Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis Syndrome: Relapse and Tonsillar Regrowth After Childhood Tonsillectomy.

OBJECTIVES/HYPOTHESIS: Tonsillectomy is an effective treatment for periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome, but the role of adenoidectomy, as well as later tonsillar regrowth, is unclear. To find out if the volume of lymphoid tissue is pivotal to the efficacy, we analyzed the association between the relapse of the symptoms of PFAPA syndrome and regrowth of tonsillar tissue after tonsillectomy or adenotonsillectomy. STUDY DESIGN: Prospective cohort study of operated PFAPA pateints. METHODS: We invited all patients that had undergone tonsillectomy or adenotonsillectomy due to PFAPA syndrome at the Oulu University Hospital, Oulu, Finland, between the years 1990 and 2007, at the age of ≤12 years, to a follow-up visit, after an average period of 9.8 years after their diagnoses. Out of the 132 invited, 94 (71%) participated in the follow-up study. RESULTS: At the follow-up study visit, 5 (5%) of the 94 PFAPA syndrome cases experienced recurrent fevers. The regrowth of palatine tonsillar tissue was seen in four of them (80%) as compared to 19/89 (21%) of symptom-free patients (P = .006). Two of the patients with clear PFAPA relapse at the time of the study visit were reoperated with clear effect on the symptoms. At the time of the study visit, 59/63 (94%) of the patients who had undergone adenotonsillectomy and 30/31 of the patients (97%) who had undergone tonsillectomy earlier were free of fever flares (P = .99). CONCLUSION: Palatine tonsil regrowth was associated with PFAPA syndrome relapse after tonsillectomy. Reoperation might be a treatment option in these patients. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E2149-E2152, 2021.

Oral Aphthous: Pathophysiology, Clinical Aspects and Medical Treatment.

Oral aphthosis is a painful inflammatory process of the oral mucosa. Oral aphthous can appear alone or secondary to numerous distinct disease processes. If recurrence occurs frequently, it is called recurrent aphthous stomatitis. The pathophysiology of oral aphthous ulcers remains unclear but various bacteria are part of its microbiology. Three morphological types hold great importance in literature because these types help manage the illness properly. Google Scholar and PubMed databases were used to retrieve the relevant data and information. Different keywords including "Aphthous", "Aphthosis", "Canker sores", "Aphthous stomatitis", "Aphthous ulcer causes", "Aphthous ulcer AND Microbiota" and "Aphthous ulcer AND treatment". The causes for oral aphthous ulcerations are widespread and ranges from localized trauma to rare syndromes, underlying intestinal disease, or even malignant disease processes. A detailed history and thorough examination of systems can assist the physician or dermatologist in defining whether it is related to a systemic disease process or truly idiopathic. Management of oral aphthous ulcers is challenging. For oral aphthous or recurrent aphthous ulcers from an underlying disease, topical medications are preferred due to their minimum side effects. Systemic medications are necessary if the disease progresses. Within the limitation of research and literature provided, it is safe to say that topical corticosteroids are the first line of treatment. Herein, the author discusses the pathophysiology, types, causes, diagnosis, and appropriate treatment ladder of oral aphthous stomatitis as described in the literature.

Behçet syndrome: A great imitator.

Behçet syndrome is considered to be a multisystemic vasculitis involving the skin, mucosa, eyes, joints, nervous system, cardiovascular system, and gastrointestinal system. The exact pathogenesis of the disease is unknown, but autoimmune factors are thought to play the main role. Vasculitis in Behçet syndrome can involve any kind and size of vessels, and this explains why the disease has the ability of multisystemic involvement. The commonest clinical presentation of Behçet syndrome is recurrent and painful mucocutaneous ulcerations known as aphthosis. The other clinical manifestations vary among patients and populations. The disease tends to be more severe in men. Ocular, vascular, and central nervous system involvements are the major causes of morbidity and mortality. Behçet syndrome is a mimicker of many diseases with its several faces and considered as one of the great imitators in dermatology.

World Workshop on Oral Medicine VII: Relative frequency of oral mucosal lesions in children, a scoping review.

