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Background-Aim: To evaluate the effect of vitamin D supplementation on the frequency and duration of attacks in patients of PFAPA syndrome with low vitamin D levels., Methods: This retrospective study comprised PFAPA patients with vitamin D deficiency/insufficiency between 2018 and 2023. The frequency and duration of PFAPA attacks before and after vitamin D supplementation were noted., Results: Seventy-one patients were included. Of the 71 patients, 24 (33.8%) had vitamin D insufficiency, and 47 (66.2%) had vitamin D deficiency. In patients with vitamin D insufficiency, mean attack frequency and mean attack duration before vitamin D supplementation were 4.3 ± 1.9/year and 2.2 ± 1.6 days, respectively, while mean attack frequency and mean attack duration after vitamin D supplementation were 3.5 ± 2.7/year per year and 1.3 ± 0.9 days respectively (p = 0.2, p = 0.2, respectively). In patients with vitamin D deficiency, mean attack frequency and mean attack duration before vitamin D supplementation were 7.4 ± 2.1/year and 2.2 ± 1.6 days, respectively, while mean attack frequency and mean attack duration after vitamin D supplementation were 3.3 ± 2.4/year and 1.3 ± 0.9 days respectively (p < 0.01, p = 0.04, respectively). When the vitamin D level and the frequency of attacks were compared, the cut-off value of vitamin D was found to be 29.7 nmol/L., Conclusions: In PFAPA patients with low vitamin D levels, the frequency and duration of PFAPA attacks were reduced with vitamin D supplementation. Especially at vitamin D level cut-off > 29.7 nmol/L, the frequency of attacks reduced significantly., (© 2023. The Author(s), under exclusive licence to Royal Academy of Medicine in Ireland.)

Fibrinogen is a protein that reflects systemic inflammation and regulates the immune response to disease. However, there is a scarcity of data on fibrinogen in recurrent aphthous stomatitis (RAS). We aimed to test the hypothesis that fibrinogen is involved in the aetiology of RAS. Between November 2016 and November 2018, we included 109 minor RAS patients and 29 age- and sex-matched controls in a single-center, observational study. Their clinical history and ulcer manifestations led to the diagnosis of minor RAS. The ulcer severity score (USS) was used to assess disease severity, and fibrinogen was also collected. We conducted three analyses: Analysis 1 (comparison of fibrinogen levels between patients and controls), Analysis 2 (comparison of fibrinogen levels between high and low USS patients) and Analysis 3 (comparison of fibrinogen levels between before and after anti-inflammatory treatment in patients). The fibrinogen levels in the 109 minor RAS patients were statistically higher than in the 29 controls (mean [SD], 2.6 [0.5] vs. 2.3 [0.3]; Student's t-test, p < 0.001). However, there were no significant differences in fibrinogen levels among the 43 patients with high USS and the 39 patients with low USS (mean [SD], 2.7 [0.5] vs. 2.6 [0.4]; Student's t-test, p = 0.278). Furthermore, fibrinogen levels were significantly higher before anti-inflammatory treatment in comparison to those after anti-inflammatory treatment in the 35 paired patients (mean [SD], 2.6 [0.4] vs. 2.5 [0.4]; Student's t-test, p = 0.026). Interestingly, fibrinogen levels were significantly higher in the 35 paired patients after anti-inflammatory treatment compared to the 29 control subjects (mean [SD], 2.5 [0.4] vs. 2.3 [0.3]; Student's t-test, p = 0.026]. Fibrinogen may play a role in the aetiology of RAS and may be a drug target for RAS treatment. Clinicians should be alert that high serum fibrinogen levels might be associated with the risk of RAS., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in pediatric patients. It is clinically characterized by fever flares lasting 3-7 days, reappearing every 2-8 weeks with a distinctive clockwork regularity. PFAPA generally begins before 5 years of age and usually ceases 3-5 years after onset. Recurrences may be observed in adolescence and adulthood in up to 20% of cases. The authors aim to describe a case of PFAPA recurrence in adolescence temporally associated with allergen-specific immunotherapy (ASIT). A 16-year-old female patient was referred to the rheumatology unit due to recurrent episodes of fever one month after initiating ASIT for allergic rhinitis. These episodes occurred every 4 weeks and lasted 3 days. During these episodes, she also presented with a sore throat, tonsillar exudates, and cervical lymphadenopathy. Abortive treatment with oral prednisolone was attempted in these episodes, with complete resolution of fever after a single dose. After reviewing her medical background, she had previously experienced febrile episodes accompanied by aphthous ulcers and tonsillar exudates occurring every 7-8 weeks from age 2-7. The etiopathogenesis of PFAPA remains uncertain. Environmental triggers, particularly those with immunomodulator effects, may interfere with the immune responses responsible for PFAPA occurrence, but the mechanisms are still unclear. The authors describe the first report of the reappearance of PFAPA flares, possibly due to ASIT. Further studies are needed to fully clarify if ASIT constitutes a true environmental trigger of PFAPA.

