Recurrent aphthous stomatitis | Medicina Clínica (English Edition)

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It is characterised by multiple recurrent ulcers (aphthae), round or ovoid, with circumscribed margins, erythematous borders and a yellowish-grey pseudomembranous base. They are usually located on the oral mucosa, lips and tongue surface and are very painful for the first 4–5 days. Episodes of ulcers may recur at intervals of days to months, with the first lesions usually occurring in childhood or adolescence.<a class="elsevierStyleCrossRefs" href="#bib0005">1,2</a>EpidemiologyIts prevalence in the general population varies between 5 and 25%, reaching up to 60% in some studies, depending on the origin of the groups and populations studied, as well as the design of the studies and their methodology.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>The peak onset of RAS is in the second decade of life, with the first episode often occurring in childhood or adolescence. As people age, the recurrence rate, as well as the severity of episodes, tends to decrease. It is uncommon after the age of 40, although it has also been described in the elderly population.<a class="elsevierStyleCrossRefs" href="#bib0020">4,5</a>AetiopathogenesisSo far, its aetiopathogenesis has not been clarified and multiple factors are thought to play a role. In genetically predisposed patients, the effect of certain triggering factors would initiate an immune dysfunction affecting certain areas of the oral mucosa.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>Factors that have been implicated as triggers of the inflammatory response in RAS include: genetic factors, immunological factors, mechanical injury, viral and bacterial infections, changes in the oral microbiota, allergies, vitamin and microelement deficiencies, hormonal factors, stress and drugs. Their involvement is described below.Genetic factorsIts role was confirmed in studies conducted in relatives and twins with RAS where a positive family history of the disease was reported in 24–46% of cases. In addition, patients with a family history of RAS have more common recurrences and a more severe course.<a class="elsevierStyleCrossRef" href="#bib0005">1</a>Genetic risk factors may determine individual susceptibility to RAS and include several DNA polymorphisms, especially those related to alterations in the metabolism of interleukins, interferon gamma (IFN-γ ) and tumour necrosis factor alpha (TNF-α).<a class="elsevierStyleCrossRef" href="#bib0030">6</a> In addition, in patients with RAS, an increased incidence of HLA-A33, HLA-B35 and HLA-B81, HLA-B12, HLA-B51, HLA-DR7 and HLA-DR5, and a decreased incidence of HLA-B5 and HLA-DR4<a class="elsevierStyleCrossRef" href="#bib0035">7</a> was observed.Immunological factorsMany authors suggest that the Th1-type immune response plays a crucial role in the development of RAS, as there is significantly higher secretion of Th1 cytokines in patients with RAS compared to controls.<a class="elsevierStyleCrossRef" href="#bib0040">8</a> Increased production of interleukin-2 (IL-2), IFN-γ, and TNF-α by peripheral blood mononuclear cells was also observed, both in the acute phase of the disease and in remission. Meanwhile, the secretion of anti-inflammatory cytokines, such as transforming growth factor-beta (TGF-β) and IL-10 was significantly lower in patients with RAS.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> This observation confirms that imbalance in the production of pro- and anti-inflammatory cytokines may contribute to the development of autoimmunisation and RAS in predisposed subjects.<a class="elsevierStyleCrossRef" href="#bib0045">9</a>Mechanical injuriesLocal trauma is one of the most common causes, as it induces oedema, causes inflammation of cells and leads to increased viscosity of the submucosal extracellular matrix, thus more easily triggering RAS.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> These lesions are often caused by dental procedures, orthopaedic devices or sharp or broken teeth. It can also be caused by accidental biting of the tongue or cheek, or by eating hot food.<a class="elsevierStyleCrossRef" href="#bib0055">11</a>Most studies indicate a lower incidence of RAS in smokers compared to non-smokers. This could be explained by a higher level of keratinisation of the oral mucosa in response to smoking, which makes it less prone to injury and irritation.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>InfectionsThe role of different viruses and bacteria has been studied to substantiate the infectious aetiology of RAS. On the one hand, several studies have attempted to isolate DNA from herpes simplex virus, cytomegalovirus, varicella-zoster and Epstein-Barr virus in aphthous ulcers, or have performed serological testing of these viruses, but none have confirmed their direct role in the aetiopathogenesis of the condition.<a class="elsevierStyleCrossRef" href="#bib0060">12</a> On the other hand, Helicobacter pylori has been investigated as a potential factor in RAS without finding any direct evidence. Some studies have shown a beneficial effect of its eradication in patients with RAS. However, the underlying mechanism seems to be related to increased serum levels of vitamin B12 after eradication, rather than to the direct action of the bacteria.<a class="elsevierStyleCrossRef" href="#bib0065">13</a>MicrobiotaOral microbiota has been studied in patients with RAS, with a lower level of Streptococcus spp. and an increase in Acinetobacter johnsonii in patients with RAS compared to healthy controls.<a class="elsevierStyleCrossRef" href="#bib0070">14</a> In addition, during the active ulcer phase, an increase in fungal spp. was evident, particularly Malassezia and Candida albicans. This evidence is consistent with the hypothesis of a microbial shift in RAS in favour of opportunistic pathogens.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> There is no evidence that the increased species in RAS lesions play a role in disease onset or progression.AllergiesHypersensitivity to certain food substances such as chocolate, gluten, cow's milk, nuts, preservatives and food dyes may induce the pro-inflammatory cascade that triggers RAS. In some patients, clinical improvement was observed after an elimination diet. However, these findings have not been confirmed by further research.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> Sodium lauryl sulphate (SLS), a common ingredient in toothpastes<a class="elsevierStyleCrossRef" href="#bib0080">16</a> or materials for dental procedures such as nickel in orthodontic appliances or eugenol contained in cement used for dental restoration, may also trigger RAS.<a class="elsevierStyleCrossRef" href="#bib0085">17</a>Vitamin and micronutrient deficienciesVitamin and mineral deficiencies have also been proposed as possible aetiological factors in RAS. Several studies have found lower levels of iron, folic acid, zinc or vitamins B1 and B12, and vitamin D, in patients with RAS. Some of these nutritional deficiencies may be secondary to other diseases.<a class="elsevierStyleCrossRefs" href="#bib0035">7,18</a>Hormonal factorsThe relationship between the occurrence of aphthous ulcers and the menstrual cycle in women has not been clearly established. It seems that exacerbation of RAS is observed in the luteal phase of the cycle, while remission often occurs during pregnancy or with the use of contraceptives.<a class="elsevierStyleCrossRef" href="#bib0060">12</a>StressIn predisposed patients, stressful events are thought to exacerbate RAS, with mental stressors having a greater impact than physical stressors.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> However, no direct correlation has been found between the level of stress and the severity of RAS episodes. This suggests that stress may act as a trigger or modifier rather than an aetiological factor.<a class="elsevierStyleCrossRef" href="#bib0100">20</a>DrugsDifferent cases of drug-induced RAS have been reported, including non-steroidal anti-inflammatory drugs,<a class="elsevierStyleCrossRef" href="#bib0105">21</a> beta-blockers, angiotensin-converting enzyme inhibitors,<a class="elsevierStyleCrossRef" href="#bib0110">22</a> nicorandil, antibiotics, bisphosphonates,<a class="elsevierStyleCrossRef" href="#bib0115">23</a> chemotherapeutics such as 5-fluorouracil and doxorubicin, and immunosuppressants such as calcineurin and mammalian target of rapamycin (mTOR) inhibitors.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> More recently, cases have also been reported with tocilizumab<a class="elsevierStyleCrossRef" href="#bib0120">24</a> and orlistat.<a class="elsevierStyleCrossRef" href="#bib0125">25</a> Ulcers usually disappear with discontinuation of treatment. Therefore, it is imperative to examine the medication history of patients with RAS. In addition, abuse of illegal drugs such as cocaine or amphetamines also increases the incidence rate of RAS.<a class="elsevierStyleCrossRef" href="#bib0035">7</a>Clinical presentationsPatients with RAS usually experience prodromal burning sensations 2−48 h before an ulcer develops. Ulcers are round or oval with well-defined erythematous margins and a shallow ulcerated centre covered with a grey or yellowish fibrinous pseudomembrane. Ulcers usually develop on the non-keratinised oral mucosa, with the buccal mucosa and lips (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>) being the most common sites. Episodes of ulcers may recur at intervals ranging from a few days to months.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> They are usually very painful, with pain similar to that of a burn, which increases on contact with hot food or spices. Their presence can make speech, chewing and swallowing difficult.<a class="elsevierStyleCrossRef" href="#bib0130">26</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>There are 3 forms of presentation for aphthous ulcers in RAS: minor (or Mikulicz's aphthous ulcers), major (or Sutton's disease) and herpetiform, which differ in morphology, distribution, severity and prognosis. Their general characteristics are described in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.<a class="elsevierStyleCrossRef" href="#bib0135">27</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Differential diagnosisThe main causes of both chronic and acute oral mucosa ulcers are listed in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Some patients experience longer flares that are sometimes continuous and may be accompanied by occasional genital ulcers. This corresponds to a condition known as complex aphthosis and has an underlying systemic cause. Complex aphthosis, as well as recurrent ulcers that have an underlying systemic cause, should be considered as a distinct medical condition. The term RAS should be used for recurrent ulceration in the absence of systemic disease.<a class="elsevierStyleCrossRef" href="#bib0130">26</a> Differential diagnoses should be established with autoinflammatory syndromes and immunodeficiency states, including nutritional defects, immune defects and neutrophil defects. <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> lists the main diseases in the differential diagnosis of RAS.<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>DiagnosisIt is based on clinical history and findings. No specific diagnostic test is currently available. It is essential to consider a possible systemic cause, especially in adult patients who suddenly develop RAS.