E-IJD® - SPECIAL ARTICLE
|Year : 2022 | Volume
| Issue : 6 | Page : 834
|Recurrent aphthous stomatitis: An enigmatic entity and sign of systemic disease
Marcus L Elias, Mahnaz Fatahzadeh, Robert A Schwartz
Department of Dermatology and Pathology, Rutgers New Jersey Medical School, and Oral Medicine, Rutgers School of Dental Medicine, Newark, New Jersey, USA, India
|Date of Web Publication||23-Feb-2023|
Robert A Schwartz
Professor and Head Dermatology, Rutgers New Jersey Medical School, 185 South Orange Ave, Newark - 07103, NJ
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Recurrent aphthous stomatitis (RAS) is a common oral disease characterized by intermittent eruptions of painful oral ulcerations. Hippocrates first described aphthous stomatitis with the Greek word aphthi meaning “to inflame.” RAS affects 10–20% of the population with the incidence being the highest among young adults. The peak age of onset is between 10 and 19 years of age. It has three main forms of presentation. The most common being minor RAS, along with the major and herpetiform types. Many local and systemic factors are associated with RAS pathogenesis. The main concern with oral aphthae in many cases is local pain, which can be severe enough to interfere with eating, speaking, and swallowing. It is important to differentiate RAS from systemic diseases with aphthae—such as Behçet's syndrome and the newly-delineated, autoinflammatory PFAPA (periodic fever with aphthous stomatitis, pharyngitis, and adenitis) syndrome—as well as from other aphthous-like ulcerations like herpes simplex virus (HSV) or Coxsackie oral lesions. The management depends upon the clinical presentation and symptomatology—focusing on analgesic, antimicrobial, and immunomodulatory drugs.
Keywords: Aphthous stomatitis, aphthous ulcer, Behçet's disease, herpetiform ulcers, HIV, PFAPA (periodic fever with aphthous stomatitis, pharyngitis, and adenitis)
|How to cite this article:|
Elias ML, Fatahzadeh M, Schwartz RA. Recurrent aphthous stomatitis: An enigmatic entity and sign of systemic disease. Indian J Dermatol 2022;67:834
|How to cite this URL:|
Elias ML, Fatahzadeh M, Schwartz RA. Recurrent aphthous stomatitis: An enigmatic entity and sign of systemic disease. Indian J Dermatol [serial online] 2022 [cited 2023 Mar 31];67:834. Available from: https://www.e-ijd.org/text.asp?2022/67/6/834/370358
| Introduction|| |
Aphthous ulcers are small, shallow, non-contagious sores affecting oral mucous membranes, save for gingiva and hard palate. They are common, recurrent, and annoying. These aphthae must be distinguished from vesicular eruptions, which may create 'aphthous-like' ulcers following rupture. A recent study on patients with benign oral mucosal lesions reported that 13.7% suffered from RAS. Aphthous stomatitis typically occurs on the movable oral mucosa such as labial and buccal mucosa, soft palate, ventral tongue, and floor of the mouth. Aphthous stomatitis may be classified based upon symptomatology. The former Aphthous stomatitis is characterized by a mild clinical course of up to four recurrences of one or more ulcers per year with each episode lasting up to 14 days. In complex aphthosis, patients experience the nearly continuous presence of numerous, large painful oral ulcers that take 4–6 weeks to heal. The affected patients often have at least one active ulcer.,
Aphthous ulcers are also classified based on size, number, and morphology into minor, major, and herpetiform subtypes [Table 1]. The minor form, also known as Mikulicz ulcer, is the most common, accounting for approximately 80% of the patients.,,, These tend to be small, less than 5 mm in diameter, and are usually multiple. Preceding their appearance is often a burning sensation. They have a predilection for the non-keratinized oral epithelium and usually heal within 2 weeks without scarring [Figure 1].,,,, The major RAS, also known as periadenitis mucosa necrotica recurrens or Sutton's disease, affects approximately 5–10% of all RAS patients. These are more severe, causing more damage and pain than the minor form; the aphthae are deeper and generally greater than 1 cm in diameter. The major aphthae have a post-pubertal onset, are often solitary, and have a predilection for the posterior oral cavity. They may persist for weeks to months and heal with fibrotic scars. These major aphthae typically form on the lips, soft palate, and oropharynx and often cause scarring. This form of RAS may be associated with human immunodeficiency virus (HIV) infection, implicating a disturbance of immune function in their pathogenesis.,,,, RAS in HIV patients must be differentiated from infectious ulcers, which may have atypical presentations.