Introduction: Recurrent Aphthous Stomatitis (RAS) is the most common type of ulceration in the oral cavity which can occur due to several factors., Aims: To determine the factors related to the incidence of RAS and examine the social class inequality in RAS among the Indonesian population using data from the fifth wave of the Indonesian Family Life Survey (IFLS5) in 2014., Methods: This study is a descriptive study with a cross-sectional design using secondary data from IFLS5 data in 2014 (n = 28,410). Socio-economic position (SEP) was calculated by Adult Equivalent Scale and categorized into 4 classes. Outcome is RAS. Mediating factors were psychosocial (stress), eating behavioral (food consumption), and systemic diseases. Descriptive analysis, chi-square and a series of logistic regressions were performed to analyze the data. Odds ratio (OR) and 95% confidence interval (CI) were used to report the results., Results: Only 18.39% of IFLS5 respondents experienced the incidence of recurrent aphthous stomatitis in 2014. The bivariate (chi-square) results showed that there was a relationship between the incidence of RAS and the related independent variables. Logistic regression showed the highest possibility of RAS in respondents aged 18-34 years, female, unmarried, high school education level, living in the city, having frequent stress levels, having food habits that frequently drinking soda, sweet foods, chili sauce, fried food and has systemic diseases such as, asthma, cancer, rheumatism, and digestion. The lowest SEP group had the highest probability of occurrence of RAS over the other groups among the different models., Conclusions: There are several factors that determine the incidence of RAS. There was a monotonic gradient of inequality in RAS according to SEP group. This study might be useful to provide information regarding the relationship of determinants factors with the incidence of RAS to prevent it and promote oral health in the future., (© 2023. The Author(s).)