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>The sequence of the diagnostic process is shown in the algorithm shown in <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>.<elsevierMultimedia ident="fig0010"></elsevierMultimedia>A thorough history-taking should be carried out, gathering medical history (personal and family history of systemic or dermatological disease), drugs, allergies, dietary habits and toxins. In addition, an attempt should be made to establish the time of onset of the first lesion; the time of progression and duration of the lesions, as well as the coexistence of similar lesions in other areas. The presence of accompanying local and systemic symptoms and the association with local trauma or any other situation (stress, menstrual cycle, smoking cessation) should be investigated.<a class="elsevierStyleCrossRef" href="#bib0140">28</a>The clinical examination will complement the history-taking by a systematic inspection of the oral mucosa. Ulcers have a very characteristic appearance as described above. In addition, a physical examination of all mucocutaneous surfaces including scalp, nails and anogenital region is recommended, as well as a search for adenopathies in the head and neck regions to exclude underlying disease.<a class="elsevierStyleCrossRef" href="#bib0145">29</a>Additional tests should be performed to rule out underlying systemic disease or if there is diagnostic uncertainty.<a class="elsevierStyleCrossRef" href="#bib0150">30</a><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">-Blood tests: complete blood count, levels of iron, ferritin, folic acid, zinc, magnesium and group B vitamins. It is also recommended to request anti-transglutaminase and anti-endomysial antibodies to rule out coeliac disease, as well as antinuclear antibodies.</li><li class="elsevierStyleListItem" id="lsti0010">-Microbiological tests: Tzanck smear or PCR for herpes virus, fungal and bacterial culture, according to diagnostic doubts.</li><li class="elsevierStyleListItem" id="lsti0015">-Biopsy: the sample should include part of the ulcer and perilesional tissue, including the surrounding unaffected epithelium. It is indicated in 3 scenarios: (1) ulcer of unknown origin, with no signs of healing, after 2 weeks; (2) ulcer of known probable aetiology, but not responding to adequate treatment, after 2 weeks; and (3) ulcer caused by precipitating factors, but with no signs of healing 2 weeks after elimination of these factors.<a class="elsevierStyleCrossRef" href="#bib0155">31</a></li><li class="elsevierStyleListItem" id="lsti0020">-Histology: Microscopic features of RAS are not specific. The pre-ulcerous lesion shows subepithelial inflammatory mononuclear cells (monocytes and mainly T-type lymphocytes) with abundant mast cells, connective tissue oedema and lining of the margins with neutrophils.<a class="elsevierStyleCrossRef" href="#bib0160">32</a> In later stages, polymorphonuclear leukocytes dominate in the centre of the ulcer, while abundant mononuclear cell infiltration is observed at the edge of the lesion.<a class="elsevierStyleCrossRef" href="#bib0030">6</a></li></ul>TreatmentAt the present time there is no curative treatment for RAS, so the therapeutic objectives that we must seek, and transmit to patients, will be to relieve pain, reduce the time it takes for ulcers to heal and reduce the frequency and severity of episodes.<a class="elsevierStyleCrossRef" href="#bib0165">33</a>When recurrent aphthous ulcers appear on the oral mucosa, the first thing to do is to carry out a correct differential diagnosis, rule out associated diseases and assess treatable causes before reaching a diagnosis of RAS.<a class="elsevierStyleCrossRef" href="#bib0170">34</a>Although it is a high-prevalence disease, there are no quality clinical trials that evaluate the different treatments used for RAS, so there are no therapeutic guidelines or standardised treatment for it, and it is not included in the indications for any drug.<a class="elsevierStyleCrossRef" href="#bib0165">33</a>The therapeutic approach (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>) for the patient will be based on the clinical severity of the flares and their frequency. In patients with isolated episodes of oral aphthosis, topical medication should be used to help improve pain and reduce the time it takes for the lesions to heal. Systemic treatment is reserved for patients with repeated flares over time, severe clinical presentation or severe pain that do not respond to topical treatments. In addition, in these cases, our aim with treatment will also be to try to space out the flares.<a class="elsevierStyleCrossRefs" href="#bib0165">33–35</a><elsevierMultimedia ident="fig0015"></elsevierMultimedia>We will divide this section into prevention and general measures, topical treatments and systemic treatments.Prevention and general measuresOral hygienePatients should be urged to maintain proper oral hygiene and try to avoid trauma, as this has been linked to the development of aphthous ulcers. A soft toothbrush and alcohol-free mouthwash are advised.<a class="elsevierStyleCrossRefs" href="#bib0165">33–35</a>DietThere are no studies on the role of diet, therefore, dietary restrictions should not be recommended unless the patient associates certain foods with flares.Sodium lauryl sulphate (SLS)SLS is a common ingredient in toothpaste. It has been associated with cases of RAS, so we should recommend that patients use toothpastes without SLS. A systematic review comparing the effects of toothpastes with and without SLS showed a reduction in the number and duration of ulcers, the number of episodes and ulcer pain. Although the differences were not statistically significant for some of the characteristics mentioned.<a class="elsevierStyleCrossRef" href="#bib0080">16</a>Dietary supplementsIt is necessary to rule out nutritional deficiencies (vitamin B12, folic acid, iron, zinc, etc.) in patients with RAS and, if found, to treat them correctly, as in these cases the symptoms may improve with appropriate treatment.Vitamin B12   has been shown to prevent the symptoms of RAS. A randomised, double-blind, placebo-controlled study showed a reduction in the duration, number and pain of ulcers in patients treated with vitamin B12 1000 μ g sublingual daily for 6 months. In addition, a vitamin B12 ointment applied for 2 days also showed an improvement in pain in patients with RAS.<a class="elsevierStyleCrossRef" href="#bib0180">36</a>Zinc supplementation has been evaluated as a potential preventive measure and as treatment for its anti-inflammatory and healing properties. In one study, no statistically significant differences were found between serum zinc levels between cases of RAS patients and controls. On the other hand, a systematic review of 7 publications suggests efficacy of zinc supplementation in 5 of them, with no significant differences between the zinc-treated group and controls in the others. Until further research is available to confirm the efficacy of zinc supplementation for the prevention of RAS, it could be considered as a measure, due to its low cost and low potential for side effects.<a class="elsevierStyleCrossRef" href="#bib0185">37</a>Vitamin D deficiency has also been associated with RAS in a systematic review. No publications on improvement or control of symptoms by vitamin D supplementation have been found.There have also been studies showing improvement with 1,000 mg omega-3 daily for 6 months.<a class="elsevierStyleCrossRef" href="#bib0190">38</a>Supplementation with other vitamin complexes in patients without nutritional deficits has not shown any improvement in the clinical picture or decrease in the number of disease flares.<a class="elsevierStyleCrossRef" href="#bib0195">39</a>The use of probiotics in the treatment of RAS is supported by a meta-analysis of 3 studies showing that oral intake or topical application of probiotics significantly reduced pain compared to placebo. While probiotics alone were not effective in achieving an improvement in ulcer severity, they did provide benefits as an adjuvant to corticosteroids or topical anaesthetics.<a class="elsevierStyleCrossRefs" href="#bib0165">33,36</a>Topical treatmentsTopical glucocorticoidsThey are the first-line treatment for RAS. Topical glucocorticoids are more effective in reducing the severity and duration of lesions (systemic glucocorticoids will be more effective in reducing recurrences). They are applied from the beginning of the episode and 3–4 times a day, preferably after oral hygiene. No liquid or solid food should be eaten for the next half hour.<a class="elsevierStyleCrossRefs" href="#bib0180">36,40,41</a>Several treatment options are available:<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0025">-Triamcinolone acetone 0.1% has been the most commonly used.</li><li class="elsevierStyleListItem" id="lsti0030">-Fluocinolone acetonide 0.025–0.05%.</li><li class="elsevierStyleListItem" id="lsti0035">-Clobetasol 0.025–0.05%. It is more potent and is reserved for more severe cases.</li><li class="elsevierStyleListItem" id="lsti0040">-Dexamethasone solution (0.5 mg/5 cc) or ointment.</li></ul>Topical anaestheticsThey provide pain relief. They are applied several times a day, preferably before meals and oral hygiene, to make them easier to use.<a class="elsevierStyleCrossRefs" href="#bib0205">41,42</a> Among those used in RAS are:<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0045">-Lidocaine 1% cream and 2% gel or spray.</li><li class="elsevierStyleListItem" id="lsti0050">-Benzocaine gel 20%.</li></ul>Topical antiseptics: prevent superinfection by bacteria and fungi. They assist in oral hygiene.<a class="elsevierStyleCrossRefs" href="#bib0205">41,43</a> The following have been used:<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0055">1Triclosan 0.15%.</li><li class="elsevierStyleListItem" id="lsti0060">2Chlorhexidine 0.12–0.2%.</li></ul>Topical non-glucocorticoid anti-inflammatory agentsAmlexanox 5%. It has anti-inflammatory and anti-allergic properties. It is the only molecule approved by the FDA as a medication for the treatment of RAS, but it is not available in our setting. It is applied 2–4 times a day. Its efficacy is comparable to oral glucocorticoids. It has shown efficacy in improving pain and accelerating ulcer healing.<a class="elsevierStyleCrossRefs" href="#bib0180">36,44</a>Benzydamine rinse. It has a local anaesthetic effect that improves the pain caused by oral ulcers, but not the healing.<a class="elsevierStyleCrossRefs" href="#bib0180">36,45</a>Topical antibiotics (tetracyclines)Topical doxycycline and minocycline have been used for their antibacterial effects and possible inhibition of the collagenases and metalloproteinases that cause ulcer formation. Several studies with small numbers of patients demonstrated that topical doxycycline (100 mg in 10 ml of water) reduces the signs and symptoms of RAS in all patients. Another review indicated a decrease in healing time, but no difference in pain control versus placebo.<a class="elsevierStyleCrossRefs" href="#bib0230">46,47</a> Minocycline has been used as a 0.5% rinse with good results in reducing signs and symptoms of RAS.<a class="elsevierStyleCrossRef" href="#bib0240">48</a>Sucralfate suspensionOral rinses with 5 ml for 1–2 min 3–4 times/day and relieves pain.<a class="elsevierStyleCrossRefs" href="#bib0215">43,47</a>Hyaluronic acidSeveral publications evaluating the effectiveness of hyaluronic acid treatment in oral aphthous ulcers conclude that they are effective in reducing pain, ulcer size and inflammatory signs.