|Table 1: Clinical features of recurrent aphthous stomatitis and primary herpetic gingivostomatitis|
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|Figure 1: Minor aphthous ulcers affecting (a) soft palatal mucosa, (b) ventral tongue, (c) labial mucosa, and (d) the floor of the mouth|
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Herpetiform aphthous stomatitis is the least common variant, with an onset between 20 and 30 years of age. Herpes simplex virus (HSV) does not contribute to the formation of these ulcers.,,,,,, This form manifests as localized or diffuse crops of 10–100 ulcers each 2–3 mm in size which can coalesce to form irregular erosions [Figure 2]. Ulcers predominantly affect non-keratinized mucosa such as labial or soft palatal mucosa, and ventral tongue. The involvement of keratinized tissues such as the dorsal tongue is also possible. They resolve faster than major RAS ulcers, generally lasting 7–14 days. With their herpetiform morphology, they must be differentiated from the ulcers of primary herpetic gingivostomatitis as illustrated in [Figure 3].
|Figure 2: Herpetiform aphthous ulcers involving the left ventral tongue and the floor of the mouth|
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|Figure 3: Primary herpetic gingivostomatitis demonstrating inflammation of maxillary gingiva and punctate ulcers resembling aphthous ulcers involving the buccal and soft palatal mucosa|
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| Pathophysiology of RAS|| |
The etiology of RAS is most likely multifactorial. There is some evidence of a familial component with early onset and greater severity—as suggested by twin studies, though no specific gene has been identified. The possible systemic precipitating factors include stress, vitamin/mineral deficiencies (folate, iron, zinc, vitamin B), food allergies, gluten-sensitive enteropathy, and drugs (e.g., nicorandil, etanercept).,,,,,,,,,,,,,,,,,,,
Interestingly, the frequency of RAS increases in those who quit smoking, possibly due to a loss of either mucosal keratinization promoted by tobacco smoke, or the protective effect of nicotine. Nicotine replacement therapy has proven efficacious in improving ulcers resulting from the cessation of tobacco products. Many studies support the idea that immune dysregulation leads to an exaggerated inflammatory response and/or a relatively weak anti-inflammatory response in RAS.
Although most cases of RAS are isolated, aphthous ulcers may be seen as part of or in association with many systemic disorders. For instance, Behçet's syndrome is an autoimmune vasculitis that gives rise to recurrent oral and genital ulcerations, arthritis, pustular vasculitic cutaneous lesions, uveitis, and retinitis. Its oral ulcers are often the initial symptom. They are typically painful, variable in size, and can be shallow or deep. Behçet's syndrome can typically be differentiated from RAS by the presence of systemic symptoms. Another syndrome producing similar clinical manifestations is reactive arthritis syndrome, which is associated with oral ulcers, uveitis, conjunctivitis, and human leukocyte antigen (HLA)-B27-positive arthritis. Another autoimmune condition which may include aphthae as part of the clinical manifestations is inflammatory bowel disease.,, The differentiation of aphthae in this context from RAS rests on the review of systems for gastrointestinal complaints and pertinent systemic workup.
A hematologic disease that produces oral aphthae is cyclic neutropenia. These blanched oral aphthae are associated with neutropenic periods and fever. If fever and oral ulcers consistently occur simultaneously, a hematologic analysis should be considered. There is also a higher occurrence of aphthae among HIV patients, particularly major aphthae. Clinicians should consider the possibility of immunosuppression, whether HIV infection or underlying leukemia/lymphoma, in those who develop aphthae that are large and slow to heal.