OBJECTIVE: To detail a scoping review on the global and regional relative frequencies of oral mucosal disorders in the children based on both clinical studies and those reported from biopsy records. MATERIALS AND METHODS: A literature search was completed from 1 January 1990 to 31 December 2018 using PubMed and EMBASE. RESULTS: Twenty clinical studies (sample size: 85,976) and 34 studies from biopsy services (40,522 biopsies) were included. Clinically, the most frequent conditions were aphthous ulcerations (1.82%), trauma-associated lesions (1.33%) and herpes simplex virus (HSV)-associated lesions (1.33%). Overall, the most commonly biopsied lesions were mucoceles (17.12%), fibrous lesions (9.06%) and pyogenic granuloma (4.87%). By WHO geographic region, the pooled relative frequencies of the most common oral lesions were similar between regions in both clinical and biopsy studies. Across regions, geographic tongue (migratory glossitis), HSV lesions, fissured tongue and trauma-associated ulcers were the most commonly reported paediatric oral mucosal lesions in clinical studies, while mucoceles, fibrous lesions and pyogenic granuloma were the most commonly biopsied lesions. CONCLUSIONS: The scoping review suggests data from the clinical studies and biopsy records shared similarities in the most commonly observed mucosal lesions in children across regions. In addition, the majority of lesions were benign in nature.

Low laser therapy as an effective treatment of recurrent aphtous ulcers: a clinical case reporting two locations.

Apthous ulcers, commonly referred to as canker sores, are the most common ulcerative lesions of the oral mucosa. These are usually painful and are associated with redness and occasional bleeding from the affected area(s). Low Level Laser Therapy (LLLT) has shown excellent results in relieving the pain and complete remission of the oral ulcers. Through a clinical case, we report two locations of oral ulcers treated successfully with diode laser.

Manifestações bucais e considerações gerais da síndrome de Behçet: relato de caso / Oral manifestations and general considerations of Behçet's Syndrome: case report

Objetivo: relatar um caso de síndrome de Behçet, enfatizando o controle das manifestações bucais. Relato de caso: paciente de 21 anos de idade, já diagnosticado com síndrome de Behçet há 7 anos, sem histórico familiar, relatou o aparecimento de úlceras recorrentes, quando iniciou tratamento ortodôntico. Procurou a clínica odontológica da Universidade Estadual de Maringá queixando-se de "aftas e carne crescida" na boca. Foi realizada biópsia excisional do nódulo, e o exame histopatológico revelou tecido hiperplásico com infiltrado inflamatório crônico decorrente. Após 45 dias, observaram-se presença de novas aftas em mucosa labial, língua e gengiva assim como total cicatrização na região da biópsia. Atualmente, o paciente permanece em controle clínico médico e odontológico, estando as lesões aftosas presentes em diferentes regiões. Considerações finais: apesar de rara, essa doença é de grande relevância para o cirurgião-dentista, que deve saber diagnosticá-la e controlar suas manifestações bucais. Além disso, o acompanhamento é necessário para melhorar a qualidade de vida do paciente. (AU)

Objective: report a case of Behçet's Syndrome, emphasizing the control of oral manifestations. Case report: a 21-year-old patient, diagnosed with Behçet's Syndrome for 7 years, with no family history, reporting recurrent ulcers when orthodontic treatment was started. He sought a dental clinic at the State University of Maringá complaining of "aphthae and grown flesh" in the mouth. Excisional nodule biopsy and histopathological examination of hyperplastic tissue with chronic inflammatory infiltrate were performed. After 45 days, the presence of new aphthae were observed in the labial mucosa, tongue and gingiva, as well as total scarring in the region of the biopsy. Currently, the patient remains in clinical and dental control, remaining as aphthous interventions present in different regions. Final considerations: although rare, this disorder is of great relevance for the dental practioner, who must know how to diagnose and control its oral manifestations. In addition, follow-up is necessary to improve the patient's quality of life. (AU)

Effect of laser irradiation on aphthae pain management: A four different wavelengths comparison.