<a class="elsevierStyleCrossRefs" href="#bib0245">49,50</a>Other topical treatmentsSeries with small numbers of patients have reported the use of diclofenac 3%, a 2.5% hyaluronic acid gel,<a class="elsevierStyleCrossRef" href="#bib0080">16</a> traditional Chinese medicine, pumpkin seed oil, chamomile, turmeric and others.<a class="elsevierStyleCrossRefs" href="#bib0250">50–53</a>Topical treatments can be combined with each other, enhancing the effects they have in monotherapy.Systemic treatmentAs mentioned above, in patients with moderate to severe episodes of RAS, refractory to general care and topical treatments, systemic treatment should be considered.Systemic glucocorticoidsThese are the most commonly used systemic treatments. They have been used in different regimens, both long-term regimens with low doses, such as prednisone 5 mg a day for 3 months, and short-term regimens of prednisone 20–40 mg a day for 4–7 days and continue with tapering for 1 month, or prednisone 25 mg a day for 15 days with a dose reduction over 2 months. They improve pain, accelerate healing and reduce the number of episodes.<a class="elsevierStyleCrossRefs" href="#bib0165">33,40,47</a>Oral glucocorticoids should be used in appropriate doses and for a limited time because of the undesirable effects they may have in the long term. When episodes have not been controlled by systemic glucocorticoids, or when adverse effects occur, or when the dose or the time used have risks of adverse effects, other treatments should be considered.Non-steroidal anti-inflammatory drugs and systemic immunomodulatorsThalidomide. It has been used for its TNF-α inhibiting effect. Its teratogenic effect and other side effects such as neutropenia, abdominal pain, paresthesias and irreversible peripheral neuropathy should be taken into account, so patients should be selected correctly. For RAS it has been used at doses of 25–100 mg per day with good results on symptomatology, including a decrease in the number of recurrences.<a class="elsevierStyleCrossRef" href="#bib0250">50</a>Colchicine. An antimitotic drug with anti-inflammatory and antifibrotic effects. Used at doses between 0.5–2 mg with mixed results. The 2012 Cochrane review<a class="elsevierStyleCrossRef" href="#bib0005">1</a> concludes that it is not a useful drug in the treatment of RAS when compared to oral glucocorticoids due to equal or inferior efficacy, but with a higher rate of side effects, mainly gastrointestinal.<a class="elsevierStyleCrossRefs" href="#bib0165">33,50,54</a>Montelukast. It is a leukotriene inhibitor. It has shown improvement in pain and accelerated healing in some studies, in addition to reducing the development of new lesions, when taking 10 mg per month for 1 month and 10 mg every 2 days for another month. Less effective than prednisone, but less adverse effects and good tolerance.<a class="elsevierStyleCrossRefs" href="#bib0165">33,50</a>Levamisole. Several studies with mixed and inconclusive results.<a class="elsevierStyleCrossRef" href="#bib0165">33</a>Pentoxifylline. A drug that inhibits the production of TNF-α, neutrophils and chemotaxis. It has been studied at a dose of 400 mg 3 times a day, with a decrease in pain and ulcer size compared to placebo, but with small differences. There are insufficient data to recommend or rule out its use.Systemic antibioticsDapsone. Used at doses of 25–150 mg per day depending on response and tolerance. It has been associated in some publications with a reduction in the number and size of canker sores.Clofazimine. Antimicrobial used for the treatment of mycobacteria. It has been compared against colchicine at a dose of 100 mg per day for 1 month followed by 100 mg every other day for 6 months, showing a reduction in healing time and number of flares compared to colchicine.<a class="elsevierStyleCrossRef" href="#bib0275">55</a>Doxycycline. No oral efficacy has been shown.Other treatmentsBiologic treatments. The anti-TNFα drugs (etanercept, adalimumab, infliximab and golimumab) have published case reports of success in the treatment of severe and recalcitrant RAS. The evidence is based on case series, single cases and uncontrolled trials. In addition, some of these drugs used in systemic diseases, such as Behçet's disease or Crohn's disease, have been effective in the treatment of oral ulcers in patients with the spectrum of their diseases.<a class="elsevierStyleCrossRefs" href="#bib0275">55,56</a>IL inhibitors. Anakinra (IL-1 inhibitor), ustekinumab (anti-IL-12/23), secukinumab (anti-IL-17). Used as a treatment for systemic diseases, have shown improvement with oral ulcers as a clinical manifestation (Behçet's disease or Crohn's disease).<a class="elsevierStyleCrossRefs" href="#bib0285">57,58</a>Apremilast. It is a small phosphodiesterase-4 (anti-PDE-4) inhibitor molecule. It inhibits the production of pro-inflammatory cytokines, including TNF-α, and increases the production of anti-inflammatory mediators. It has been used for the treatment of psoriasis and psoriatic arthritis and has recently been shown to be effective in the treatment of ulcers associated with Behçet's disease. Case series of RAS with good response have also been published.<a class="elsevierStyleCrossRef" href="#bib0295">59</a>Laser therapy. CO2, neodymium:YG and diode lasers have been used. They have been employed for their role in ulcer epithelialisation. They have had similar or superior efficacy to topical glucocorticoids in some studies, with reduced pain and accelerated ulcer healing.<a class="elsevierStyleCrossRef" href="#bib0300">60</a>In conclusion, RAS is a common entity in our setting. We must first rule out whether recurrent aphthous ulcers occur in the absence of systemic disease and we are dealing with RAS. The therapeutic approach should be based on the clinical severity and frequency of flares. In patients with isolated episodes of oral aphthous ulcers, topical medication should be used. Systemic treatment is reserved for patients with repeated flares over time, severe clinical presentation or severe pain that do not respond to topical treatments.Publication ethics<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0065">1Has your work involved animal testing?: no.</li><li class="elsevierStyleListItem" id="lsti0070">2Does your work involve patients or human subjects?: no.</li><li class="elsevierStyleListItem" id="lsti0075">3Does your work involve a clinical trial?: no.</li><li class="elsevierStyleListItem" id="lsti0080">4Are all data shown in the figures and tables of the manuscript included in the results and conclusions section?: yes.</li></ul>FundingThe authors have not received funding for this study.Conflict of interestThe authors declare that they have no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:15 [ 0 => array:3 [ "identificador" => "xres1975401" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1699047" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1975400" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1699046" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Epidemiology" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Aetiopathogenesis" "secciones" => array:10 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Genetic factors" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Immunological factors" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Mechanical injuries" ] 3 => array:2 [ "identificador" => "sec0035" "titulo" => "Infections" ] 4 => array:2 [ "identificador" => "sec0040" "titulo" => "Microbiota" ] 5 => array:2 [ "identificador" => "sec0045" "titulo" => "Allergies" ] 6 => array:2 [ "identificador" => "sec0050" "titulo" => "Vitamin and micronutrient deficiencies" ] 7 => array:2 [ "identificador" => "sec0055" "titulo" => "Hormonal factors" ] 8 => array:2 [ "identificador" => "sec0060" "titulo" => "Stress" ] 9 => array:2 [ "identificador" => "sec0065" "titulo" => "Drugs" ] ] ] 7 => array:2 [ "identificador" => "sec0070" "titulo" => "Clinical presentations" ] 8 => array:2 [ "identificador" => "sec0075" "titulo" => "Differential diagnosis" ] 9 => array:2 [ "identificador" => "sec0080" "titulo" => "Diagnosis" ] 10 => array:3 [ "identificador" => "sec0085" "titulo" => "Treatment" "secciones" => array:3 [ 0 => array:3 [ "identificador" => "sec0090" "titulo" => "Prevention and general measures" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0095" "titulo" => "Oral hygiene" ] 1 => array:2 [ "identificador" => "sec0100" "titulo" => "Diet" ] 2 => array:2 [ "identificador" => "sec0105" "titulo" => "Sodium lauryl sulphate (SLS)" ] 3 => array:2 [ "identificador" => "sec0110" "titulo" => "Dietary supplements" ] ] ] 1 => array:3 [ "identificador" => "sec0115" "titulo" => "Topical treatments" "secciones" => array:7 [ 0 => array:2 [ "identificador" => "sec0120" "titulo" => "Topical glucocorticoids" ] 1 => array:2 [ "identificador" => "sec0125" "titulo" => "Topical anaesthetics" ] 2 => array:2 [ "identificador" => "sec0130" "titulo" => "Topical non-glucocorticoid anti-inflammatory agents" ] 3 => array:2 [ "identificador" => "sec0135" "titulo" => "Topical antibiotics (tetracyclines)" ] 4 => array:2 [ "identificador" => "sec0140" "titulo" => "Sucralfate suspension" ] 5 => array:2 [ "identificador" => "sec0145" "titulo" => "Hyaluronic acid" ] 6 => array:2 [ "identificador" => "sec0150" "titulo" => "Other topical treatments" ] ] ] 2 => array:3 [ "identificador" => "sec0155" "titulo" => "Systemic treatment" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0160" "titulo" => "Systemic glucocorticoids" ] 1 => array:2 [ "identificador" => "sec0165" "titulo" => "Non-steroidal anti-inflammatory drugs and systemic immunomodulators" ] 2 => array:2 [ "identificador" => "sec0170" "titulo" => "Systemic antibiotics" ] 3 => array:2 [ "identificador" => "sec0175" "titulo" => "Other treatments" ] ] ] ] ] 11 => array:2 [ "identificador" => "sec0180" "titulo" => "Publication ethics" ] 12 => array:2 [ "identificador" => "sec0185" "titulo" => "Funding" ] 13 => array:2 [ "identificador" => "sec0190" "titulo" => "Conflict of interest" ] 14 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-03-29" "fechaAceptado" => "2023-05-29" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1699047" "palabras" => array:3 [ 0 => "Recurrent aphthous stomatitis" 1 => "Diagnosis" 2 => "Treatment" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1699046" "palabras" => array:3 [ 0 => "Estomatitis aftosa recurrente" 1 => "Diagnóstico" 2 => "Tratamiento" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Recurrent aphthous stomatitis (RAS) is the most common clinical disease of the oral mucosa. Its prevalence in the general population varies between 5 and 25%, with its peak appearance in the second decade of life. So far, the etiopathogenesis is not clear. In genetically predisposed patients, the effect of certain triggering factors would initiate the proinflammatory cytokine cascade directed against certain regions of the oral mucosa. Ulcers are round or oval with well-defined erythematous margins and a shallow ulcerated center covered with a gray or yellowish fibrinous pseudomembrane. The ulcers may reappear at intervals of a few days and months. Given the appearance of periodic thrush in the oral mucosa, the first thing to do is to make a correct differential diagnosis, rule out associated systemic diseases and assess treatable causes before reaching the diagnosis of RAS. At present, there is no curative treatment." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La estomatitis aftosa recurrente (EAR) es la enfermedad clínica más frecuente de la mucosa oral. Su prevalencia en la población general varía entre el 5 y el 25%, siendo su pico de aparición en la segunda década de la vida. Hasta el momento, la etiopatogenia no está aclarada. En pacientes genéticamente predispuestos, el efecto de ciertos factores desencadenantes iniciaría la cascada de citocinas proinflamatorias dirigidas contra determinadas regiones de la mucosa oral. Las úlceras son redondas u ovaladas con márgenes eritematosos bien definidos y centro poco profundo ulcerado cubierto con una pseudomembrana fibrinosa de color gris o amarillento. Pueden reaparecer a intervalos de pocos días y meses. Ante la aparición de aftas periódicas en la mucosa bucal, lo primero será realizar con correcto diagnóstico diferencial, descartar enfermedades sistémicas asociadas y valorar causas tratables antes de llegar al diagnóstico de EAR. En el momento actual no existe tratamiento curativo." ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "The following are Supplementary data to this article:<elsevierMultimedia ident="upi0005"></elsevierMultimedia><elsevierMultimedia ident="upi0010"></elsevierMultimedia>" "etiqueta" => "Appendix A" "titulo" => "Supplementary data" "identificador" => "sec0200" ] ] ] ] "multimedia" => array:8 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 532 "Ancho" => 1207 "Tamanyo" => 102793 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Oval ulcer with well-defined erythematous margins and shallow ulcerated centre covered with a greyish fibrinous pseudomembrane on the right lower gum." ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2586 "Ancho" => 2508 "Tamanyo" => 242326 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Sequence of the diagnostic process." ] ] 2 => array:8 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 2702 "Ancho" => 2508 "Tamanyo" => 512038 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Therapeutic approach." ] ] 3 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "RAS, recurrent aphthous stomatitis.Adapted from Akintoye et al.<a class="elsevierStyleCrossRef" href="#bib0135">27</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Minor RAS \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Major RAS \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Herpetiform RAS \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sex \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Women = men \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Women = men \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Women > men \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Peak age \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2nd decade \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1st-2nd decade \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3rd decade \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Size \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><10 mm \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>10 mm \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2−3 mm \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Number \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1−5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1−10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10−100 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Morphology \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Round or ovalGreyish-white pseudomembranesErythematous halo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Round or oval, crater-shapedGreyish-white pseudomembranesErythematous halo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DeepConvergingIrregular contours \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Site \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Non-keratinised mucosa: lips, cheeks, tongue, floor of the mouth \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mucosa nokeratinised: lips, soft palate, pharynx \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lips, cheeks, tongue, floor of mouth, gums \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Healing \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4−14 days \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>6 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><30 days \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Healing \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Uncommon \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Common \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Uncommon \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3287836.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Clinical classification." ] ] 4 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0025" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "CMV, cytomegalovirus; HIV, human immunodeficiency virus; IgA, immunoglobulin A; PFAPA, periodic fever, aphthous stomatitis, pharyngitis and adenopathy; MAGIC, mouth and genital ulcers with inflamed cartilage syndrome." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Recurrent oral stomatitis \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Traumatic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dental appliances, necrotising sialometaplasia \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Nutritional deficits \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Iron, folic acid, zinc, B1, B2, B6, B12 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Viral infections \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HSV, Coxsackie A, herpes zoster virus, CMV, Epstein-Barr, HIV \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bacterial infections \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tuberculosis, syphilis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fungal infections \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Coccidioides immitis, Cryptococcus neoformans, Blastomyces dermatitidis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pharmacological \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fixed drug rash, linear IgA dermatosis, drug-induced bullous pemphigoid, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Autoimmune diseases \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Crohn's disease, Behçet's disease, celiac disease, systemic lupus erythematosus, lichen erythematosus, lupus erythematosus, erosive lichen planus, Wegener's granulomatosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Haematological diseases \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anaemia, neutropenia, hypereosinophilic syndrome \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fever-associated syndromes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cyclic neutropenia, PFAPA syndrome, Sweet's syndrome, familial Mediterranean fever, hyperimmunoglobulinaemia D syndrome \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vesicular-bullous diseases \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pemphigus vulgaris, linear IgA disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hereditary diseases \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Epidermolysis bullosa, chronic granulomatous disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Other \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MAGIC Syndrome, IgG4-related disease, tumours, smoking \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3287837.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Causes of acute and chronic oral ulcers." ] ] 5 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0030" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "RAS, recurrent aphthous stomatitis; MAGIC, mouth and genital ulcers with inflamed cartilage syndrome; PFAPA, periodic fever, adenopathy, pharyngitis and aphthae; HIV, human immunodeficiency virus." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Disease \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Comment \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Recurrent acute stomatitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Recurrent round or oval oral ulcers with well-defined erythematous margins and a centre covered with grey or yellowish fibrinous pseudomembrane \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Behçet's disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oral ulcers similar to recurrent aphthous stomatitis and, in addition, genital ulcers, eye inflammation, skin lesions, as well as joint, vascular, neurological, pulmonary, gastrointestinal and genitourinary manifestations. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MAGIC Syndrome (mouth and genital ulcers with inflamed cartilage) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Overlap syndrome between Behçet's syndrome and relapsing polychondritis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sweet's Syndrome (or acute neutrophilic dermatosis) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Superficial ulceration similar to RAS. In addition, there is sudden onset fever, leukocytosis and well-demarcated skin lesions such as papules or plum-coloured plaques. It usually occurs in middle-aged women. In 50% of patients there is an associated malignancy (e.g., acute myeloid leukaemia). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PFAPA Syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Recurrent febrile episodes (every 3–6 weeks) accompanied by pharyngitis, oral thrush and cervical lymphadenopathy. It appears in children before the age of 5 and symptoms disappear 4 years after onset. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cyclic neutropenia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Autosomal dominant disorder of bone marrow stem cells characterised by cyclical onset of fever, malaise, pharyngitis and aphthous stomatitis beginning in infancy. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HIV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oral lesions in HIV patients may be attributed to infections, neoplasms (e.g., Kaposi's sarcoma) or non-specific causes such as ulcerations. Morphologically these ulcers are similar to those of RAS. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Coeliac disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Canker sores have no distinguishing features from those of RAS, but usually resolve with proper management of celiac disease. They may also reflect nutritional deficitsThe prevalence of patients with coeliac disease who have concurrent RAS varies from 10−18%. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inflammatory bowel disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Multiple small aphthous ulcers in the upper and lower gastrointestinal tractMay reflect nutritional deficits \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3287838.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Main entities for the differential diagnosis of diseases with recurrent ulcers." ] ] 6 => array:5 [ "identificador" => "upi0005" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "Ecomponente" => array:2 [ "fichero" => "mmc1.jpg" "ficheroTamanyo" => 812184 ] ] 7 => array:5 [ "identificador" => "upi0010" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "Ecomponente" => array:2 [ "fichero" => "mmc2.jpg" "ficheroTamanyo" => 1662108 ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:60 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Oral mucosal disease: recurrent aphthous stomatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "C. 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Review

Recurrent aphthous stomatitis

Estomatitis aftosa recurrente

Raquel Conejero del Mazoa,

Corresponding author

raquel_conejero@hotmail.com

Corresponding author.