Aphthous ulcers are also a component of the PFAPA syndrome (periodic fever with aphthous stomatitis, pharyngitis, and adenitis). Commonly between the ages of 1 and 4 years, PFAPA is first evident with abrupt fevers for 2–7 days, pharyngitis with or without tonsillar exudates, cervical lymphadenopathy, and aphthous ulcers. Its symptoms may recur every 2–12 weeks. These non-scarring aphthae are often on the lips or buccal mucosa; they are smaller and less painful than those of the Behçet's syndrome. Though normally resolving in between episodes, the ulcers may be present the day preceding cyclical fever. The PFAPA syndrome seldom lasts beyond 10 years of age., Although a self-limiting disease, the symptomatic treatment for PFAPA involves oral steroids. Severe cases may require tonsillectomy, which has been shown to resolve most PFAPA symptoms except for the fevers.,,
| Diagnostic Workup|| |
The diagnostic workup should start with a thorough history of the number, size, duration, and frequency of ulcers as well as the age of onset, familial incidence, and presence of mucocutaneous lesions elsewhere in the body. The patients should also be questioned about medications and over-the-counter products they use, xerostomia, environmental exposures, food sensitivity, oral hygiene practices, hematinic deficiency, psychological stress, HIV status, and symptoms of organ system involvement. When positive findings on history, physical, or review of systems raise the suspicion of systemic conditions with aphthous ulcers rather than isolated RAS, additional investigations are warranted [Table 2]. The management of these systemic conditions helps improve aphthous manifestations. Local therapy directed at ulcers also provides additional benefits.
RAS should be distinguished from other diseases that can produce oral ulcerations [Table 2]. Most commonly, RAS needs to be differentiated from the aphthous-like HSV-induced ulcers, whether primary or recurrent. Primary herpetic gingivostomatitis (PHGS) is usually evident with fever, lymphadenopathy, sore throat, halitosis, bright gingival erythema, and a vesiculoulcerative eruption in and around the oral cavity., It is highly contagious, posing a risk of autoinoculation and transmission to others. In general, the presence of perioral lesions, gingival inflammation, and systemic signs and symptoms as well as involvement of both movable and non-moveable oral mucosa distinguish PHGS from aphthae.
In the immunocompetent host, recurrent intraoral herpes (RIH) has a propensity to arise on the hard palate and gingival mucosa, which contrasts with the ulcers of RAS that almost exclusively form on the buccal and labial mucosa, ventral tongue, and soft palate. Aphthae in RAS are typically more than 3 mm in size compared with HSV ulcers, which start as vesicles, tend to be smaller, and clustered together. These vesicles ulcerate upon rupture. In the immunocompromised host, RIH may involve both keratinized and non-keratinized mucosa rendering differentiation from RAS challenging. Aphthous ulcers have non-specific histology but laboratory studies such as Tzanck smear, biopsy, viral culture, and polymerase chain reation (PCR) for patients with active lesions—or serologic testing for those without—may be used to diagnose aphthous-like conditions such as HSV or hand-foot-mouth disease.,
Herpangina and hand-foot-and-mouth disease, caused by Coxsackie A viruses, also produce oral ulcerations. However, herpangina and hand-foot-and-mouth disease ulcers begin as vesicles and occur with fever and malaise, which is not typical for RAS. Furthermore, the hand-foot-and-mouth disease has characteristic cutaneous findings of non-pruritic macules, papules, or vesicles on the hands, feet, buttocks, arms, or legs.
