Review Article of American Journal of Dermatological Research and Reviews
Management of Oro-Cutaneous Manifestations in Behçet disease and Recurrent Oral Aphthosis, review article
Khalifa E. Sharquie1, Fatema A. Al-Jaralla2
1Department of Dermatology, College of Medicine, University of Baghdad. Iraqi and Arab Board for Dermatology & Venereology, Baghdad Teaching Hospital, Medical City, Baghdad, Iraq. 2Department of Dermatology, College of Medicine, University of Baghdad, Baghdad, Iraq.
Recurrent oral aphthosis is a major health problem affecting 20% of population. Its pathogenesis is not well elucidated, however, it’s considered as part of major criteria of Behçet disease. Many therapies advised to manage these ulcerations in both diseases and most of them are symptomatic, however, in the last decades; some of them have shown therapeutic as well as prophylactic roles. Herein, we review the different aspects of these therapies with emphasis on Iraqi experience.
Keywords: Recurrent oral aphthosis, Behçet disease, Management
How to cite this article:
Khalifa E. Sharquie, Fatema A. Al-Jaralla. Management of Oro-Cutaneous Manifestations in Behçet disease and Recurrent Oral Aphthosis, review article.American Journal of Dermatological Research and Reviews, 2020, 3:20. DOI: 10.28933/ajodrr-2020-02-1205
1. Davatchi F, Chams-Davatchi C, Shams H, Shahram F, Nadji A, Akhlaghi M, et al. Behcet’s disease: epidemiology, clinical manifestations, and diagnosis. Expert Rev Clin Immunol. 2017 Jan. 13 (1): 57-65.
2. Behcet H. Uber rezidiverendeaphthose durch ein virus verursachte Geschwure am Mund, am Auge, und an den Genitalien. Dermatol Wochenschr. 1937. 105: 1152-7.
3. Krause I, Yankevich A, Fraser A, Rosner I, Mader R, Zisman D, et al. Prevalence and clinical aspects of Behcet’s disease in the north of Israel. Clin Rheumatol. 2007 Apr. 26(4): 555-60.
4. Al-Rawi, Z. S., & Neda, A. H. (n.d.). Prevalence of Behçet’s Disease among Iraqis. Adamantiades Behçet’s Disease, 37–41. doi:10.1007/0-306-48382-3-6.
5. Al-Araji A1, Sharquie K, Al-Rawi Z. Prevalence and patterns of neurological involvement in Behcet’s disease: a prospective study from Iraq. J Neurol Neurosurg Psychiatry. 2003 May;74(5): 608-13
6. Zeidan MJ, Saadoun D, Garrido M, Klatzmann D, Six A, Cacoub P. Behçet’s disease physiopathology: a contemporary review. Auto Immun Highlights. 2016; 7: 4–4.
7. Davatchi F, Sadeghi Abdollahi B, Chams-Davatchi C, Shahram F, Ghodsi Z, Nadji A, et al. Impact of the positive pathergy test on the performance of classification/diagnosis criteria for Behcet’s disease. Mod Rheumatol. 2013; 23: 125–132.
8. Alpsoy E. Behçet’s disease: A comprehensive review with a focus on epidemiology, etiology and clinical features, and management of mucocutaneous lesions. J Dermatol. 2016; 43: 620–632.
9. Al-Hassan AA , Al-Naseri SA , Al-Ghurabi BH , Al-Faham M , Al-Nnema AJ ,Shereef SM. Distribution of HLA-Antigens Class I and II in Iraqi Arab population. IJGE. 2005; 1:92-99.
10. Al-Rawi ZS, Sharquie KE, Khalifa SJ, Al-Hadithi FM, Munir JJ. Behçet’s disease in Iraqi patients. Ann Rheum Dis. 1986; 45: 987-90.
11. Akman A, Kacaroglu H, Donmez L, Bacanli A, Alpsoy E. Relationship between periodontal findings and Behcet’s disease: a controlled study. J Clin Periodontol. 2007; 34: 485–491.
12. Eglin RP, Lehner T, Subak-Sharpe JH. Detection of RNA complementary to herpes-simplex virus in mononuclear cells from patients with Behcet’s syndrome and recurrent oral ulcers. Lancet. 1982; 2: 1356–1361.
13. Cho SB, Cho S, Bang D. New insights in the clinical understanding of Behcet’s disease. Yonsei Med J. 2012; 53: 35–42.