Recurrent Aphthous Stomatitis (RAS) is an oral condition characterized by painful ulcerations of the mucosa, healing spontaneously in 10-14 days but sometimes, due to their number, size and frequency of recurrence, lesions may be the cause of a severe disconfort with an impact on the quality of life of the patients due to the increased difficulty to eat, swallow and speak. For RAS, different protocols and treatments have been proposed as standard topical treatment to provide symptomatic relief, immunomodulating drugs as thalidomide, colchicine and steroids have been also proposed with the outcome to relief the pain, accelerating the healing process and increase the duration of ulcer-free period but without definitive results and without side effects. In this study we analysed the effect of laser treatment of aphthous lesions with four devices available on the market, two with wavelength in the infra-red region (2940 nm 808 nm) and two with a wavelength in the visible region (450 nm and 635 nm). Diode lasers 808 nm and 450 nm defined almost the same results with an improvement starting already after the application and gradually improving until 7 days after treatment without any statistically significant difference between them. Diode 635 nm was the device gaining the earliest effect reducing the pain already during the treatment and maintaining it at low level immediately after the laser application and after 3 and 7 days with levels of pain comparable with them obtained with 808 nm and 450 nm lasers. Er:YAG laser with the used parameters obtained a pain relief only during the treatment. The originality of this study was to compare different laser wavelengths, some of them never used for this purpose, and to compare also the two different ways to use lasers, the photobiomodulation (LLLT) and the high-power irradiation.

Recurrent aphthous stomatitis may be a precursor or risk factor for specific cancers: A case-control frequency-matched study.

BACKGROUND: Recurrent aphthous stomatitis (RAS) is considered a prophase symptom in patients with specific cancers. This study assessed the association between RAS and subsequent onset of cancer based on a nationwide population-based database in Taiwan. MATERIALS AND METHODS: We selected study participants from the National Health Insurance Research Database from January 2000 to December 2008. Patients in the non-RAS cohort were matched to case study patients at a 1:1 ratio through frequency matching. All participants were followed up for at least 5 years, and those who received cancer diagnoses during follow-up were identified. RESULTS: Among 52 307 patients with and 52 304 patients without RAS, the combined hazard ratio (HR) of all subsequent cancer cases was 1.3 (95% confidence interval [CI]: 1.25-1.35, P = 0). RAS diagnosis was associated with risk for cancers of the head and neck (aHR = 2, 95% CI: 1.8-2.3), colon (aHR = 1.2, 95% CI: 1.1-1.4), liver (aHR = 1.1, 95% CI: 1-1.3), pancreas (aHR = 1.4, 95% CI: 1.1-1.7), skin (aHR = 1.4, 95% CI: 1.2-1.7), breast (aHR = 1.2, 95% CI: 1.1-1.4), and prostate (aHR = 1.5, 95% CI: 1.3-1.8), as well as hematologic cancers (aHR = 1.6, 95% CI: 1.3-1.9). A higher risk was observed for male patients (aHR = 1.35, 95% CI: 1.28-1.42) than for female patients (aHR = 1.25, 95% CI: 1.18-1.31) with RAS. CONCLUSIONS: RAS was associated with specific cancers. Susceptible RAS patients should be screened for specific cancers.

INFLUENCE OF OZONE THERAPY ON ORAL TISSUE IN MODELING OF CHRONIC RECURRENT APHTHOUS STOMATITIS.

Chronic recurrent aphthous stomatitis (CRAS) belongs to the group of chronic, inflammatory, ulcerative diseases of the oral mucosa. The aim of this study was to determine the effects of ozone on the morphofunctional peculiarities of the soft tissues in modeling chronic recurrent aphthous stomatitis. We performed experimental investigation for study of the morpho-functional state of tissues of the oral mucosa in CRAS with using of previously proposed and widely used modeling scheme with ovalbumin and aluminum hydroxide. Two groups of animals were formed (Dutch rabbits, males, aging three-month, weighting 2-2.4 kg). Group of 8 animals with obtained mucosal changes was our comparison group. Other group of 8 animals with obtained mucosal changes was treated by ozone therapy. Histological investigation has been performed. Microscopical examination of tissue had shown that ozone therapy reduces inflammation and edema and is useful in wound healing in soft tissue as disappearance of necrobiotic processes, epithelialization of aphthous defect, growth of akantotic bands, pronounced reducing of inflammatory cells and changing of cellular ratio (with of neutrophils part from 38.30±2.46% to 6.34±0.63%, eosinophils from 5.49±0.23% to 2.87±0.05%), restoration of the cellular layers of the epithelium, moderately pronounced sclerosis of the papillary layer of the lamina propria. Described results allow to conclude that correction of tissual changes in chronic recurrent aphthous stomatitis could be obtained with ozone therapy using.