Other ulcerative disorders which occasionally produce aphthous-like oral ulcers include cytomegalovirus (CMV), varicella-zoster virus (VZV), syphilis, pemphigus, lichen planus, and erythema multiforme.,,, An atypical form of pemphigus can start with small lesions resembling RAS; however, the jagged edges of ulcers, vesicular onset, and chronicity of pemphigus can help exclude RAS. Oral ulcerations of erythema multiforme also start with vesicles, which upon eruption cause irregular superficial erosions clinically distinguishable from the aphthous ulcerations.
| Treatment and Management|| |
Treatment for RAS can be challenging. There are many categories of drugs that are used to treat the symptoms, which can range from bothersome to incapacitating. The primary goals of the treatment for RAS include (1) to manage the pain of the ulcer(s), (2) to promote healing and reduce duration, and (3) to restore normal oral function. An important step in the management of RAS is educating the patient about the potential role of the environmental, dietary, and traumatic triggers as well as avoidance of products which may precipitate an episode or cause irritation to the existing ulcers.
For the local disease, the mainstays of therapy are topical anti-inflammatory agents. The topical corticosteroids triamcinolone, fluocinonide gel, and clobetasol ointment with or without mucosal adhesive agents such as orabase or zilactin, decrease the duration of the ulcers and increase the time between the episodes., Another topical treatment with anti-inflammatory effects is amlexanox, the only FDA-approved drug for RAS. Amlexanox works by inhibiting leukotrienes and histamines, resulting in accelerated healing times and resolution of pain. Mucosal adhering agents, used alone, provide hours of pain relief by forming an impermeable barrier, protecting the existing ulcer from further trauma. Zilactin, a hydroxypropyl cellulose film, is a mucosal adhering agent that remains on the oral mucosa longer than orabase., A mucoadhesive buccal film of benzydamine hydrochloride may also be effective. Sucralfate suspensions also serve as physical barriers that decrease the pain and duration of oral and genital lesions in Behçet's disease.,
Other topical agents used to combat RAS include antimicrobial mouthwashes. These rinses are intended to prevent microbial contamination and the resulting superinfection. The two proto-typical agents that have been employed include antibiotics (mainly tetracycline) and antiseptic agents such as chlorhexidine gluconate. Tetracycline has been reported to decrease the pain and duration of ulcers. Chlorhexidine gluconate also limits the number of ulcer days, reduces secondary infections, and increases the interval between ulcer recurrences. However, neither mouth rinse has been shown to prevent recurrences from happening altogether. The Chinese herbal medicines may be a reasonable approach, although the current evidence is limited.
For many individuals, especially those with major RAS, pain from aphthae can impair oral function to the point of causing weight loss. As a result, the patients should be encouraged to maintain normal fluid and nutritional intake, while avoiding spicy and abrasive foods. Individuals sensitive to sodium lauryl sulfate should avoid toothpastes that contain it. Topical anesthetics, such as 2% lidocaine, are applied directly to the ulcer to decrease pain. A few randomized trials have also shown that laser cauterization reduces RAS pain, though it demonstrated no changes in the healing time or recurrence rate.,
For many RAS patients, topical agents are sufficient to manage symptoms and promote healing. However, the efficacy of topical medications is limited. On the other hand, the use of systemic agents should be reserved for patients with systemic diseases, with frequent episodes of copious painful aphthae, ulcerations that are resistant to topical therapy, or erosions that develop in the oropharynx or esophagus. Systemic steroids like prednisone will generally heal the pain and inflammation of most ulcers., Similarly, biologics such as anti-tumor necrosis factor (TNF)-α agents (e.g., infliximab) have also been successful in the trials for recalcitrant/severe RAS, though steroids and biologics both carry serious side effect risks., A low-dose oral steroid therapy for PFAPA syndrome may expeditiously halt flares. The need for frequent treatment with prednisone or other systemic immunosuppressants is a sign to initiate therapy with less toxic immunomodulatory agents such as colchicine, dapsone, pentoxifylline, levamisole, and thalidomide.
The use of dapsone and colchicine for aphthae prophylaxis has been particularly beneficial in patients with Behçet's disease and complex aphthosis. These agents prevent ulcer formation by suppressing inflammation. Colchicine can cause some gastrointestinal side effects, particularly diarrhea., Dapsone is contraindicated in patients with glucose-6-phosphate-dehydrogenase deficiency, as it can cause hemolytic anemia. Another rare potential complication of dapsone is agranulocytosis, so laboratory monitoring is required.