14. Emmi L, Brugnolo F, Salvati G, et al. Immunopathological aspects of Behçet’s disease. Clin Exp Rheumatol. 1995; 13(6): 687-91.
15. Kaneko S, Suzuki N, Yamashita N, Nagafuchi H, Nakajima T, Wakisaka S, et al. Characterization of T cells specific for an epitope of human 60-kD heat shock protein (hsp) in patients with Behcet’s disease (BD) in Japan. Clin Exp Immunol. 1997 ; 108(2): 204-12.
16. Hasan A, Fortune F, Wilson A, Warr K, Shinnick T, Mizushima Y, et al. Role of gamma delta T cells in pathogenesis and diagnosis of Behcet’s disease. Lancet. 1996 ; 347(9004): 789-94.
17. Nanke Y,Yago T,KotakeS.The role of Th17 cells in the pathogenesis of Behçet’s disease. J Clin Med. 2017; 6(7):E74.
18. Hallett MB, Lloyds D. Neutrophil priming: the cellular signals that say ‘amber’ but not ‘green’. Immunol Today. 1995; 16(6): 264-8.
19. Sakane T, Takeno M, Suzuki N, Inaba G. Behçet’s disease. N Engl J Med. 1999; 21. 341(17): 1284-91.
20. Sakane T, Suzuki N, Takeno M. Innate and acquired immunity in Behçet’s disease. 8th International Congress on Behçet’s Disease. Reggio Emilia, Italy, 7-9 October 1998. Program and Abstracts: 56.
21. Takeno M, Shimayano Y, Suzuki N, Sakane T. Prolonged survival of autoprimed neutrophils from patients with Behçet ’s disease.: 8th International Congress on Behçet’s Disease. Reggio Emilia, Italy, 7-9 October 1998. Program and Abstracts: 57.
22. Becatti M, Emmi G, Bettiol A, Silvestri E, Di Scala G, Taddei N, et al. Behçet’s syndrome as a tool to dissect the mechanisms of thrombo-inflammation: clinical and pathogenetic aspects. Clin Exp Immunol. 2018 Nov 25
23. Kiraz S, Ertenli I, Oztürk MA, et al. Pathological haemostasis and “prothrombotic state” in Behçet’s disease. Thromb Res. 2002; 105(2):125-33.
24. Al-Araji A.H.. ‘History, Epidemiology, and Diagnostic (Classification) Criteria’, in Al-Rawi Z, Sharquie KE, Al-Araji A.H (ed.) Behçet’s disease, Clinical aspects. Baghdad: Roche pharmaceutical, 2002; p4-6.
25. 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(3): 338-47.
26. Hatemi G, Silman A, Bang D, et al. EULAR recommendations for the management of Behçet disease. Ann Rheum Dis. 2008 Dec. 67(12): 1656-62.
27. E. Alpsoy and A. Akman, “Behçet’s disease: an algorithmic approach to its treatment”. Archives of Dermatological Research. 2009; 301: 693–702.
28. Khandwala, R. G. Van Inwegen, and M. C. Alfano, “5% amlexanox oral paste, a new treatment for recurrent minor aphthous ulcers: I. Clinical demonstration of acceleration of healing and resolution of pain,” Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics, 1997; 83: 222–230.
29. Tanaka, T. Matsuda, Y. Yukinari, H. Yamada, Y. Ichikawa, T. Sakane et al.The beneficial effect of rebamipide on recurrent oral aphthous ulcers in Behcet’s disease,” in Behcet’s Disease, M. Hamza, Ed. 1997; 477–480,
30. E. Alpsoy, H. Er, C. Durusoy, and E. Yilmaz. The use of sucralfate suspension in the treatment of oral and genital ulceration of Behcet disease: a randomized, placebo-controlled, double-blind study. Archives of Dermatology. 1999; 135: 529–532.
31. M. A. G. Edres, C. Scully, and M. Gelbier. Use of proprietary agents to relieve recurrent aphthous stomatitis. British Dental Journal, 1997;182: 144–146.
32. E. Alpsoy, C. Zouboulis, and G. E. Ehrlich. Mucocutaneous lesions of Behçet’s disease .Yonsei Medical Journal. 2007; 48: 573–585.
33. N. Alli, G. Karakayali, I. Kahraman, and F. Artuz, Local intralesional therapy with rhGM-CSF for a large genital ulcer in Behcet’s disease. British Journal of Dermatology.1997; 136: 639–640.