Anti-TNF Treatment for Extraintestinal Manifestations of Inflammatory Bowel Disease in the Swiss IBD Cohort Study.

BACKGROUND: Extraintestinal manifestations (EIMs) in patients with inflammatory bowel disease (IBD) are frequently observed. Little is known about the efficacy of anti-tumor necrosis factor (TNF) in EIM management. We assessed the effect of 3 anti-TNF agents (infliximab, adalimumab, and certolizumab pegol) on EIM evolution. METHODS: Data on 1249 patients from the Swiss IBD Cohort Study (SIBDCS) were analyzed. All EIMs were diagnosed by relevant specialists. Response was classified into improvement, stable disease, and clinical worsening based on the physician's interpretation. RESULTS: Of the 366 patients with at least 1 EIM, 213 (58.2%) were ever treated with an anti-TNF. A total of 299 treatments were started for 355 EIMs. Patients with EIM were significantly more often treated with anti-TNF compared with those without EIM (58.2% versus 21.0%, P < 0.001). Infliximab was the most frequently used drug (63.2%). In more than 71.8%, a clinical response of the underlying EIM to anti-TNF therapy was observed. In 92 patients (43.2%), anti-TNF treatments were started for the purpose of treating EIM rather than IBD. Response rates to anti-TNF were generally good and best for psoriasis, aphthous stomatitis, uveitis, and peripheral arthritis. In 11 patients, 14 EIM occurred under anti-TNF treatment. CONCLUSIONS: Anti-TNF was frequently used among patients with EIM. In more than 40%, anti-TNF treatments are started to treat EIM rather than IBD. Given the good response rates, anti-TNF seems to be a valuable option in the treatment of EIM, whereas appearance of EIM under anti-TNF does not seem to be a source of considerable concern.

Estrés oxidativo en las enfermedades bucales / Oxidative stress in the oral illnesses

Introducción: toda enfermedad está basada en trastornos a nivel molecular, por lo que el profesional de la salud debe interpretar las variadas manifestaciones internas de las enfermedades producidas por alteraciones de las biomoléculas que interactúan sistémicamente, en las cuales tienen un papel importante el estrés oxidativo. Objetivo: realizar una revisión bibliográfica sobre el estrés oxidativo y las enfermedades que afectan a la cavidad bucal. Métodos: se realizó una revisión bibliográfica en el periodo comprendido entre septiembre de 2014 a enero de 2016. Se consultaron las bases de datos de sistemas referativos, como MEDLINE, PubMed y SciELO con la utilización de descriptores como oxidative stress in oral deseases y su contraparte en español. Se incluyeron artículos en idioma inglés y español y publicaciones de los últimos cinco años, solo seis con mayor tiempo de publicación. Se revisaron 110 artículos, y se circunscribió el estudio a 49 que enfocaron estas temáticas de manera más integral. Análisis e integración de los resultados: tiene el estrés oxidativo gran relación con la enfermedad periodontal, la mucositis, los estados pulpares, síndrome de Sjögren, síndrome de ardor bucal, aftas bucales y lesiones premalignas como leucoplasia y liquen plano bucal. Conclusiones: existe relación entre el estrés oxidativo y muchas enfermedades que afectan la cavidad bucal, lo que influye en la patogenia de estas.(AU)