Pentoxifylline is an anti-inflammatory agent used for its immunomodulatory effects. Its mechanism of action involves the inhibition of TNF-α as well as other inflammatory cytokines. A few uncontrolled trials of pentoxifylline have yielded excellent results in the treatment of RAS,, but a recent controlled, double-blind study showed only modest benefits and suggested that pentoxifylline serves as a non-first-line agent. Additionally, apremilast, a phosphodiesterase-4 inhibitor, is useful for limiting RAS in Behçet's disease; apremilast decreases pro-inflammatory cytokines TNF-α, interferon-gamma, IL-10, and IL-23.
Levamisole has demonstrated the ability to reduce the frequency and duration of ulcers in RAS patients. Although not a common treatment option, levamisole alone and in combination with low-dose prednisolone may be effective therapies. Levamisole normalizes the CD4:CD8 ratio that is aberrant in patients. It is generally given at the first sign of ulceration and has been effective in delaying recurrences. Its side effects include some taste disturbances and nausea, though overall it is well tolerated.,,
Thalidomide, a dangerous teratogen reintroduced in 1998 for the treatment of erythema nodosum leprosum, has been proven effective in HIV patients with aphthae, particularly when aphthae are severe. Other studies have shown thalidomide to be effective in immunocompetent patients with Behçet's disease and Crohn's disease. Thalidomide leads to diminished pain, improved oral function, resolution of ulcers, and suppression of recurrences. In vitro studies have documented that thalidomide changes the TNF-α concentration, but the exact mechanism remains unknown., In the United States, thalidomide can only be prescribed through a monitoring and registration program, mandated by its teratogenicity and side effects including neuropathy, headaches, and constipation.
Level of evidence
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Kansky AA, Didanovic V, Dovsak T, Brzak BL, Pelivan I, Terlevic D. Epidemiology of oral mucosal lesions in Slovenia. Radiother Oncol 2018;52:263-6.
Ship JA, Chavez EM, Doerr PA, Henson BS, Sarmadi M. Recurrent aphthous stomatitis. Quintessence Int 2000;31:95-112.
Letsinger JA, McCarty MA, Jorizzo JL. Complex aphthosis: A large case series with evaluation algorithm and therapeutic ladder from topicals to thalidomide. J Amer Acad Dermatol 2005;52:500-8.
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;43:620-32.
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.
Barrons RW. Treatment strategies for recurrent oral aphthous ulcers. Am J Health Syst Pharm 2001;58:41-50.
Akintoye SO, Greenberg MS. Recurrent aphthous stomatitis. Dent Clin 2014;58:281-97.
Stoopler ET, Sollectio TP. Recurrent aphthous stomatitis. Update for the general practitioner. N Y State Dent J 2003;69:27-9.
McBride DR. Management of aphthous ulcers. Am Fam Physician 2000;62:149-54, 160.
Kerr AR, Ship JA. Management strategies for HIV-associated aphthous stomatitis. Am J Clin Dermatol 2003;4:669-80.
Shashy RG, Ridley MB. Aphthous ulcers: A difficult clinical entity. Am J Otolaryngol 2000;21:389-93.
Tarakji B, Gazal G, Al-Maweri SA, Azzeghaiby SN, Alaizari N. Guideline for the diagnosis and treatment of recurrent aphthous stomatitis for dental practitioners. J Int Oral Health 2015;7:74-80.
Fatahzadeh M, Schwartz RA. Human herpes simplex virus infections: Epidemiology, pathogenesis, symptomatology, diagnosis, and management. J Amer Acad Dermatol 2007;57:737-63.
Fatahzadeh M, Schwartz RA. Human herpes simplex labialis. Clin Dermatol 2007;32:625-30.
Ślebioda Z, Szponar E, Kowalska A. Recurrent aphthous stomatitis: Genetic aspects of etiology. Postepy Dermatol Alergol 2013;30:96-102.