34. V. G. Kaklamani and P. G. Kaklamanis. Treatment of behçet’s disease—an update. Seminars in Arthritis and Rheumatism, 2001;30: 299–312.
35. H. Yazici, S. Yurdakul, and V. Hamuryudan. Behçet disease. Current Opinion in Rheumatology. 2001;13: 18–22.
36. J. M. M. Gardner-Medwin, N. J. Smith, and R. J. Powell. Clinical experience with thalidomide in the management of severe oral and genital ulceration in conditions such as Behcet’s disease: use of neurophysiological studies to detect thalidomide neuropathy. Annals of the Rheumatic Diseases.1994; 53: 828–832.
37. P. De Merieux, L. E. Spitler, and H. E. Paulus.Treatment of Behcet’s syndrome with levamisole. Arthritis and Rheumatism.1981; 24: 64–70.
38. Fresko, S. Yurdakul, V. Hamuryudan et al. The management of Behcet’s syndrome. Annales de Medecine Interne. 1999;150: 576–581.
39. Aktulga E, Altaç M, Müftüoglu A, Ozyazgan Y, Pazarli H. A double blind study of colchicine in Behçet’s disease. Haematologica. 1980; 65: 399-402.
40. Yurdakul S, Mat C, Tüzün Y, Ozyazgan Y, Hamuryudan V. A double-blind trial of colchicine in Behçet’s syndrome. Arthritis Rheum. 2001; 44: 2686-2692.
41. Gürler A, Boyvat A, Türsen U. Clinical manifestations of Behçet’s disease: an analysis of 2147 patients. Yonsei Med J. 1997; 38: 423-427.
42. Evereklioglu C. Current concepts in the etiology and treatment of Behçet disease. Surv Ophthalmol. 2005; 50: 297-350.
43. D. BenEzra, E. Cohen, T. Chajek et al. Evaluation of conventional therapy versus cyclosporine A in Behcet’s syndrome. Transplantation Proceedings.1988; 20:136–143.
44. H. Yazici, H. Pazarli, C. G. Barnes et al. A controlled trial OF azathioprine in Behçet’s syndrome. The New England Journal of Medicine.1999; 322:281–285.
45. L. Jorizzo, W. L. White, C. M. Wise, M. D. Zanolli, and E. F. Sherertz Low-dose weekly methotrexate for unusual neutrophilic vascular reactions: cutaneous polyarteritis nodosa and Behcet’s disease. Journal of the American Academy of Dermatology. 1991; 24: 973–978.
46. P. Neri, C. Mariotti, L. Cimino, L. Mercanti, and A. Giovannini. Long-term control of cystoid macular oedema in noninfectious uveitis with Mycophenolate Mofetil. International Ophthalmology. 2009; 29:127–133.
47. V. Hamuryudan, C. Mat, S. Saip et al. Thalidomide in the treatment of the mucocutaneous lesions of the Behcet syndrome: a randomized, double-blind, placebo-controlled trial. Annals of Internal Medicine. 1998;128: 443–450.
48. B. De Wazières, H. Gil, N. Magy, S. Berthier, D. A. Vuitton, and J. L. Dupond. Treatment of recurrent oro-genital ulceration with low dose of thalidomide. Pilot study in 17 patients. La Revue de Médecine Interne. 1999; 20: 567–570.
49. M. M. Gardner-Medwin, N. J. Smith, and R. J. Powell. Clinical experience with thalidomide in the management of severe oral and genital ulceration in conditions such as Behcet’s disease: use of neurophysiological studies to detect thalidomide neuropathy. Annals of the Rheumatic Diseases.1994; 53:828–832.
50. T. Saylan and I. Saltik. Thalidomide in the treatment of Behcet’s syndrome. Archives of Dermatology. 1982; 118: 536.
51. D. M. Hamza. Treatment of Behçet’s disease with thalidomide. Clinical Rheumatology. 1986; 5: 365–371.
52. E. Alpsoy, C. Durusoy, E. Yilmaz et al. Interferon alfa-2a in the treatment of Behçet disease: a randomized placebo-controlled and double-blind study. Archives of Dermatology. 2002; 138: 467–471.
53. Olivieri, L. Latanza, S. Siringo, G. Peruz, and V. Di Iorio. Successful treatment of severe Behçet’s disease with infliximab in an Italian olympic athlete. The Journal of Rheumatology. 2008; 35: 930–932.