Introduction: the basis of disease is the occurrence of disorders at the molecular level, so the health professional should be able to understand the varied internal manifestations of a disease caused by alterations in the biomolecules that systemically interact and the important role that the oxidative stress plays in this process. Objective: to make a literature review on the oxidative stress and the diseases affecting the oral cavity. Methods: a literature review was made in the period of September 2014 through January 2016. MEDLINE, PubMed and SciELO databases were consulted; the subject headings were oxidative stress in oral diseases in Spanish and in English. Several articles in English and Spanish and publications of the last five years, in addition to 6 articles published prior to this period, were all included. A total of 110 articles were reviewed, but for the study, 49 were selected on account of a more comprehensive approach on these topics. Data analysis and integration: the oxidative stress is closely related to periodontal disease, mucositis, pulpal diseases, Sjögren syndrome, burning mouth syndrome, oral aphthas and premalignant lesions such as leukoplakia and oral lichen planus. Conclusions: there is association of the oxidative stress and many other diseases affecting the oral cavity, which has an impact on the pathogenesis of many diseases(AU)

Acute oral ulcers.

Accurate diagnosis of acute oral ulcers can be challenging. Important historic details include the pattern of recurrence, anatomic areas of involvement within the mouth and elsewhere on the mucocutaneous surface, associated medical symptoms or comorbidities, and symptomology. Careful mucocutaneous examination is essential. When necessary, biopsy at an active site without ulceration is generally optimal. Depending on the clinical scenario, supplemental studies that may be useful include cultures; perilesional biopsy for direct immunofluorescence testing; and evaluation for infectious diseases, gluten sensitivity, inflammatory bowel disease, human immunodeficiency virus infection, connective tissue diseases, or hematinic deficiencies. Clinicians should maintain a broad differential diagnosis when evaluating patients with acute oral ulcers.

Basic Characteristics of Adults with Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenopathy Syndrome in Comparison with the Typical Pediatric Expression of Disease.

Autoinflammatory diseases are caused by inflammasome dysregulation leading to overproduction of proinflammatory cytokines and a pathological delay in the inflammation switching off. The progress of cellular biology has partially clarified pathogenic mechanisms behind monogenic autoinflammatory diseases, whereas little is known about the polygenic ones. Although the genetic susceptibility of periodic fever, aphthous stomatitis, pharyngitis, and adenopathy (PFAPA) syndrome is still obscure, the presence of overlapping symptoms with monogenic periodic fevers, the recurrence in family members, the important role played by dysregulated interleukin- (IL-) 1ß secretion during flares, the overexpression of inflammasome-associated genes during attacks, and, last but not least, the therapeutic efficacy of IL-1ß blockade strongly indicate a potential genetic involvement in its pathogenesis, probably linked with environmental factors. PFAPA syndrome has a typical inception in the pediatric age, but a delayed onset during adulthood has been described as well. Treatments required as well as effectiveness of tonsillectomy remain controversial, even if the disease seems to have a self-limited course mostly in children. The purpose of this review is to provide an overview of this complex polygenic/multifactorial autoinflammatory disorder in which the innate immune system undoubtedly plays a basic role.

Epithelial Cell Apoptosis in Recurrent Aphthous Ulcers.

A recurrent aphthous ulcer (RAU) is a common inflammatory ulcerative lesion affecting oral mucosa. We studied the eventual apoptosis of epithelial cells from the point of view of ulcer and inflammation. RAU lesions and healthy mucosa samples were immunostained for caspase-3 and high-mobility group box 1 (HMGB1). DNA nicks were identified using TUNEL staining. We studied the effects of tumor necrosis factor α (TNFα) and interferon γ (IFNγ) on the toll-like receptor 2 and 4 (TLR2 and TLR4) expression of human oral SCC-25 keratinocytes. We also studied the effects of self-DNA, all-thiol-HMGB1, and disulfide-HMGB1 on epithelial cells, with or without IFNγ. At the edge of RAU lesions, all epithelial cell layers were caspase-3(+), TUNEL(+), and HMGB-1(+) and had widened intercellular spaces. In contrast, healthy epithelial cells were negative for caspase-3 and TUNEL staining. HMGB1 was seen in only the basal cell layers, and the cells retained close cell-to-cell contacts. Self-DNA increased TNF-α mRNA (P = 0.02) in SCC-25 cells. Both TNFα and IFNγ (P = 0.01) increased TLR2. Upon TNFα stimulation, SCC-25 cells lost their nuclear HMGB1 staining. HMGB1 did not increase IL-8, IL-6, or TNF-α mRNA in SCC-25 cells, which was unaffected by the presence of IFNγ. We conclude that in healthy epithelium, the most superficial cells at the end of their life cycle are simply desquamated. In contrast, RAU is characterized by top-to-bottom apoptosis such that dead cells may slough off, leading to an ulcer. Because of a lack of scavenging anti-inflammatory macrophages, apoptotic cells probably undergo secondary necrosis releasing proinflammatory danger signals, which may contribute to the peripheral inflammatory halo. This is supported by self-DNA-induced TNFα synthesis. In contrast to TLR4- and TLR2-binding lipopolysaccharide used as a positive control, disulfide-HMGB1 did not stimulate proinflammatory cytokines.