Objective: This meta-analysis was designed to provide new insights into the relationship between Helicobacter pylori (H. pylori) infection and recurrent aphthous stomatitis (RAS)., Materials and Methods: We included and evaluated studies on H. pylori infection and RAS from PubMed, EMBASE, Cochrane Library, and Web of Science databases published up to January 31, 2023. The characteristics of these studies were collected, and the quality was evaluated by Newcastle-Ottawa Scale (NOS). The random effects model was used to calculate the pooled odds ratio (OR) and 95% confidence interval (CI). To further explore the sources of heterogeneity, meta-regression analysis and subgroup analyses were performed. Funnel plot, Egger's test, and Begg's test were used to assess publication bias., Results: In total, fifteen case-control studies with 1137 individuals (601 cases and 536 controls) were included. The H. pylori was found to be significantly associated with RAS (OR: 1.83 95% CI: 1.41-2.37, P = 0.001). In the subgroup analyses, studies that used PCR (OR: 2.03 95% CI: 1.31-3.15) or UBT (OR: 1.83 95% CI: 1.13-2.96) yielded a significant positive association, while a non-significant association (OR: 1.12 95% CI: 0.61-2.08) was found from studies that used ELISA method. Sensitivity analyses showed that the results were robust. No significant publication bias was found., Conclusions: The current evidence does not rule out an association between H. pylori and RAS. The effect of H. pylori on RAS varies in detection methods and sources of sample. Large samples, multiple clinical studies, and improved methods are still needed to determine the exact effect of H. pylori on RAS., Clinical Significance: H. pylori infection may be a risk factor for the pathogenesis of RAS., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Oral mucositis is a frequently seen complication in the first weeks after hematopoietic stem cell transplantation recipients which can severely affects patients quality of life. In this study, a labelled and label-free proteomics approach were used to identify differences between the salivary proteomes of autologous hematopoietic stem cell transplantation (ASCT) recipients developing ulcerative oral mucositis (ULC-OM; WHO score ≥ 2) or not (NON-OM)., Methods: In the TMT-labelled analysis we pooled saliva samples from 5 ULC-OM patients at each of 5 timepoints: baseline, 1, 2, 3 weeks and 3 months after ASCT and compared these with pooled samples from 5 NON-OM patients. For the label-free analysis we analyzed saliva samples from 9 ULC-OM and 10 NON-OM patients at 6 different timepoints (including 12 months after ASCT) with Data-Independent Acquisition (DIA). As spectral library, all samples were grouped (ULC-OM vs NON-OM) and analyzed with Data Dependent Analysis (DDA). PCA plots and a volcano plot were generated in RStudio and differently regulated proteins were analyzed using GO analysis with g:Profiler., Results: A different clustering of ULC-OM pools was found at baseline, weeks 2 and 3 after ASCT with TMT-labelled analysis. Using label-free analysis, week 1-3 samples clustered distinctly from the other timepoints. Unique and up-regulated proteins in the NON-OM group (DDA analysis) were involved in immune system-related processes, while those proteins in the ULC-OM group were intracellular proteins indicating cell lysis., Conclusions: The salivary proteome in ASCT recipients has a tissue protective or tissue-damage signature, that corresponded with the absence or presence of ulcerative oral mucositis, respectively., Trial Registration: The study is registered in the national trial register (NTR5760; automatically added to the International Clinical Trial Registry Platform)., (© 2023. The Author(s).)

This case series from 3 academic hospital-based pediatric and adolescent gynecology services outlines the temporal association between vulvar ulcers in female adolescents and COVID-19 vaccination. We identified 8 cases and describe each patient's presentation, differential diagnosis, diagnostic workup, complications, treatment modalities, and overall course of illness. All cases seek to illustrate the clinical experiences of patients and providers interfacing with vulvar aphthous ulcers and contribute to the emerging literature exploring the novel association between vulvar aphthous ulcers and COVID-19 vaccination. To date, this is the largest described case series of this association in the literature. Key Words: COVID-19, Vaccine, Aphthous ulcers, Vulva, Adolescent., (Copyright © 2023. Published by Elsevier Inc.)

Periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome is one of the most common autoinflammatory fever disorders in the childhood which may co-exists with familial Mediterranean fever (FMF) causing treatment complexity. As the role of surgery in PFAPA syndrome is still controversial, in this paper, our aim is to present our results of tonsillectomy/adenotonsillectomy in the treatment of PFAPA syndrome. Archives of a tertiary care hospital were investigated for patients who underwent tonsillectomy or adenotonsillectomy due to PFAPA Syndrome between 2010 and 2020. 344 patients were found but only 281 of them were accessible. Through phone call interview and chart review methods, preoperative and postoperative the number and severity of the attacks and general satisfaction after the operation were recorded and analyzed. Also, patients with concomitant FMF were analyzed separately. A total of 281 patients were included in the study. There was no improvement in 10 (3.55%) patients. Eight (2.84%) patients showed mild improvement, 29 (10.32%) patients had moderate improvement and 234 (83.27%) patients had full recovery after tonsillectomy. There were 266 PFAPA patients without FMF. No improvement, mild improvement, moderate improvement, and full recovery in this patient group were 5 (1.9%), 6 (2.3%), 25 (9.4%) and 230 (86.5%), respectively. FMF was present in 5.33% (15/281) of the patients. In PFAPA + FMF group 5 patients had no improvement (33.3%), 2 had mild improvement (13.3%), 4 had moderate improvement (26.7%) and 4 had full recovery (26.7%). Benefit of tonsillectomy was significantly lower in the patients with concomitant FMF when compared to the patients who did not have FMF (p < 0.001). Age of diagnosis, age of operation, severity of the disease, type of operation, and gender were found to have no significant relationship with the benefit from surgery (p < 0.05). According to the findings of this study, tonsillectomy is an effective long-term treatment for PFAPA syndrome with success rate of 83.27%. Also, preoperatively FMF should be considered in these patients, which dramatically reduces surgical efficacy., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Aims: Spondyloarthritis (SpA) is a group of autoinflammatory disorders, of which the primary extra-articular manifestation is inflammatory bowel disease (IBD). The oral cavity being a part of gastrointestinal tract, is significantly compromised in IBD, and in many cases, it is the first site of clinical manifestations of IBD. This study aimed to identify changes in the oral mucosa associated with the onset of IBD and their association with endoscopic/histological findings., Materials and Methods: The study assessed 80 patients with SpA and 52 healthy controls. Oral, rheumatological, and gastroenterological assessments were performed. The ileocolonoscopy was performed via digital magnification chromoendoscopy. The statistical analysis consisted of Chi-square, Fisher's exact, and multiple correspondence discriminant analysis tests., Results: From the disease cohort, 63.0% patients showed oral lesions (p = 0.050). These manifestations ranged from gingivitis (55.0%, p = 0.001), aphthous stomatitis (3.8%, p = 0.091), angular cheilitis (2.6%, p = 0.200), and perioral erythema with scaling (1.3%, p = 0.300). All patients who presented with alterations in colonic mucosa also had oral lesions associated with IBD (p = 0.039), specifically gingivitis/aphthous stomatitis (p = 0.029)., Conclusion: The patients with SpA without IBD present significant oral signs and symptoms. Gingivitis seems to be the most relevant because of its associations with early endoscopic and histological findings., Clinical Relevance: An integral approach to the diagnostic tests that includes evaluations of oral, rheumatological and gastroenterological tissues may favor timely attention and improve patients' quality of life., (© 2022. The Author(s).)

A special form of the rare infantile Sweet syndrome (acute febrile neutrophilic dermatosis) is facultative healing in the form of postinflammatory elastolysis with acquired cutis laxa, named "Marshall" syndrome after the authors who first described it. We report the case of a 3-year-old child in whom the cutaneous manifestation led to diagnosis of Takayasu arteritis. Postinflammatory elastolysis with acquired cutis laxa is a clinically relevant cutaneous indicator of life-threatening cardiovascular complications such as aortitis, aortic aneurysm, coronary stenosis and heart failure in children with Sweet's syndrome. Cutis laxa usually precedes cardiac complications or, as in our case, occurs simultaneously; thus, immediate cardiac and rheumatologic examinations are important to initiate systemic therapy with anti-inflammatory and immunomodulatory agents early to prevent complications., (© 2022. The Author(s).)

Objective: Recurrent aphthous stomatitis (RAS) is a condition that affects 20% of the world population and is characterized by painful ulcers in the oral mucosa. So far, the epidemiology and risk factors of RAS have been infrequently studied. Our objective was to determine whether sleep-related factors are related to the occurrence of RAS in the first prospective study carried out on this topic., Methods: A cohort of 11210 Spanish students, 13-17 years old, was followed up for one year. Sleep disorders were assessed at baseline using a standard validated questionnaire., Results: We detected 2655 new cases of RAS with a total of 287,262 person-week of follow-up. Subjects with high (4th quartile) Insomnia Index showed an incidence rate ratio (IRR) of RAS of 1.29 (95% confidence interval (CI) 1.15-1.45), while subjects with high Hypersomnia Index presented an IRR of 1.42 (95% CI 1.26-1.61). A high score of sleep-related phenomena was also associated with an increased IRR: 1.53 (95% CI 1.37-1.69). Adolescents with high level of sleep satisfaction were at lower risk of RAS: 0.88 (95% CI 0.77-1.01)., Conclusion: These findings suggest that sleep disorders are moderately associated with RAS in adolescents., (wileyonlinelibrary.com/journal/odi.)