Lee M-TG, Lin H-Y, Lee S-H, Lee S-H, Chang S-S, Chen S-C, et al
. Risk of skin ulcerations associated with oral nicorandil therapy: A population-based study. Br J Dermtol 2015;173:498-509.
Rzepecki V, Reynes J, Le Moing V, Braquet P, Faucherre V, Lohan L, et al
. Severe HIV-associated aphthous stomatitis treated with etanercept. Med Mal Infect 2019;49:219-20.
Ślebioda Z, Szponar E, Kowalska A. Etiopathogenesis of recurrent aphthous stomatitis and the role of immunologic aspects: Literature review. Arch Immunol Ther Exp 2014;62:205-15.
Najafi S, Firooze Moqadam I, Mohammadzadeh M, Bidoki AZ, Yousefi H, Farhadi E, et al
. Interleukin-10 gene polymorphisms in recurrent aphthous stomatitis. Immunol Invest 2014;43:405-9.
Buno IJ, Huff JC, Weston WL, Cook DT, Brice SL. Elevated levels of interferon gamma, tumor necrosis factor α, interleukins 2, 4, and 5, but not interleukin 10, are present in recurrent aphthous stomatitis. Arch Dermatol 1998;134:827-31.
Ozyurt K, Çelik A, Sayarlıoglu M, Colgecen E, Incı R, Karakas T, et al
. Serum Th1, Th2 and Th17 cytokine profiles and alpha-enolase levels in recurrent aphthous stomatitis. J Oral Pathol Med 2014;43:691-5.
Celasun B. Oral epithelial barrier function and the role of nuclear factor kappa-β pathway in the pathogenesis of aphthous ulceration. Turk J Gastroenterol 2013;24:508-14.
Gallo C, Barros F, Sugaya N, Nunes F, Borra R. Differential expression of toll-like receptor mRNAs in recurrent aphthous ulceration. J Oral Pathol Med 2012;41:80-5.
Bratel J, Hakeberg M. Anamnestic findings from patients with recurrent aphthous stomatitis. Swed Dent J 2014;38:143-9.
Mills MP, Mackler BF, Cade Nelms D, Peavy DL. Quantitative distribution of inflammatory cells in recurrent aphthous stomatitis. J Dent Res 1980;59:562-6.
Natah SS, Häyrinen-Immonen R, Hietanen J, Malmström M, Konttinen YT. Immunolocalization of tumor necrosis factor-α expressing cells in recurrent aphthous ulcer lesions (RAU). J Oral Pathol Med 2000;29:19-25.
Landesberg R, Fallon M, Insel R. Alterations of T helper/inducer and T suppressor/inducer cells in patients with recurrent aphthous ulcers. Oral Surg Oral Med Oral Pathol 1990;69:205-8.
Regezi J, Macphail L, Richards D, Greenspan J. A study of macrophages, macrophage-related cells, and endothelial adhesion molecules in recurrent aphthous ulcers in HIV-positive patients. J Dent Res 1993;72:1549-53.
Ship II. Inheritance of aphthous ulcers of the mouth. J Dent Res 1965;44:837-44.
Miller MF, Garfunkel AA, Ram C, Ship II. Inheritance patterns in recurrent aphthous ulcers: Twin and pedigree data. Oral Surg Oral Med Oral Pathol 1977;43:886-91.
Boulinguez S, Reix S, Bedane C, Debrock C, Bouyssou-Gauthier ML, Sparsa A, et al
. Role of drug exposure in aphthous ulcers: A case-control study. Br J Dermatol 2000;143:1261-5.
Challacombe S, Scully C, Keevil B, Lehner T. Serum ferritin in recurrent oral ulceration. J Oral Pathol Med 1983;12:290-9.
Merchant N, Ferguson M, Ali A, Hole D, Gillis C. The detection of IgA-reticulin antibodies and their incidence in patients with recurrent aphthae. J Oral Med 1986;41:31-4.