54. Olivieri, A. Padula, P. Leccese, S. D’Angelo, and V. Giasi. Long-lasting remission of severe Behçet’s disease after the end of infliximab therapy. Journal of Rheumatology. 2009; 36: 855.
55. Melikoglu, I. Fresko, C. Mat et al. Short-term trial of etanercept in Behçet’s disease: a double blind, placebo controlled study. Journal of Rheumatology2005; 32:98–105.
56. Cantarini, G. Lopalco, F. Caso et al. Effectiveness and tuberculosis-related safety profile of interleukin-1 blocking agents in the management of Behçet’s disease. Autoimmunity Reviews 2015;14:1–9.
57. Gül, I. Tugal-Tutkun, C. A. Dinarello et al. Interleukin-1β-regulating antibody XOMA 052 (gevokizumab) in the treatment of acute exacerbations of resistant uveitis of Behçet’s disease: an open-label pilot study. Annals of the Rheumatic Diseases 2012; 71: 563–566.
58. G. Mumcu, T. Ergun, Y. Elbir et al. Clinical and immunological effects of azithromycin in Behçet’s disease. Journal of Oral Pathology and Medicine 2005; 34: 13–16.
59. G. Mumcu, N. Inanç, F. T. Özdemir et al. Effects of azithromycin on intracellular cytokine responses and mucocutaneous manifestations in Behçet’s disease. International Journal of Dermatology 2013; 52,: 1561–1566.
60. F. Kaneko, N. Oyama, and A. Nishibu. Streptococcal infection in the pathogenesis of Behcet’s disease and clinical effects of minocycline on the disease symptoms. Yonsei Medical Journal 1997; 38: 444–454.
61. T. Matsuda, S. Ohno, S. Hirohata 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 in R and D 2003; 4: 19–28.
62. G. Hatemi, M. Melikoglu, R. Tunc et al. Apremilast for the treatment of Behçet’s syndrome: a phase II randomized, placebo-controlled, double-blind study. Arthritis & Rheumatism 2013; 65:322.
63. C. M. Lockwood, G. Hale, H. Waldman, and D. R. W. Jayne. Remission induction in Behçet’s disease following lymphocyte depletion by the anti-CD52 antibody CAMPATH 1-H. Rheumatology 2003; 42: 1539–1544.
64. L. Tasli, C. Mat, C. De Simone, and H. Yazici. Lactobacilli lozenges in the management of oral ulcers of Behçet’s syndrome. Clinical and Experimental Rheumatology 2006; 24:83–86.
65. International Study Group for Behçet’s disease:Criteria for diagnosis of Behçet’s disease, Lancet; 1990. 335: 1078–1080.
66. Sharquie K. Suppression of Behçet’s disease with dapsone. Br J Dermatol 1984; 110: 493–494.
67. Sharquie, K.E., Najim, R.A. and Abu-Raghif, A.R. Dapsone in Behcet’s Disease: A Double-Blind, Placebo-Controlled, Cross-Over Study. The Journal of Dermatology 2002; 29:267-279.
68. Sharquie K. Treatment of Behçet’s disease with dapsone, Abstract-9th International Conference on Behçet’s disease. Yonsei Med J 2000; 41: 48.
69. Stendahl O. The inhibition of polymorphonu- clear leukocyte cytotoxicity by dapsone: A possi- ble mechanism in the treatment of dermatitis herpetiformis. J Clin Invest 1978; 62: 214.
70. Miyachi Y, Niwa Y. Effect of potassium iodide, colchicine and dapsone on generation of ploy- morphonuclear leukocyte-derived oxygen inter- mediates. Br J Dermatol 1982; 107: 209.
71. Maloff BL. Dapsone inhibited LTB4 binding and bioresponse at the cellular and physiologic levels. Eur J Pharmacol 1988; 158: 85.
72. Anderson R. In vitro and in vivo effects of dap- sone on neutrophil and lymphocyte functions in normal individuals and patients with lepromatous leprosy. Antimicrob Agents 1981; 19: 490–495.
73. Coleman MD. Studies of the inhibitory effects of analogous of dapsone on neutrophil function in vitro. J Pharm Pharmacol 1997; 49: 53.
74. Sharquie KE1, Najim RA, Al-Dori WS, Al-Hayani RK. Oral zinc sulfate in the treatment of Behcet’s disease: a double blind cross-over study. J Dermatol 2006; 33(8): 541-6.
75. Sharquie KE1, Helmi RM, Noiami AA, Al-Hayani RK, Kadhom MA The therapeutic role of isotretinoin in the management of Behçet’s disease: a single-blinded, controlled therapeutic study. J Drugs Dermatol. 2013 Apr; 12(4): e68-73.