Vitamin B12, a water-soluble vitamin, plays a vital role in the formation of hematopoietic stem cells and has been associated with oral mucosal diseases, mainly recurrent aphthous stomatitis (RAS). The latter is a debilitating condition, and B12 was proposed as a potential treatment given its role in regenerating oral mucosal tissue. There is conflicting evidence that B12 deficiency causes RAS. Five of the seven randomized controlled trials reviewed used the inactive form of B12 (cyanocobalamin) as intervention, while the other two used the active form (methylcobalamin). Of the latter two, buccal discs (500 μg B12) showed significant improvement and reduced perceived pain in 77% of the subjects, and submucosal injections showed a significant difference in pain, starting from the second day. Moreover, three studies administered vitamin B12 sublingually with different dosages, which revealed that the higher dose (1000 μg) achieved a significant reduction in outbreaks, number, and duration of ulcers, especially after six months. Multivitamins showed no difference in new RAS episodes and duration. Injectable B12 was compared with the oral form, and nearly 50% of the injection group reported a desired response by the eighth week. An ointment form (500 μg) showed a significant reduction in pain levels after two days of treatment. Based on the available literature, we suggest that a daily dose of 1000 μg of vitamin B12 sublingually for six months can be used to treat RAS. Nevertheless, this conclusion should be considered tentative due to the lack of high quality, large scale studies.

Background: Nonsexually acquired genital ulcers have been described among girls who are prepubertal after various viral illnesses due to mucosal inflammation from an immunologic response. Until recently, nonsexually acquired genital ulcers have only been associated with viral infections., Case: We present a case of an adolescent girl developing nonsexually acquired genital ulcers after both her first and second coronavirus disease 2019 (COVID-19) vaccine doses. Her course followed an expected timeline for severity and resolution of ulcers., Conclusions: Aphthous ulcers may arise from inflammatory effects of COVID-19 vaccination. Clinical monitoring after COVID-19 vaccination from all formulations should include assessment for nonsexually acquired genital ulcers if vaginal pain is reported., Competing Interests: Financial Disclosure The authors did not report any potential conflicts of interest., (Copyright © 2022 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: As a recurrent disease, periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is characterized by episodes of febrile attacks and is often prominent in children under five years of age. However, the etiology of this condition has not been fully understood yet., Materials and Methods: The search in the extensive literature of peer-reviewed articles published from the inception to December 2021 was conducted to identify the relevant studies, using the electronic databases of MEDLINE/PubMed, Embase, Scopus, the Cochrane Library, and the Web of Science., Results: The analysis of complex relationships indicates that inflammatory factors, such as various cytokines and acute-phase proteins (APPs), play leading roles in the pathogenesis of this disease. Accordingly, this article summarizes the current state of knowledge to explain the mechanisms involved in inflammatory responses among patients with PFAPA syndrome and investigate its role in the pathogenesis of this disease. Moreover, the possibilities for further implementation of new therapeutic strategies are pointed out., Conclusion: It is concluded that some pathophysiological processes are associated with immune dysregulation, which itself may be secondary to environmental factors, genetic background, and underlying diseases, including latent infections that multiply inflammatory mediators. elevated inflammatory markers similarly play a significant part in the clinical outcomes of this condition, whose pyrogenic nature is the reason for the development of episodes of febrile attacks in the population of patients suffering from PFAPA syndrome., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Objectives: To describe a homogeneous group of patients with undifferentiated recurrent fevers followed-up in a tertiary referral center for systemic autoinflammatory diseases (SAIDs)., Methods: Patients with undifferentiated recurrent fevers seen at our Center from 2008 to 2021 and followed-up for at least one year were included in a retrospective study. Monogenic recurrent fevers, patients carrying variants of unknown origin and PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis) syndrome were excluded., Results: Fifty patients (34 male, 16 female) were included in the study. The median age at onset was 3 years, and the median follow-up was 3.3 years. At baseline, arthralgia (70%) and abdominal pain (65%) were the most frequent manifestations. NSAIDs or steroids on demand had a variable and transient effect. Tonsillectomy was ineffective in the 10 patients (20%) that underwent surgery. Forty-eight patients (96%) were treated with colchicine. A complete response (absence of fever) was achieved in 31 patients (64.6%). Nine patients (18%) showed a partial response, with a median reduction of fever episodes per year of 72%. Nine patients (16.7%) were considered resistant to colchicine. The presence of generalized lymphadenopathy and, to a lesser extent, exudative tonsillitis was associated with a lack of response to colchicine., Conclusions: We describe the largest series of patients with syndrome of undifferentiated recurrent fever (SURF) reported in the literature so far. SURF should be considered as a distinct clinical entity in the context of multifactorial autoinflammatory diseases., (Copyright © 2022. Published by Elsevier Inc.)