, Laura García Forcénb, María Elena Navarro Aguilarc

a Servicio de Dermatología, Hospital Royo Villanova, Zaragoza, Spain

b Centro de Salud Ejea de los Caballeros, Ejea de los Caballeros, Zaragoza, Spain

c Servicio de Urgencias, Hospital San Jorge, Huesca, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Recurrent aphthous stomatitis &#40;RAS&#41; is a very common clinical entity of the oral mucosa&#46; It is characterised by multiple recurrent ulcers &#40;aphthae&#41;&#44; round or ovoid&#44; with circumscribed margins&#44; erythematous borders and a yellowish-grey pseudomembranous base&#46; They are usually located on the oral mucosa&#44; lips and tongue surface and are very painful for the first 4&#8211;5 days&#46; Episodes of ulcers may recur at intervals of days to months&#44; with the first lesions usually occurring in childhood or adolescence&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Epidemiology</span><p id="par0010" class="elsevierStylePara elsevierViewall">Its prevalence in the general population varies between 5 and 25&#37;&#44; reaching up to 60&#37; in some studies&#44; depending on the origin of the groups and populations studied&#44; as well as the design of the studies and their methodology&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The peak onset of RAS is in the second decade of life&#44; with the first episode often occurring in childhood or adolescence&#46; As people age&#44; the recurrence rate&#44; as well as the severity of episodes&#44; tends to decrease&#46; It is uncommon after the age of 40&#44; although it has also been described in the elderly population&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;5</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Aetiopathogenesis</span><p id="par0020" class="elsevierStylePara elsevierViewall">So far&#44; its aetiopathogenesis has not been clarified and multiple factors are thought to play a role&#46; In genetically predisposed patients&#44; the effect of certain triggering factors would initiate an immune dysfunction affecting certain areas of the oral mucosa&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Factors that have been implicated as triggers of the inflammatory response in RAS include&#58; genetic factors&#44; immunological factors&#44; mechanical injury&#44; viral and bacterial infections&#44; changes in the oral microbiota&#44; allergies&#44; vitamin and microelement deficiencies&#44; hormonal factors&#44; stress and drugs&#46; Their involvement is described below&#46;</p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Genetic factors</span><p id="par0030" class="elsevierStylePara elsevierViewall">Its role was confirmed in studies conducted in relatives and twins with RAS where a positive family history of the disease was reported in 24&#8211;46&#37; of cases&#46; In addition&#44; patients with a family history of RAS have more common recurrences and a more severe course&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Genetic risk factors may determine individual susceptibility to RAS and include several DNA polymorphisms&#44; especially those related to alterations in the metabolism of interleukins&#44; interferon gamma &#40;IFN-&#947; &#41; and tumour necrosis factor alpha &#40;TNF-&#945;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> In addition&#44; in patients with RAS&#44; an increased incidence of HLA-A33&#44; HLA-B35 and HLA-B81&#44; HLA-B12&#44; HLA-B51&#44; HLA-DR7 and HLA-DR5&#44; and a decreased incidence of HLA-B5 and HLA-DR4<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> was observed&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Immunological factors</span><p id="par0040" class="elsevierStylePara elsevierViewall">Many authors suggest that the Th1-type immune response plays a crucial role in the development of RAS&#44; as there is significantly higher secretion of Th1 cytokines in patients with RAS compared to controls&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Increased production of interleukin-2 &#40;IL-2&#41;&#44; IFN-&#947;&#44; and TNF-&#945; by peripheral blood mononuclear cells was also observed&#44; both in the acute phase of the disease and in remission&#46; Meanwhile&#44; the secretion of anti-inflammatory cytokines&#44; such as transforming growth factor-beta &#40;TGF-&#946;&#41; and IL-10 was significantly lower in patients with RAS&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> This observation confirms that imbalance in the production of pro- and anti-inflammatory cytokines may contribute to the development of autoimmunisation and RAS in predisposed subjects&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Mechanical injuries</span><p id="par0045" class="elsevierStylePara elsevierViewall">Local trauma is one of the most common causes&#44; as it induces oedema&#44; causes inflammation of cells and leads to increased viscosity of the submucosal extracellular matrix&#44; thus more easily triggering RAS&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> These lesions are often caused by dental procedures&#44; orthopaedic devices or sharp or broken teeth&#46; It can also be caused by accidental biting of the tongue or cheek&#44; or by eating hot food&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Most studies indicate a lower incidence of RAS in smokers compared to non-smokers&#46; This could be explained by a higher level of keratinisation of the oral mucosa in response to smoking&#44; which makes it less prone to injury and irritation&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Infections</span><p id="par0055" class="elsevierStylePara elsevierViewall">The role of different viruses and bacteria has been studied to substantiate the infectious aetiology of RAS&#46; On the one hand&#44; several studies have attempted to isolate DNA from herpes simplex virus&#44; cytomegalovirus&#44; varicella-zoster and Epstein-Barr virus in aphthous ulcers&#44; or have performed serological testing of these viruses&#44; but none have confirmed their direct role in the aetiopathogenesis of the condition&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> On the other hand&#44; <span class="elsevierStyleItalic">Helicobacter pylori</span> has been investigated as a potential factor in RAS without finding any direct evidence&#46; Some studies have shown a beneficial effect of its eradication in patients with RAS&#46; However&#44; the underlying mechanism seems to be related to increased serum levels of vitamin B<span class="elsevierStyleInf">12</span> after eradication&#44; rather than to the direct action of the bacteria&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Microbiota</span><p id="par0060" class="elsevierStylePara elsevierViewall">Oral microbiota has been studied in patients with RAS&#44; with a lower level of <span class="elsevierStyleItalic">Streptococcus</span> spp&#46; and an increase in <span class="elsevierStyleItalic">Acinetobacter johnsonii</span> in patients with RAS compared to healthy controls&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> In addition&#44; during the active ulcer phase&#44; an increase in fungal spp&#46; was evident&#44; particularly <span class="elsevierStyleItalic">Malassezia</span> and <span class="elsevierStyleItalic">Candida albicans</span>&#46; This evidence is consistent with the hypothesis of a microbial shift in RAS in favour of opportunistic pathogens&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> There is no evidence that the increased species in RAS lesions play a role in disease onset or progression&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Allergies</span><p id="par0065" class="elsevierStylePara elsevierViewall">Hypersensitivity to certain food substances such as chocolate&#44; gluten&#44; cow&#39;s milk&#44; nuts&#44; preservatives and food dyes may induce the pro-inflammatory cascade that triggers RAS&#46; In some patients&#44; clinical improvement was observed after an elimination diet&#46; However&#44; these findings have not been confirmed by further research&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Sodium lauryl sulphate &#40;SLS&#41;&#44; a common ingredient in toothpastes<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> or materials for dental procedures such as nickel in orthodontic appliances or eugenol contained in cement used for dental restoration&#44; may also trigger RAS&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Vitamin and micronutrient deficiencies</span><p id="par0070" class="elsevierStylePara elsevierViewall">Vitamin and mineral deficiencies have also been proposed as possible aetiological factors in RAS&#46; Several studies have found lower levels of iron&#44; folic acid&#44; zinc or vitamins B<span class="elsevierStyleInf">1</span> and B<span class="elsevierStyleInf">12</span>&#44; and vitamin D&#44; in patients with RAS&#46; Some of these nutritional deficiencies may be secondary to other diseases&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#44;18</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Hormonal factors</span><p id="par0075" class="elsevierStylePara elsevierViewall">The relationship between the occurrence of aphthous ulcers and the menstrual cycle in women has not been clearly established&#46; It seems that exacerbation of RAS is observed in the luteal phase of the cycle&#44; while remission often occurs during pregnancy or with the use of contraceptives&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Stress</span><p id="par0080" class="elsevierStylePara elsevierViewall">In predisposed patients&#44; stressful events are thought to exacerbate RAS&#44; with mental stressors having a greater impact than physical stressors&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> However&#44; no direct correlation has been found between the level of stress and the severity of RAS episodes&#46; This suggests that stress may act as a trigger or modifier rather than an aetiological factor&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Drugs</span><p id="par0085" class="elsevierStylePara elsevierViewall">Different cases of drug-induced RAS have been reported&#44; including non-steroidal anti-inflammatory drugs&#44;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> beta-blockers&#44; angiotensin-converting enzyme inhibitors&#44;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> nicorandil&#44; antibiotics&#44; bisphosphonates&#44;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> chemotherapeutics such as 5-fluorouracil and doxorubicin&#44; and immunosuppressants such as calcineurin and mammalian target of rapamycin &#40;mTOR&#41; inhibitors&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> More recently&#44; cases have also been reported with tocilizumab<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> and orlistat&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> Ulcers usually disappear with discontinuation of treatment&#46; Therefore&#44; it is imperative to examine the medication history of patients with RAS&#46; In addition&#44; abuse of illegal drugs such as cocaine or amphetamines also increases the incidence rate of RAS&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Clinical presentations</span><p id="par0090" class="elsevierStylePara elsevierViewall">Patients with RAS usually experience prodromal burning sensations 2&#8722;48&#8239;h before an ulcer develops&#46; Ulcers are round or oval with well-defined erythematous margins and a shallow ulcerated centre covered with a grey or yellowish fibrinous pseudomembrane&#46; Ulcers usually develop on the non-keratinised oral mucosa&#44; with the buccal mucosa and lips &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41; being the most common sites&#46; Episodes of ulcers may recur at intervals ranging from a few days to months&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> They are usually very painful&#44; with pain similar to that of a burn&#44; which increases on contact with hot food or spices&#46; Their presence can make speech&#44; chewing and swallowing difficult&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">There are 3&#8239;forms of presentation for aphthous ulcers in RAS&#58; minor &#40;or Mikulicz&#39;s aphthous ulcers&#41;&#44; major &#40;or Sutton&#39;s disease&#41; and herpetiform&#44; which differ in morphology&#44; distribution&#44; severity and prognosis&#46; Their general characteristics are described in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Differential diagnosis</span><p id="par0100" class="elsevierStylePara elsevierViewall">The main causes of both chronic and acute oral mucosa ulcers are listed in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">Some patients experience longer flares that are sometimes continuous and may be accompanied by occasional genital