized, blind, controlled, parallel, double-center clinical trial. Quintessence Int. 2014;45:691–701
93. Saikaly SK, Khachemoune A. Honey and wound healing: an update. Am J Clin Dermatol. 2017;18:237–251
94. Deshmukh RA, Bagewadi AS. Comparison of effectiveness of curcumin with triamcinolone acetonide in the gel form in treatment of minor recurrent aphthous stomatitis: a randomized clinical trial. Int J Pharm Investig. 2014;4:138–141
95. Danek Z, Gajdziok J, Dolezel P, et al. Buccal films as a dressing for the treatment of aphthous lesions. J Oral Pathol Med. 2017;46:301–306
96. Deen K, Curchin C, Wu J. Successful treatment of recurrent aphthous ulcers with nicotine lozenges in a lifelong non-smoker. Australas J Dermatol. 2015;56:143–144
97. Motamedi MR, Golestannejad Z. Use of pure nicotine for the treatment of aphthous ulcers. Dent Res J (Isfahan). 2015;12:197–198
98. Subramanyam RV. Occurrence of recurrent aphthous stomatitis only on lining mucosa and its relationship to smoking-a possible hypothesis. Med Hypotheses. 2011;77:185–187
99. Bhat S, Sujatha D. A clinical evaluation of 5% amlexanox oral paste in the treatment of minor recurrent aphthous ulcers and comparison with the placebo paste: a randomized, vehicle controlled, parallel, single center clinical trial. Indian J Dent Res. 2013;24:593–598
100. Khademi H, Iranmanesh P, Moeini A. Evaluation of the effectiveness of the iralvex gel on the recurrent aphthous stomatitis management. Int Sch Res Notices. 2014;2014:175378
101. Mansour G, Ouda S, Shaker A, et al. Clinical efficacy of new aloe vera- and myrrh-based oral mucoadhesive gels in the management of minor recurrent aphthous stomatitis: a randomized, double-blind, vehicle-controlled study. J Oral Pathol Med. 2014;43:405–409
102. Jiang XW, Zhang Y, Zhang H, et al. Double-blind, randomized, controlled clinical trial of the effects of diosmectite and basic fibroblast growth factor paste on the treatment of minor recurrent aphthous stomatitis. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;116:570–575
103. Babaee N, Zabihi E, Mohseni S, et al. Evaluation of the therapeutic effects of aloe vera gel on minor recurrent aphthous stomatitis. Dent Res J (Isfahan). 2012;9:381–385
104. Liu HL, Chiu SC. The effectiveness of vitamin B12 for relieving pain in aphthous ulcers: a randomized, double-blind, placebo-controlled trial. Pain Manag Nurs. 2015;16:182–187
105. Al-Omiri MK, Alhijawi M, AlZarea BK, et al. Ozone treatment of recurrent aphthous stomatitis: a double blinded study. Sci Rep. 2016;6:27772
106. Ofluoglu D, Ergun S, Warnakulasuriya S, et al. An evaluation of the efficacy of a topical gel with triester glycerol oxide (TGO) in the treatment of minor recurrent aphthous stomatitis in a Turkish cohort: a randomized, double-blind, placebo-controlled clinical trial. Med Oral Patol Oral Cir Bucal. 2017;22:e159–e166
107. Yarom N, Zelig K, Epstein JB, et al. The efficacy of minocycline mouth rinses on the symptoms associated with recurrent aphthous stomatitis: a randomized, double-blind, crossover study assessing different doses of oral rinse. Oral Surg Oral Med Oral Pathol Oral Radiol. 2017;123:675–679
108. Mehdipour M, Taghavi Zenooz A, Sohrabi A, et al. A comparison of the effect of triamcinolone ointment and mouthwash with or without zinc on the healing process of aphthous stomatitis lesions. J Dent Res Dent Clin Dent Prospects. 2016;10:87–91
109. Soylu Ozler G, Okuyucu S, Akoglu E. The efficacy of sucralfate and chlorhexidine as an oral rinse in patients with recurrent aphthous stomatitis. Adv Med. 2014;2014:986203
110. Seyyedi SA, Sanatkhani M, Pakfetrat A, et al. The therapeutic effects of chamomilla tincture mouthwash on oral aphthae: a randomized clinical trial. J Clin Exp Dent. 2014;6:e535–e538
111. Lalla RV, Choquette LE, Feinn RS, et al. Multivitamin therapy for recurrent aphthous stomatitis: a randomized, double-masked, placebo-controlled trial. J Am Dent Assoc. 2012;143:370–376
112. Spivakovsky S, Keenan AV. No effect seen for multivitamin therapy on recurrent aphthous stomatitis patients. Evid Based Dent. 2013;14:26
113. El Khouli AM, El-Gendy EA. Efficacy of omega-3 in treatment of recurrent aphthous stomatitis and improvement of quality of life: a randomized, double-blind, placebo-controlled study. Oral Surg Oral Med Oral Pathol Oral Radiol. 2014;117:191–196