Grönhagen CM, Nyberg F. Cutaneous lupus erythematosus: An update. Indian Dermatol Online J 2014;5:7-13.
Porter S, Scully C, Standen G. Autoimmune neutropenia manifesting as recurrent oral ulceration. Oral Surg Oral Med Oral Pathol 1994;78:178-80.
Chattopadhyay A, Chatterjee S. Risk indicators for recurrent aphthous ulcers among adults in the US. Community Dent Oral Epidemiol 2007;35:152-9.
McRobbie H, Hajek P, Gillison F. The relationship between smoking cessation and mouth ulcers. Nicotine Tob Res 2004;6:655-9.
Hill SC, Stavrakoglou A, Coutts IR. Nicotine replacement therapy as a treatment for complex aphthosis. J Dermatolog Treat 2010;21:317-8.
Wu IB, Schwartz RA. Reiter's syndrome: The classic triad and more. J Amer Acad Dermatol 2008;59:113-21.
Fatahzadeh M, Schwartz RA, Kapila R, Rochford C. Orofacial Crohn's disease: An oral enigma. Acta Dermatovenerol Croat 2009;17:289-300
Feder H, Salazar J. A clinical review of 105 patients with PFAPA (a periodic fever syndrome). Acta Paediatr 2010;99:178-84.
Wurster VM, Carlucci JG, Feder HM Jr, Edwards KM. Long-term follow-up of children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome. J Pediatr 2011;159:958-64.
Batu ED. Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome: Main features and an algorithm for clinical practice. Rheumatol Int 2019;39:957-70.
Licameli G, Lawton M, Kenna M, Dedeoglu F. Long-term surgical outcomes of adenotonsillectomy for PFAPA syndrome. Arch Otolaryngol Head Neck Surg 2012;138:902-6.
Wekell P. Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome - PFAPA syndrome. Presse Med 2019;48:e77-87.
Gaggiano C, Rigante D, Sota J, Grosso S, Cantarini L. Treatment options for Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome in children and adults: A narrative review. Clin Rheumatol 2019;38:11-7.
Gupta R, Warren T, Wald A. Genital herpes. Lancet 2007;370:2127-37.
Fatahzadeh M. Primary oral herpes: Diagnosis and management. J N J Dent Assoc 2012;83:12-3.
Scully C, Challacombe SJ. Pemphigus vulgaris: Update on etiopathogenesis, oral manifestations, and management. Crit Rev Oral Biol Med 2002;13:397-408.
McCartan B, Healy C. The reported prevalence of oral lichen planus: A review and critique. J Oral Pathol Med 2008;37:447-53.
Lozada-Nur F, Miranda C, Maliksi R. Double-blind clinical trial of 0.05% clobetasol proprionate ointment in orabase and 0.05% fluocinonide ointment in orabase in the treatment of patients with oral vesiculoerosive diseases. Oral Surg Oral Med Oral Pathol 1994;77:598-604.
Liu C, Zhou Z, Liu G, Wang Q, Chen J, Wang L, et al
. Efficacy and safety of dexamethasone ointment on recurrent aphthous ulceration. Am J Med 2012;125:292-301.
Abbasi F, Raoof M, Khatami R, Shadman N, Borjian-Boroojeni F, Nazari F. Effectiveness of amlexanox and adcortyl for the treatment of recurrent aphthous ulcers. J Clin Exp Dent 2016;8:e368.
Khandwala A, Van Inwegen RG, Alfano MC. 5% amlexanox oral paste, a new treatment for recurrent minor aphthous ulcers: I. Clinical demonstration of acceleration of healing and resolution of pain. Oral Surg Oral Med Oral Pathol 1997;83:222-30.
Rodu B, Russell CM, Ray KL. Treatment of oral ulcers with hydroxypropylcellulose film (Zilactin). Compendium 1988;9:420-2.
Sharma D, Sharma A, Garg R. Design, development and in vitro/ex vivo evaluation of mucoadhesive buccal film of benzydamine hydrochloride for the effective treatment of aphthous stomatitis. Recent Pat Drug Deliv Formul 2018;12:277-94.