ulcers&#46; This corresponds to a condition known as complex aphthosis and has an underlying systemic cause&#46; Complex aphthosis&#44; as well as recurrent ulcers that have an underlying systemic cause&#44; should be considered as a distinct medical condition&#46; The term RAS should be used for recurrent ulceration in the absence of systemic disease&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> Differential diagnoses should be established with autoinflammatory syndromes and immunodeficiency states&#44; including nutritional defects&#44; immune defects and neutrophil defects&#46; <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> lists the main diseases in the differential diagnosis of RAS&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Diagnosis</span><p id="par0110" class="elsevierStylePara elsevierViewall">It is based on clinical history and findings&#46; No specific diagnostic test is currently available&#46; It is essential to consider a possible systemic cause&#44; especially in adult patients who suddenly develop RAS&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">The sequence of the diagnostic process is shown in the algorithm shown in <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">A thorough history-taking should be carried out&#44; gathering medical history &#40;personal and family history of systemic or dermatological disease&#41;&#44; drugs&#44; allergies&#44; dietary habits and toxins&#46; In addition&#44; an attempt should be made to establish the time of onset of the first lesion&#59; the time of progression and duration of the lesions&#44; as well as the coexistence of similar lesions in other areas&#46; The presence of accompanying local and systemic symptoms and the association with local trauma or any other situation &#40;stress&#44; menstrual cycle&#44; smoking cessation&#41; should be investigated&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">The clinical examination will complement the history-taking by a systematic inspection of the oral mucosa&#46; Ulcers have a very characteristic appearance as described above&#46; In addition&#44; a physical examination of all mucocutaneous surfaces including scalp&#44; nails and anogenital region is recommended&#44; as well as a search for adenopathies in the head and neck regions to exclude underlying disease&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Additional tests should be performed to rule out underlying systemic disease or if there is diagnostic uncertainty&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0135" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Blood tests</span>&#58; complete blood count&#44; levels of iron&#44; ferritin&#44; folic acid&#44; zinc&#44; magnesium and group B vitamins&#46; It is also recommended to request anti-transglutaminase and anti-endomysial antibodies to rule out coeliac disease&#44; as well as antinuclear antibodies&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0140" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Microbiological tests</span>&#58; Tzanck smear or PCR for herpes virus&#44; fungal and bacterial culture&#44; according to diagnostic doubts&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0145" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Biopsy&#58;</span> the sample should include part of the ulcer and perilesional tissue&#44; including the surrounding unaffected epithelium&#46; It is indicated in 3 scenarios&#58; &#40;1&#41; ulcer of unknown origin&#44; with no signs of healing&#44; after 2 weeks&#59; &#40;2&#41; ulcer of known probable aetiology&#44; but not responding to adequate treatment&#44; after 2 weeks&#59; and &#40;3&#41; ulcer caused by precipitating factors&#44; but with no signs of healing 2 weeks after elimination of these factors&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0150" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Histology</span>&#58; Microscopic features of RAS are not specific&#46; The pre-ulcerous lesion shows subepithelial inflammatory mononuclear cells &#40;monocytes and mainly T-type lymphocytes&#41; with abundant mast cells&#44; connective tissue oedema and lining of the margins with neutrophils&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> In later stages&#44; polymorphonuclear leukocytes dominate in the centre of the ulcer&#44; while abundant mononuclear cell infiltration is observed at the edge of the lesion&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p></li></ul></p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Treatment</span><p id="par0155" class="elsevierStylePara elsevierViewall">At the present time there is no curative treatment for RAS&#44; so the therapeutic objectives that we must seek&#44; and transmit to patients&#44; will be to relieve pain&#44; reduce the time it takes for ulcers to heal and reduce the frequency and severity of episodes&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">When recurrent aphthous ulcers appear on the oral mucosa&#44; the first thing to do is to carry out a correct differential diagnosis&#44; rule out associated diseases and assess treatable causes before reaching a diagnosis of RAS&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">Although it is a high-prevalence disease&#44; there are no quality clinical trials that evaluate the different treatments used for RAS&#44; so there are no therapeutic guidelines or standardised treatment for it&#44; and it is not included in the indications for any drug&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">The therapeutic approach &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41; for the patient will be based on the clinical severity of the flares and their frequency&#46; In patients with isolated episodes of oral aphthosis&#44; topical medication should be used to help improve pain and reduce the time it takes for the lesions to heal&#46; Systemic treatment is reserved for patients with repeated flares over time&#44; severe clinical presentation or severe pain that do not respond to topical treatments&#46; In addition&#44; in these cases&#44; our aim with treatment will also be to try to space out the flares&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33&#8211;35</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0175" class="elsevierStylePara elsevierViewall">We will divide this section into prevention and general measures&#44; topical treatments and systemic treatments&#46;</p><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Prevention and general measures</span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Oral hygiene</span><p id="par0180" class="elsevierStylePara elsevierViewall">Patients should be urged to maintain proper oral hygiene and try to avoid trauma&#44; as this has been linked to the development of aphthous ulcers&#46; A soft toothbrush and alcohol-free mouthwash are advised&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33&#8211;35</span></a></p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Diet</span><p id="par0185" class="elsevierStylePara elsevierViewall">There are no studies on the role of diet&#44; therefore&#44; dietary restrictions should not be recommended unless the patient associates certain foods with flares&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Sodium lauryl sulphate &#40;SLS&#41;</span><p id="par0190" class="elsevierStylePara elsevierViewall">SLS is a common ingredient in toothpaste&#46; It has been associated with cases of RAS&#44; so we should recommend that patients use toothpastes without SLS&#46; A systematic review comparing the effects of toothpastes with and without SLS showed a reduction in the number and duration of ulcers&#44; the number of episodes and ulcer pain&#46; Although the differences were not statistically significant for some of the characteristics mentioned&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Dietary supplements</span><p id="par0195" class="elsevierStylePara elsevierViewall">It is necessary to rule out nutritional deficiencies &#40;vitamin B<span class="elsevierStyleInf">12</span>&#44; folic acid&#44; iron&#44; zinc&#44; etc&#46;&#41; in patients with RAS and&#44; if found&#44; to treat them correctly&#44; as in these cases the symptoms may improve with appropriate treatment&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">Vitamin B<span class="elsevierStyleInf">12</span> &#8239; has been shown to prevent the symptoms of RAS&#46; A randomised&#44; double-blind&#44; placebo-controlled study showed a reduction in the duration&#44; number and pain of ulcers in patients treated with vitamin B<span class="elsevierStyleInf">12</span> 1000&#8239;&#956; g sublingual daily for 6 months&#46; In addition&#44; a vitamin B<span class="elsevierStyleInf">12</span> ointment applied for 2 days also showed an improvement in pain in patients with RAS&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">Zinc supplementation has been evaluated as a potential preventive measure and as treatment for its anti-inflammatory and healing properties&#46; In one study&#44; no statistically significant differences were found between serum zinc levels between cases of RAS patients and controls&#46; On the other hand&#44; a systematic review of 7 publications suggests efficacy of zinc supplementation in 5 of them&#44; with no significant differences between the zinc-treated group and controls in the others&#46; Until further research is available to confirm the efficacy of zinc supplementation for the prevention of RAS&#44; it could be considered as a measure&#44; due to its low cost and low potential for side effects&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">Vitamin D deficiency has also been associated with RAS in a systematic review&#46; No publications on improvement or control of symptoms by vitamin D supplementation have been found&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">There have also been studies showing improvement with 1&#44;000&#8239;mg&#8239;omega-3 daily for 6 months&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">Supplementation with other vitamin complexes in patients without nutritional deficits has not shown any improvement in the clinical picture or decrease in the number of disease flares&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a></p><p id="par0225" class="elsevierStylePara elsevierViewall">The use of probiotics in the treatment of RAS is supported by a meta-analysis of 3&#8239;studies showing that oral intake or topical application of probiotics significantly reduced pain compared to placebo&#46; While probiotics alone were not effective in achieving an improvement in ulcer severity&#44; they did provide benefits as an adjuvant to corticosteroids or topical anaesthetics&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33&#44;36</span></a></p></span></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Topical treatments</span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Topical glucocorticoids</span><p id="par0230" class="elsevierStylePara elsevierViewall">They are the first-line treatment for RAS&#46; Topical glucocorticoids are more effective in reducing the severity and duration of lesions &#40;systemic glucocorticoids will be more effective in reducing recurrences&#41;&#46; They are applied from the beginning of the episode and 3&#8211;4 times a day&#44; preferably after oral hygiene&#46; No liquid or solid food should be eaten for the next half hour&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36&#44;40&#44;41</span></a></p><p id="par0235" class="elsevierStylePara elsevierViewall">Several treatment options are available&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">-</span><p id="par0240" class="elsevierStylePara elsevierViewall">Triamcinolone acetone 0&#46;1&#37; has been the most commonly used&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">-</span><p id="par0245" class="elsevierStylePara elsevierViewall">Fluocinolone acetonide 0&#46;025&#8211;0&#46;05&#37;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">-</span><p id="par0250" class="elsevierStylePara elsevierViewall">Clobetasol 0&#46;025&#8211;0&#46;05&#37;&#46; It is more potent and is reserved for more severe cases&#46;</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">-</span><p id="par0255" class="elsevierStylePara elsevierViewall">Dexamethasone solution &#40;0&#46;5&#8239;mg&#47;5&#8239;cc&#41; or ointment&#46;</p></li></ul></p></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Topical anaesthetics</span><p id="par0260" class="elsevierStylePara elsevierViewall">They provide pain relief&#46; They are applied several times a day&#44; preferably before meals and oral hygiene&#44; to make them easier to use&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">41&#44;42</span></a> Among those used in RAS