76. Sharquie KE, Noaimi AA, Abdulla HI, Hussein SA. Oral Acetretin Versus Oral Zinc Gluconate as a Comparative Cross-over Therapeutic Study in Treatment of Behçet disease. A thesis Submitted to the Council of the College of Dentistry Al-Mustansiryia University in Partial Fulfillment of the Requirement for the Degree of Master of Science in Oral Medicine. 2014.
77. Al-Waiz MM1, Sharquie KE, A-Qaissi MH, Hayani RK. Colchicine and benzathine penicillin in the treatment of Behçet disease: a case comparative study. Dermatol Online J. 2005; 11(3): 3.
78. Insel PA. Analgesic-Antipyretic and Anti-inflammatory Agents and Drugs employed in the Treatment of Gout:colchicine. In: Googman & GilmanÕs. The Pharmacological Basis of Therapetics. 9th edition. The Mc Graw- Hill Companies, 1996. CD-ROM.
79. Isogai E, Isogai H, Yoshikaea K, Microbial Ecology of oral flora in BD. 5th International conference on BD(abstract) 1989.
80. Jurge S, Kuffer R, Scully C, Porter SR. Recurrent aphthous stomatitis. Oral Dis. 2006; 12: 1–21.
81. Andrews diseases of the skin, Clinical dermatology. Philadelphia. WB Saundres Company. 12th Ed.2016; 34: 803-12.
82. Kocyigit a, Dogan r, et al.total antioxidant status and oxidativestress in recurrent aphthous stomatitis.int J Dermatol. 2015; 55: 130–135.
83. Hay KD, Reade PC. The use of an elimination diet in the treatment of recurrent aphthous ulceration of the oral cavity. Oral Surg 1984; 57: 504–7.
84. Quijano D, Rodríguez M. Topical corticosteroids in recurrent aphthous stomatitis. Systematic review. Acta Otorrinolaringol Esp. 2008; 59: 298–307.
85. Chavan, Mahesh, et al. Recurrent aphthous stomatitis: a review. Journal of Oral Pathology & Medicine 2012; 41: 577-583.
86. Gonzaliz Molos MA., Morales P., Rodriguez A. and Isabel I. R. Treatment of severe chronic oral erosive lesions with clobetasol propionate in aqueous solution. Oral surg. Oral med. Oral pathol. Oral radiol. Endod. 2002 Mar. 93(3): 264-70.
87. James WA and Richard LM. Aphthous ulcers, a review of literatures. Journal Am. Dent. Assoc. 1980; 101: 803-8.
88. Baccaglini L, Lalla RV, Bruce AJ, Sartori-Valinotti JC, Latortue MC, Carrozzo M. Urban legends:recurrent aphthous stomatitis. Oral Dis. 2011; 17: 755–70.
89. Skulason S, Holbrook WP, Kristmundsdottir T. Clinical assessment of the effect of a matrix metalloproteinase inhibitor on aphthous ulcers. Acta Odontol Scand. 2009; 67: 25–9.
90. Yilmaz S, Cimen KA. Familial Behçet’s disease. Rheumatol Int. 2010; 30: 1107–1109.
91. Hara A, Murata T, Ucmura R, Fukui K and Matsukwa H. Identification of connexin in human oral mucosa and therapeutic effect of Irsogladine maleate on aphthous stomatitis. J.gastroenerology. 1999; 3.
92. Shaare AB, Herlofson BB and Barkvoll. Triclosan reduces the incidence of recurrent of aphthous ulcers. J. Clinical periodontal. 1997; 23(8): 778-81.
93. Scully C, Porter S. Oral mucosal disease: Recurrent aphthous stomatitis. Br J Oral Maxillofac Surg.2008; 46: 198–206.
94. Sharquie KE, Najim RA. Honey as a new skin tissue preservative. J. Pan-Arab League Dermatol. 2001; 12: 49-54.
95. Sharquie KE. ‘Mucocutaneous Manifestations’, in Al-Rawi Z, Sharquie KE, Al-Araji A(ed.) Behçet’s disease, Clinical aspects. Baghdad: Roche pharmaceutical 2002.p14.
96. Sharquie KE, Al-Tammimy SM, Al-Mashhadani S, Hayani RK, Al-Nuaimy AA. Lactic acid 5 percent mouthwash is an effective mode of therapy in treatment of recurrent aphthous ulcerations. Dermatol Online J. 2006; 12(7): 2.