Increased beta 2 defensin in recurrent aphthous ulcer.

OBJECTIVES: It was hypothesized that beta 2 defensin (BD-2) is increased in RAU lesions compared with healthy controls to promote anti-microbial host defence. METHODS: RAU and control mucosa samples were subjected to quantitative real-time PCR and immunostained for BD-2, CD68, mast cell tryptase and 4-hydroxynonenal (4HNE). The effect of tumour necrosis factor-α (TNF-α) ± interleukin-17C (IL-17C), without and with vitamin K3, was studied on BD-2 expression in epithelial SCC-25 cells. RESULTS: Although BD-2 mRNA did not differ between healthy and RAU mucosa, BD-2 stained strongly in acute-phase RAU epithelium (P = 0.001). In controls, subepithelial BD-2(+) cells were mast cells and macrophages, whereas in RAU, most infiltrating leucocytes were BD-2(+) (P = 0.004). In cell culture, BD-2 was increased 124-fold by TNF-α (P < 0.0001) and 208-fold synergistically together with IL-17C (P < 0.0001). 4HNE staining of RAU epithelium was not significantly increased, and vitamin K3-induced reactive oxygen species (ROS) did not affect BD-2. CONCLUSIONS: Anti-microbial BD-2 was not affected by oxidative stress but was highly increased in the epithelial and immigrant cells in the acute-phase RAU lesions, probably in part synergistically by TNF-α and epithelial IL-17C, which are known to be induced by activation of danger-signal receptors by pathogen- and/or damage-associated molecular patterns.

Palatal ulceration.

Palatal ulcers are a common presentation and can be conveniently divided into developmental and acquired causes, the latter of which is subdivided into acute and chronic causes. Most commonly seen dermatologic causes have associated skin manifestations. Acute and multiple ulcers are usually infectious or drug induced in origin. Recurrent ulcers are largely dominated by aphthosis, while chronic ulcers are seen in immunocompromised patients and can occasionally be malignant. It is essential to involve the oral and maxillofacial surgeons early in the therapeutic management to tackle the inevitable complications that may ensue in the chronic cases.

[Oral toxicity of targeted anticancer therapies]. / Toxicité endobuccale des thérapies ciblées anticancéreuses.

While toxicity of targeted anticancer therapies on the oral mucosa seems relatively frequent in clinical practice, it has not been properly characterized to date, apart from aphthous-like lesions due to mTOR inhibitors. Herein, we report the main oral lesions associated with these new therapies, with a description of the most frequent but also the most characteristic clinical manifestations of these drugs, such as anti-EGFR-induced mucositis, BRAF-inhibitor-associated hyperkeratosis, benign migratory glossitis and osteonecrosis of the jaw observed with angiogenesis inhibitors, as well as lesions more specifically linked with imatinib.

Clinical and genetic characterization of Japanese sporadic cases of periodic Fever, aphthous stomatitis, pharyngitis and adenitis syndrome from a single medical center in Japan.