are&#58;<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">-</span><p id="par0265" class="elsevierStylePara elsevierViewall">Lidocaine 1&#37; cream and 2&#37; gel or spray&#46;</p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">-</span><p id="par0270" class="elsevierStylePara elsevierViewall">Benzocaine gel 20&#37;&#46;</p></li></ul></p><p id="par0275" class="elsevierStylePara elsevierViewall">Topical antiseptics&#58; prevent superinfection by bacteria and fungi&#46; They assist in oral hygiene&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">41&#44;43</span></a> The following have been used&#58;<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">1</span><p id="par0280" class="elsevierStylePara elsevierViewall">Triclosan 0&#46;15&#37;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">2</span><p id="par0285" class="elsevierStylePara elsevierViewall">Chlorhexidine 0&#46;12&#8211;0&#46;2&#37;&#46;</p></li></ul></p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Topical non-glucocorticoid anti-inflammatory agents</span><p id="par0290" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Amlexanox</span> 5&#37;&#46; It has anti-inflammatory and anti-allergic properties&#46; It is the only molecule approved by the FDA as a medication for the treatment of RAS&#44; but it is not available in our setting&#46; It is applied 2&#8211;4 times a day&#46; Its efficacy is comparable to oral glucocorticoids&#46; It has shown efficacy in improving pain and accelerating ulcer healing&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36&#44;44</span></a></p><p id="par0295" class="elsevierStylePara elsevierViewall">Benzydamine rinse&#46; It has a local anaesthetic effect that improves the pain caused by oral ulcers&#44; but not the healing&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36&#44;45</span></a></p></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Topical antibiotics &#40;tetracyclines&#41;</span><p id="par0300" class="elsevierStylePara elsevierViewall">Topical doxycycline and minocycline have been used for their antibacterial effects and possible inhibition of the collagenases and metalloproteinases that cause ulcer formation&#46; Several studies with small numbers of patients demonstrated that topical doxycycline &#40;100&#8239;mg in 10&#8239;ml of water&#41; reduces the signs and symptoms of RAS in all patients&#46; Another review indicated a decrease in healing time&#44; but no difference in pain control versus placebo&#46;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">46&#44;47</span></a> Minocycline has been used as a 0&#46;5&#37; rinse with good results in reducing signs and symptoms of RAS&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a></p></span><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Sucralfate suspension</span><p id="par0305" class="elsevierStylePara elsevierViewall">Oral rinses with 5&#8239;ml for 1&#8211;2&#8239;min 3&#8211;4 times&#47;day and relieves pain&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">43&#44;47</span></a></p></span><span id="sec0145" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Hyaluronic acid</span><p id="par0310" class="elsevierStylePara elsevierViewall">Several publications evaluating the effectiveness of hyaluronic acid treatment in oral aphthous ulcers conclude that they are effective in reducing pain&#44; ulcer size and inflammatory signs&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">49&#44;50</span></a></p></span><span id="sec0150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Other topical treatments</span><p id="par0315" class="elsevierStylePara elsevierViewall">Series with small numbers of patients have reported the use of diclofenac 3&#37;&#44; a 2&#46;5&#37; hyaluronic acid gel&#44;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> traditional Chinese medicine&#44; pumpkin seed oil&#44; chamomile&#44; turmeric and others&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">50&#8211;53</span></a></p><p id="par0320" class="elsevierStylePara elsevierViewall">Topical treatments can be combined with each other&#44; enhancing the effects they have in monotherapy&#46;</p></span></span><span id="sec0155" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0175">Systemic treatment</span><p id="par0325" class="elsevierStylePara elsevierViewall">As mentioned above&#44; in patients with moderate to severe episodes of RAS&#44; refractory to general care and topical treatments&#44; systemic treatment should be considered&#46;</p><span id="sec0160" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0180">Systemic glucocorticoids</span><p id="par0330" class="elsevierStylePara elsevierViewall">These are the most commonly used systemic treatments&#46; They have been used in different regimens&#44; both long-term regimens with low doses&#44; such as prednisone 5&#8239;mg a day for 3 months&#44; and short-term regimens of prednisone 20&#8211;40&#8239;mg a day for 4&#8211;7 days and continue with tapering for 1 month&#44; or prednisone 25&#8239;mg a day for 15 days with a dose reduction over 2 months&#46; They improve pain&#44; accelerate healing and reduce the number of episodes&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33&#44;40&#44;47</span></a></p><p id="par0335" class="elsevierStylePara elsevierViewall">Oral glucocorticoids should be used in appropriate doses and for a limited time because of the undesirable effects they may have in the long term&#46; When episodes have not been controlled by systemic glucocorticoids&#44; or when adverse effects occur&#44; or when the dose or the time used have risks of adverse effects&#44; other treatments should be considered&#46;</p></span><span id="sec0165" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0185">Non-steroidal anti-inflammatory drugs and systemic immunomodulators</span><p id="par0340" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Thalidomide&#46;</span> It has been used for its TNF-&#945; inhibiting effect&#46; Its teratogenic effect and other side effects such as neutropenia&#44; abdominal pain&#44; paresthesias and irreversible peripheral neuropathy should be taken into account&#44; so patients should be selected correctly&#46; For RAS it has been used at doses of 25&#8211;100&#8239;mg per day with good results on symptomatology&#44; including a decrease in the number of recurrences&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a></p><p id="par0345" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Colchicine&#46;</span> An antimitotic drug with anti-inflammatory and antifibrotic effects&#46; Used at doses between 0&#46;5&#8211;2&#8239;mg with mixed results&#46; The 2012 Cochrane review<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> concludes that it is not a useful drug in the treatment of RAS when compared to oral glucocorticoids due to equal or inferior efficacy&#44; but with a higher rate of side effects&#44; mainly gastrointestinal&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33&#44;50&#44;54</span></a></p><p id="par0350" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Montelukast&#46;</span> It is a leukotriene inhibitor&#46; It has shown improvement in pain and accelerated healing in some studies&#44; in addition to reducing the development of new lesions&#44; when taking 10&#8239;mg per month for 1 month and 10&#8239;mg every 2 days for another month&#46; Less effective than prednisone&#44; but less adverse effects and good tolerance&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33&#44;50</span></a></p><p id="par0355" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Levamisole&#46;</span> Several studies with mixed and inconclusive results&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p><p id="par0360" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Pentoxifylline</span>&#46; A drug that inhibits the production of TNF-&#945;&#44; neutrophils and chemotaxis&#46; It has been studied at a dose of 400&#8239;mg 3 times a day&#44; with a decrease in pain and ulcer size compared to placebo&#44; but with small differences&#46; There are insufficient data to recommend or rule out its use&#46;</p></span><span id="sec0170" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0190">Systemic antibiotics</span><p id="par0365" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Dapsone&#46;</span> Used at doses of 25&#8211;150&#8239;mg per day depending on response and tolerance&#46; It has been associated in some publications with a reduction in the number and size of canker sores&#46;</p><p id="par0370" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Clofazimine&#46;</span> Antimicrobial used for the treatment of mycobacteria&#46; It has been compared against colchicine at a dose of 100&#8239;mg per day for 1 month followed by 100&#8239;mg every other day for 6 months&#44; showing a reduction in healing time and number of flares compared to colchicine&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a></p><p id="par0375" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Doxycycline&#46;</span> No oral efficacy has been shown&#46;</p></span><span id="sec0175" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0195">Other treatments</span><p id="par0380" class="elsevierStylePara elsevierViewall">Biologic treatments&#46; The <span class="elsevierStyleItalic">anti-TNF&#945; drugs</span> &#40;etanercept&#44; adalimumab&#44; infliximab and golimumab&#41; have published case reports of success in the treatment of severe and recalcitrant RAS&#46; The evidence is based on case series&#44; single cases and uncontrolled trials&#46; In addition&#44; some of these drugs used in systemic diseases&#44; such as Beh&#231;et&#39;s disease or Crohn&#39;s disease&#44; have been effective in the treatment of oral ulcers in patients with the spectrum of their diseases&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">55&#44;56</span></a></p><p id="par0385" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">IL inhibitors&#46;</span> Anakinra &#40;IL-1 inhibitor&#41;&#44; ustekinumab &#40;anti-IL-12&#47;23&#41;&#44; secukinumab &#40;anti-IL-17&#41;&#46; Used as a treatment for systemic diseases&#44; have shown improvement with oral ulcers as a clinical manifestation &#40;Beh&#231;et&#39;s disease or Crohn&#39;s disease&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">57&#44;58</span></a></p><p id="par0390" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Apremilast&#46;</span> It is a small phosphodiesterase-4 &#40;anti-PDE-4&#41; inhibitor molecule&#46; It inhibits the production of pro-inflammatory cytokines&#44; including TNF-&#945;&#44; and increases the production of anti-inflammatory mediators&#46; It has been used for the treatment of psoriasis and psoriatic arthritis and has recently been shown to be effective in the treatment of ulcers associated with Beh&#231;et&#39;s disease&#46; Case series of RAS with good response have also been published&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a></p><p id="par0395" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Laser therapy&#46;</span> CO2&#44; neodymium&#58;YG and diode lasers have been used&#46; They have been employed for their role in ulcer epithelialisation&#46; They have had similar or superior efficacy to topical glucocorticoids in some studies&#44; with reduced pain and accelerated ulcer healing&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a></p><p id="par0400" class="elsevierStylePara elsevierViewall">In conclusion&#44; RAS is a common entity in our setting&#46; We must first rule out whether recurrent aphthous ulcers occur in the absence of systemic disease and we are dealing with RAS&#46; The therapeutic approach should be based on the clinical severity and frequency of flares&#46; In patients with isolated episodes of oral aphthous ulcers&#44; topical medication should be used&#46; Systemic treatment is reserved for patients with repeated flares over time&#44; severe clinical presentation or severe pain that do not respond to topical treatments&#46;</p></span></span></span><span id="sec0180" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0200">Publication ethics</span><p id="par0405" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">1</span><p id="par0410" class="elsevierStylePara elsevierViewall">Has your work involved animal testing&#63;&#58; no&#46;</p></li><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">2</span><p id="par0415" class="elsevierStylePara elsevierViewall">Does your work involve patients or human subjects&#63;&#58; no&#46;</p></li><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">3</span><p id="par0420" class="elsevierStylePara elsevierViewall">Does your work involve a clinical trial&#63;&#58; no&#46;</p></li><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">4</span><p