97. Sharquie KE, AL-mashhaddani, Al-Nuaimy AA, Hayani RK, Shubber SA. Lactic Acid 5% Mouthwash is an Effective Therapeutic and Prophylactic Agent in Treatment of Recurrent Aphthous Ulcer. The Iraq postgradute medical journal. 2012; 11: 3.
98. Sharquie K, Noaimi A, Latif. Treatment of Recurrent Aphthous Stomatitis by 100% Topical Pumpkin Seed Oil. Journal of Cosmetics, Dermatological Sciences and Applications 2017; 7:324-335.
99. Fridh G, Koch G. Effect of a mouth rinse containing aminoglycosidase and glucose oxidase on recurrent aphthous ulceration in children and adolescent. Swed. Dent. J. 1999; 23(2-3): 49-57.
100. Sylvia LB. Clinical evaluation of the use of low intensity Ultrasound in the treatment of recurrent aphthous stomatitis. Oral surg. Oral med. Oral path. Oral radiol Endod 1997; 83.
101. Babaee N, Mansourian A, Momen-Heravi F, Moghadamnia A, Momen-Beitollahi J. The efficacy of a paste containing Myrtus communis (Myrtle) in the management of recurrent aphthous stomatitis: a randomized controlled trial. Clin Oral Investig. 2010; 14: 65–70.
102. Hamdy AA, Ibrahem MA. Management of aphthous ulceration with topical quercetin:a randomized clinical trial. J Contemp Dent Pract. 2010; 11: 16.
103. Moghadamnia AA, Motallebnejad M, Khanian M. The efficacy of the bioadhesive patches containing licorice extract in the management of recurrent aphthous stomatitis. Phytother Res. 2009; 23: 246–50.
104. Hoseinpour H, Peel SA, Rakhshandeh H, Forouzanfar A, Taheri M, Rajabi O. Evaluation of Rosa damascena mouthwash in the treatment of recurrent aphthous stomatitis:a randomized, double-blinded, placebo-controlled clinical trial. Quintessence Int. 2011; 42: 483–91.
105. Noaimi A.A, Ahmed S. D, Treatment of Recurrent Aphthous Stomatitis by 100% Topical Sesame Seed oil. A Thesis Submitted to the Scientific Council of Dermatology and Venereology as a Partial Fulfillment of the Requirement for the Degree of Fellowship of Iraqi Board for Medical Specializations in Dermatology and Venereology, 2019.
106. Fontes V, Machet L, Huttenberger B, Lorette G, Vaillant L. Recurrent aphthous stomatitis: treatment with colchicine .An open trial of 54 cases. Ann Dermatol Venereol. 2002; 129: 1365–1369.
107. Altenburg A, Zouboulis CC. Current concepts in the treatment of recurrent aphthous stomatitis. Skin Therapy Lett. 2008; 13(7): 1–4.
108. Calabrese L, Fleischer AB. Thalidomide: current and potential clinical applications. Am J Med. 2000; 108: 487–495.
109. 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.
110. Brocklehurst P, Tickle M, Glenny AM, Lewis MA, Pemberton MN, Taylor J. Systemic interventions for recurrent aphthous stomatitis (mouth ulcers) Cochrane Database Syst Rev. 2012; 9: CD005411.
111. 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.
112. 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: 189–195.
113. 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: 734–738.
114. Sharquie KE. and Hayani RK. BCG as a new therapeutic and prophylactic agent in patients with severe oral aphthosis. Clinical Experimental Rhum. 2004; 22: 120.
115. Sun A., Chainy CP., Chioa PS., Wang JT., Liv BY. and Wu YC. Immunomodulation by levamisole in patients with recurrent aphthous stomatitis or oral lichen planus. Journal Oral Pathol Med. 1994. 23: 172-177.
116. Sharquie KE1, Helmi RM, Noiami AA, Al-Hayani RK, Kadhom MA. Therapeutic Role of Isotretinoin in the Management of Recurrent Aphthous Stomatitis (Single-Blind Controlled Therapeutic Study). Journal of Cosmetics, Dermatological Sciences and Applications. 2015; 5: 15-21.
117. Sand FL, Thomsen SF. Efficacy and safety of TNF-α inhibitors in refractory primary complex aphthosis: a patient series and overview of the literature. J Dermatolog Treat. 2013; 24(6): 444-6.