PURPOSE: To investigate clinical presentation, genetic background and cytokine profile of Japanese sporadic cases of periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome. METHODS: Nine PFAPA syndrome patients were recruited. DNA sequence analysis of auto inflammatory disorder susceptibility genes, MEFV, MVK, NLRP3, and TNFRSF1A, were performed. Serum cytokine levels and monocyte IL-1ß levels were measured by ELISA. RESULTS: The study population consisted of six males and three females (mean age of onset 26.8 months). Febrile episodes lasted 3-6 days with symptom-free intervals ranging from 2 to 12 weeks. Fever was accompanied by pharyngitis (n = 8), aphthous stomatitis (n = 4), and cervical adenitis (n = 5). White blood cells and C-reactive protein were increased during the attack phase. Mean IgD serum levels were 7.32 ± 9.51 mg/dl during the attack phase, and were mildly elevated in two patients. Heterozygous MEFV, NLRP3 and TNFRSF1A variants were detected in four, one and three cases, respectively. Serum TNF-α and IL-18 levels were elevated during the attack-free and attack periods compared with controls. Other cytokines, IL-1ß, IL-1ra, IL-6, and sTNFR1, were only increased during the attack phase. Oral prednisolone was administered to eight patients and immediately reduced fever. Tonsillectomy performed in five patients induced cessation of fever in four patients. One case with repeated fever attacks after tonsillectomy showed increased monocyte IL-1ß production, similar to the other active case with genetic variants of auto inflammatory disorder-associated genes. CONCLUSIONS: Japanese PFAPA syndrome patients may have cytokine regulation dysfunction as a result of genetic variants of auto inflammatory disorder-associated genes.

IL-17C and its receptor IL-17RA/IL-17RE identify human oral epithelial cell as an inflammatory cell in recurrent aphthous ulcer.

BACKGROUND: Recurrent aphthous ulcer (RAU) is an ulcerative disease of non-keratinized oral mucosa. Colon and bronchial epithelial cells produce interleukin-17C (IL-17C) upon stimulation of Toll-like receptor 2 (TLR2), TLR3 and TLR5, which are highly expressed in epithelial cells in RAU lesions. We therefore investigated the eventual presence and function of IL-17C in cultured human oral keratinocytes (HOK) and control biopsies compared to RAU lesions. METHODS: Expression of IL-17A, IL-17C, IL-17RA and IL-17RE was analysed in cultured HOK cells using quantitative real-time polymerase chain reaction (qRT-PCR). HOK cells were stimulated with IL-17C and analysed for IL-8 and tumour necrosis factor-α (TNF-α) using qRT-PCR. Control mucosa (n = 5) was immunostained for IL-17A, IL-17C, IL-8, TNF-α and mast cell tryptase and compared with RAU lesions (n = 5) using the mean grey scale value. RESULTS: IL-17C, but no IL-17A, mRNA was found in cultured HOK cells. Components of the heterodimeric IL-17RA/IL-17RE receptor for IL-17C were also highly expressed. Stimulation of HOK with IL-17C increased TNF-α mRNA (P = 0.03; IL-8 increase was not statistically significant). HOK in RAU lesions stained intensively for IL-17C compared to controls (P = 0.006). This was associated with increased epithelial immunostaining of TNF-α (P = 0.04) and IL-8 (P = 0.02). Most of the inflammatory cells which stained for IL-17A in control mucosa and RAU lesions were also mast cell tryptase positive. CONCLUSION: IL-17C is highly expressed in epithelial cells in RAU lesions, where it seems to stimulate oral keratinocytes via IL-17RA/IL-17RE to produce pro-inflammatory cytokines. Human oral epithelial cells are probably important inflammatory cells in RAU.

Mammalian target of rapamycin inhibitor-associated stomatitis.

With the recent introduction of inhibitors of mammalian target of rapamycin (mTOR) in oncology, distinct cutaneous and oral adverse events have been identified. In fact, stomatitis and rash are documented as the most frequent and potentially dose-limiting side effects. Clinically, mTOR inhibitor-associated stomatitis (mIAS) more closely resembles aphthous stomatitis than oral mucositis due to conventional anticancer therapies. While most cases of mIAS are mild to moderate and self-limiting, more severe and persistent mIAS can become a dose-limiting toxicity. Small ulcerations may cause significant pain and mucosal sensitivity may occur in the absence of clinical changes. Use of clinical assessment tools that are primarily driven by ulceration size may underestimate mIAS, and assessment should include patient-reported outcomes. This article provides an up-to-date review of the clinical presentation, terminology, pathogenesis, assessment and management of mIAS and other mTOR inhibitor-associated oral adverse events. In addition, areas of future research are considered.