114. Nosratzehi T, Akar A. Efficacy of omega-3 in treatment of recurrent aphthous stomatitis: a randomised, double-blind, placebo-controlled study. Chin J Dent Res. 2016;19:159–164
115. Ghaffari S, Barikbin L, Ashnagar S, et al. Enoxaparin for the treatment of recurrent aphthous stomatitis: a pilot exploratory clinical trial. Minverva Stomatol. 2013;62:281–287
116. Fromer MJ. FDA introduces new phase 0 for clinical trials: some enthusiastic, some skeptical. Oncol Times. 2006;28:18–19
117. Sharda N, Shashikanth MC, Kant P, et al. Levamisole and low-dose prednisolone in the treatment of reccurent aphthous stomatitis. J Oral Pathol Med. 2014;43:309–316
118. Facon T, Dimopoulos MA, Dispenzieri A, et al. Final analysis of survival outcomes in the randomized phase 3 FIRST trial. Blood. 2017 [Nov 17]. DOI:10.1182/blood-2017-07-795047
119. Kalampokis I, Rabinovich CE. Successful management of refractory pediatric-onset complex aphthosis with lenalidomide. J Clin Rheumatol. 2014;20:221–223
120. Brocklehurst P, Tickle M, Glenny AM, et al. Systemic interventions for recurrent aphthous stomatitis (mouth ulcers). Cochrane Database Syst Rev. 2012;12:CD005411
121. Belenguer-Guallar I, Jimenez-Soriano Y, Claramunt-Lozano A. Treatment of recurrent aphthous stomatitis. A literature review. J Clin Exp Dent. 2014;6:e168–e174
122. Aggarwal H, Singh MP, Nahar P, et al. Efficacy of low-level laser therapy in treatment of recurrent aphthous ulcers - a sham controlled, split mouth follow up study. J Clin Diagn Res. 2014;8:218–221
123. Prasad RS, Pai A. Assessment of immediate pain relief with laser treatment in recurrent aphthous stomatitis. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;116:189–193
124. Yilmaz HG, Albaba MR, Caygur A, et al. Treatment of recurrent aphthous stomatitis with Er,Cr:YSGG laser irradiation: a randomized controlled split mouth clinical study. J Photochem Photobiol B. 2017;170:1–5
125. Han M, Fang H, Li QL, et al. Effectiveness of laser therapy in the management of recurrent aphthous stomatitis: a systematic review. Scientifica (Cairo). 2016;2016:9062430
126. Najeeb S, Khurshid Z, Zohaib S, et al. Management of recurrent aphthous ulcers using low-level lasers: a systematic review. Medicina (Kaunas). 2016;52:263–268
127. Suter VGA, Sjolund S, Bornstein MM. Effect of laser on pain relief and wound healing of recurrent aphthous stomatitis: a systematic review. Lasers Med Sci. 2017;32:953–963
128. Albrektson M, Hedstrom L, Bergh H. Recurrent aphthous stomatitis and pain management with low-level laser therapy: a randomized controlled trial. Oral Surg Oral Med Oral Pathol Oral Radiol. 2014;117:590–594
129. Zand N, Fateh M, Ataie-Fashtami L, et al. Promoting wound healing in minor recurrent aphthous stomatitis by non-thermal, non-ablative CO(2) laser therapy: a pilot study. Photomed Laser Surg. 2012;30:719–723
130. Jijin MJ, Rakaraddi M, Pai J, et al. Low-level laser therapy versus 5% amlexanox: a comparison of treatment effects in a cohort of patients with minor aphthous ulcers. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016;121:269–273
131. Lalabonova H, Daskalov H. Clinical assessment of the therapeutic effect of low-level laser therapy on chronic recurrent aphthous stomatitis. Biotechnol Biotechnol Equip. 2014;28:929–933
132. University of Copenhagen. Characterisation of the salivary and faecal microbiome in patients with recurrent aphthous stomatitis before and after treatment with probiotics [ClinicalTrials.gov identifier: NCT02976922] US National institutes of health. January 2016. ClinicalTrials.gov Internet. Available from: https://clinicaltrials.gov/
133. University of Tokushima. Effects of a night guard on aphthous stomatitis [ClinicalTrials.gov Identifier: NCT02890524]. US National institutes of health. July 2014. ClinicalTrials.gov Internet. Available from: https://clinicaltrials.gov/
134. Cairo University. Clinical evaluation of topical coenzyme Q10 in management of oral aphthous ulcer [ClinicalTrials.gov Identifier: NCT03213769] US National Institutes of Health. July 2017. ClinicalTrials.gov Internet. Available from: https://clinicaltrials.gov/
135. ®: a randomized, double blind and placebo-controlled trial [ClinicalTrials.gov Identifier: NCT02789605]. US National institutes of health. June 2016. ClinicalTrials.gov Internet. Available from: https://clinicaltrials.gov/
136. Altenburg A, El-Haj N, Micheli C, et al. The treatment of chronic recurrent oral aphthous ulcers. Dtsch Arztebl Int. 2014;111:665–673