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.
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.
Graykowski EA, Kingman A. Double-blind trial of tetracycline in recurrent aphthous ulceration. J Oral Pathol Med 1978;7:376-82.
Hunter L, Addy M. Chlorhexidine gluconate mouthwash in the management of minor aphthous ulceration. A double-blind, placebo-controlled cross-over trial. Br Dent J 1987;162:106-10.
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.
Zhang Y, Ng K-H, Kuo C-Y, Wu D-Y. Chinese herbal medicine for recurrent aphthous stomatitis: A protocol for systematic review and meta-analysis. Medicine (Baltimore) 2018;97:e13681.
Yilmaz HG, Albaba MR, Caygur A, Cengiz E, Boke-Karacaoglu F, Tumer H. 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.
Alidaee M, Taheri A, Mansoori P, Ghodsi S. Silver nitrate cautery in aphthous stomatitis: A randomized controlled trial. Br J Dermatol 2005;153:521-5.
Eisen D, Lynch DP. Selecting topical and systemic agents for recurrent aphthous stomatitis. Cutis 2001;68:201-6.
Silverman S, Lozada-Nur F, Migliorati C. Clinical efficacy of prednisone in the treatment of patients with oral inflammatory ulcerative diseases: A study of fifty-five patients. Oral Surg Oral Med Oral Pathol 1985;59:360-3.
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;24:444-6.
O'neill I, Scully C. Biologics in oral medicine: Ulcerative disorders. Oral Dis 2013;19:37-45.
Ghate JV, Jorizzo JL. Behçet's disease and complex aphthosis. J Am Acad Dermatol 1999;40:1-18; quiz 19-20.
Pakfetrat A, Mansourian A, Momen-Heravi F, Delavarian Z, Momen-Beitollahi J, Khalilzadeh O, et al
. Comparison of colchicine versus prednisolone in recurrent aphthous stomatitis: A double-blind randomized clinical trial. Clin Invest Med 2010;33:E189-95.
Davatchi F, Sadeghi Abdollahi B, Tehrani Banihashemi A, Shahram F, Nadji A, Shams H, et al
. Colchicine versus placebo in Behçet's disease: Randomized, double-blind, controlled crossover trial. Mod Rheumatol 2009;19:542-9.
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.
Wahba-Yahav AV. Pentoxifylline in intractable recurrent aphthous stomatitis: An open trial. J Amer Acad Dermatol 1995;33:680-2.
Saini A, Ferguson C, Salkey K. Use of apremilast for aphthous ulcers in a patient with Behçet's syndrome. J Drugs Dermatol 2018;17:1328-9.
Sharda N, Shashikanth M, Kant P, Jain M. Levamisole and low-dose prednisolone in the treatment of reccurent aphthous stomatitis. J Oral Pathol Med 2014;43:309-16.
Sun A, Chiang CP, Chiou PS, Wang JT, Liu BY, Wu YC. Immunomodulation by levamisole in patients with recurrent aphthous ulcers or oral lichen planus. J Oral Pathol Med 1994;23:172-7.
Parvathi Devi M, Ramesh D, Shrinivas Koppal ARB, Thriveni Rukmangada AAB. Efficacy of rebamipide and levamisole in the treatment of patients with recurrent aphthous ulcer-a comparative study. J Clin Diagn Res 2014;8:ZC119-22.
Wu J, Huang D, Pang K, Hsu S, Tyring S. Thalidomide: Dermatological indications, mechanisms of action and side effects. Br J Dermatol 2005;153:254-73.
Jacobson JM, Greenspan JS, Spritzler J, Ketter N, Fahey JL, Jackson JB, et al
. Thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection. National institute of allergy and infectious diseases AIDS clinical trials group. N Engl J Med 1997;336:1487-93.
Paghdal KV, Schwartz RA. Thalidomide and its dermatologic uses. Acta Dermatovenerol Croat 2007;15:39-44.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]