id="par0425" class="elsevierStylePara elsevierViewall">Are all data shown in the figures and tables of the manuscript included in the results and conclusions section&#63;&#58; yes&#46;</p></li></ul></p></span><span id="sec0185" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0205">Funding</span><p id="par0430" class="elsevierStylePara elsevierViewall">The authors have not received funding for this study&#46;</p></span><span id="sec0190" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0210">Conflict of interest</span><p id="par0435" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflict of interest&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Recurrent aphthous stomatitis &#40;RAS&#41; is the most common clinical disease of the oral mucosa&#46; Its prevalence in the general population varies between 5 and 25&#37;&#44; with its peak appearance in the second decade of life&#46; So far&#44; the etiopathogenesis is not clear&#46; In genetically predisposed patients&#44; the effect of certain triggering factors would initiate the proinflammatory cytokine cascade directed against certain regions of the oral mucosa&#46; Ulcers are round or oval with well-defined erythematous margins and a shallow ulcerated center covered with a gray or yellowish fibrinous pseudomembrane&#46; The ulcers may reappear at intervals of a few days and months&#46; Given the appearance of periodic thrush in the oral mucosa&#44; the first thing to do is to make a correct differential diagnosis&#44; rule out associated systemic diseases and assess treatable causes before reaching the diagnosis of RAS&#46; At present&#44; there is no curative treatment&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">La estomatitis aftosa recurrente &#40;EAR&#41; es la enfermedad cl&#237;nica m&#225;s frecuente de la mucosa oral&#46; Su prevalencia en la poblaci&#243;n general var&#237;a entre el 5 y el 25&#37;&#44; siendo su pico de aparici&#243;n en la segunda d&#233;cada de la vida&#46; Hasta el momento&#44; la etiopatogenia no est&#225; aclarada&#46; En pacientes gen&#233;ticamente predispuestos&#44; el efecto de ciertos factores desencadenantes iniciar&#237;a la cascada de citocinas proinflamatorias dirigidas contra determinadas regiones de la mucosa oral&#46; Las &#250;lceras son redondas u ovaladas con m&#225;rgenes eritematosos bien definidos y centro poco profundo ulcerado cubierto con una pseudomembrana fibrinosa de color gris o amarillento&#46; Pueden reaparecer a intervalos de pocos d&#237;as y meses&#46; Ante la aparici&#243;n de aftas peri&#243;dicas en la mucosa bucal&#44; lo primero ser&#225; realizar con correcto diagn&#243;stico diferencial&#44; descartar enfermedades sist&#233;micas asociadas y valorar causas tratables antes de llegar al diagn&#243;stico de EAR&#46; En el momento actual no existe tratamiento curativo&#46;</p></span>"
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          "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">RAS&#44; recurrent aphthous stomatitis&#46;</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Adapted from Akintoye et al&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a></p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
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                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Sex&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Women&#8239;&#61;&#8239;men&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Women&#8239;&#61;&#8239;men&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Women&#8239;&#62;&#8239;men&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Peak age&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">2nd decade&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1st-2nd decade&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">3rd decade&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t">&#60;10&#8239;mm&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#62;10&#8239;mm&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2&#8722;3 mm&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Number&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">1&#8722;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">1&#8722;10&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#8722;100&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Morphology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Round or ovalGreyish-white pseudomembranesErythematous halo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Round or oval&#44; crater-shapedGreyish-white pseudomembranesErythematous halo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DeepConvergingIrregular contours&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Site&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Non-keratinised mucosa&#58; lips&#44; cheeks&#44; tongue&#44; floor of the mouth&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mucosa nokeratinised&#58; lips&#44; soft palate&#44; pharynx&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lips&#44; cheeks&#44; tongue&#44; floor of mouth&#44; gums&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Healing&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#8722;14 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;6 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;30 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Healing&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Uncommon&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Common&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Uncommon&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab3287836.png"
              ]
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        "descripcion" => array:1 [
          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Clinical classification&#46;</p>"
        ]
      ]
      4 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">CMV&#44; cytomegalovirus&#59; HIV&#44; human immunodeficiency virus&#59; IgA&#44; immunoglobulin A&#59; PFAPA&#44; periodic fever&#44; aphthous stomatitis&#44; pharyngitis and adenopathy&#59; MAGIC&#44; mouth and genital ulcers with inflamed cartilage syndrome&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Recurrent oral stomatitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Traumatic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dental appliances&#44; necrotising sialometaplasia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nutritional deficits&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Iron&#44; folic acid&#44; zinc&#44; B<span class="elsevierStyleInf">1</span>&#44; B<span class="elsevierStyleInf">2</span>&#44; B<span class="elsevierStyleInf">6</span>&#44; B<span class="elsevierStyleInf">12</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Viral infections&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HSV&#44; Coxsackie A&#44; herpes zoster virus&#44; CMV&#44; Epstein-Barr&#44; HIV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bacterial infections&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tuberculosis&#44; syphilis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fungal infections&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Coccidioides immitis&#44; Cryptococcus neoformans&#44; Blastomyces dermatitidis</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pharmacological&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fixed drug rash&#44; linear IgA dermatosis&#44; drug-induced bullous pemphigoid&#44; erythema multiforme&#44; Stevens-Johnson syndrome&#44; toxic epidermal necrolysis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Autoimmune diseases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Crohn&#39;s disease&#44; Beh&#231;et&#39;s disease&#44; celiac disease&#44; systemic lupus erythematosus&#44; lichen erythematosus&#44; lupus erythematosus&#44; erosive lichen planus&#44; Wegener&#39;s granulomatosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Haematological diseases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anaemia&#44; neutropenia&#44; hypereosinophilic syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fever-associated syndromes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cyclic neutropenia&#44; PFAPA syndrome&#44; Sweet&#39;s syndrome&#44; familial Mediterranean fever&#44; hyperimmunoglobulinaemia D syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Vesicular-bullous diseases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pemphigus vulgaris&#44; linear IgA disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hereditary diseases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Epidermolysis bullosa&#44; chronic granulomatous disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Other&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MAGIC Syndrome&#44; IgG4-related disease&#44; tumours&#44; smoking&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Causes of acute and chronic oral ulcers&#46;</p>"
        ]
      ]
      5 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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        "detalles" => array:1 [
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          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">RAS&#44; recurrent aphthous stomatitis&#59; MAGIC&#44; mouth and genital ulcers with inflamed cartilage syndrome&#59; PFAPA&#44; periodic fever&#44; adenopathy&#44; pharyngitis and aphthae&#59; HIV&#44; human immunodeficiency virus&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Comment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Recurrent acute stomatitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Recurrent round or oval oral ulcers with well-defined erythematous margins and a centre covered with grey or yellowish fibrinous pseudomembrane&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Beh&#231;et&#39;s disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Oral ulcers similar to recurrent aphthous stomatitis and&#44; in addition&#44; genital ulcers&#44; eye inflammation&#44; skin lesions&#44; as well as joint&#44; vascular&#44; neurological&#44; pulmonary&#44; gastrointestinal and genitourinary manifestations&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MAGIC Syndrome <span class="elsevierStyleItalic">&#40;mouth and genital ulcers with inflamed cartilage&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Overlap syndrome between Beh&#231;et&#39;s syndrome and relapsing polychondritis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sweet&#39;s Syndrome &#40;or acute neutrophilic dermatosis&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Superficial ulceration similar to RAS&#46; In addition&#44; there is sudden onset fever&#44; leukocytosis and well-demarcated skin lesions such as papules or plum-coloured plaques&#46; It usually occurs in middle-aged women&#46; In 50&#37; of patients there is an associated malignancy &#40;e&#46;g&#46;&#44; acute myeloid leukaemia&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PFAPA Syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Recurrent febrile episodes &#40;every 3&#8211;6 weeks&#41; accompanied by pharyngitis&#44; oral thrush and cervical lymphadenopathy&#46; It appears in children before the age of 5 and symptoms disappear 4 years after onset&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cyclic neutropenia&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Autosomal dominant disorder of bone marrow stem cells characterised by cyclical onset of fever&#44; malaise&#44; pharyngitis and aphthous stomatitis beginning in infancy&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">HIV&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Oral lesions in HIV patients may be attributed to infections&#44; neoplasms &#40;e&#46;g&#46;&#44; Kaposi&#39;s sarcoma&#41; or non-specific causes such as ulcerations&#46; Morphologically these ulcers are similar to those of RAS&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Coeliac disease&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Canker sores have no distinguishing features from those of RAS&#44; but usually resolve with proper management of celiac disease&#46; They may also reflect nutritional deficitsThe prevalence of patients with coeliac disease who have concurrent RAS varies from 10&#8722;18&#37;&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Inflammatory bowel disease&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Multiple small aphthous ulcers in the upper and lower gastrointestinal tractMay reflect nutritional deficits&nbsp;\t\t\t\t\t\t\n
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Article information

ISSN: 23870206
Original language: English

DOI:10.1016/j.medcle.2023.05.014

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