Adamantiades-Behçet disease (ABD) is a systemic disease with vasculitis, characterized by recurrent oral aphthosis and ocular, cutaneous, articular, vascular, cardiopulmonary manifestations and it is mainly found in the territories of the antique "silk road". ABD pathogenesis remains unknown although genetic, infectious and environmental factors seem to be implicated in the development of the disease, which is considered an auto-inflammatory condition. COVID-19 infection can present some symptoms, in particular at the level of oral and pulmonary mucosa, which require a differential diagnosis with ABD. Furthermore, the immunological alterations of this disease, and the drugs used for its treatment could influence the infection by COVID-19, and its clinical evolution. Nevertheless, vaccination anti-COVID-19 is recommended in ABD patients. The most commonly used diagnostic criteria for ABD are those established in 2014 by the International Team for the Revision of the International Criteria for BD (ITR-ICBD). Furthermore, criteria for disease severity according to the Overall Damage Index of Behçet's Syndrome (BODI) have recently been proposed in order to quantify the severity of the disease as well as the evolution during follow-up. In ABD patients it is mandatory to investigate on the presence of active/latent tuberculosis, because of the common organ involvement, such as eyes and bowel. ABD has a high morbidity and low mortality, sometimes linked to the rupture of an arterial aneurysm and/or neurological complications. This article is based on a general review on ABD ranging from the history of ABD to possible causes and clinical manifestations. A specific section has been dedicated to the COVID-19 pandemic.

Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome is an autoinflammatory recurrent fever syndrome that mainly affects children. Probiotics are currently used to prevent upper respiratory tract infections and flares of diseases associated with immune dysregulation. We aimed to evaluate the response to probiotic treatment in PFAPA patients. Patients with PFAPA syndrome who received probiotics and were followed between July 2019 and July 2021 were included in this retrospective study. Demographic and clinical features and response to probiotics were assessed. Twenty out of 111 children with PFAPA syndrome (F/M:1) were included. The median (min-max) ages at symptoms onset and diagnosis were 24 (3-72) and 51.5 (11-120) months, respectively. All 20 patients received probiotics during the disease course. The probiotic preparation they received included a combination of two lactobacilli as Lactobacillus plantarum HEAL9 (Lp HEAL9) and Lactobacillus paracasei 8700:2 (Lpa 8700:2). The median age at probiotic onset was 60 (33-192) months, while the duration of probiotic use was 4.5 (3-19) months. All patients except one experienced a decrease in attack frequency with probiotic use. After probiotic treatment, the median number of episodes during 3 months decreased from 3 to 1 (p < 0.001). Eight (40%) patients had no attacks during the 3 months after probiotic initiation. And, 5 (45%) of 11 patients who had ≥ 1 attacks on probiotics mentioned that the attack severity decreased significantly after probiotic initiation. Our results suggest that probiotic strains Lactobacillus plantarum HEAL9 and Lactobacillus paracasei 8700:2 could be beneficial in PFAPA patients by decreasing the attack frequency., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background & Objective: The use of herbal medicines to treat common oral diseases increases rapidly. Recurrent aphthous stomatitis is one of the most common oral mucosal diseases, which has an unclear etiology and could lead to severe pain and dysfunction. Cinnamaldehyde is a major component of cinnamon bark oil. Biological properties of cinnamaldehyde, such as antioxidant, antitumor, antifungal, cytotoxic, and anti-mutational characteristics, have been identified. Considering the prevalence of recurrent aphthous stomatitis and the importance of using herbal resources for treatment, the present study aimed to evaluate the effect of mucosal adhesive patches containing Cinnamaldehyde on minor recurrent aphthous stomatitis lesions., Material & Methods: In this randomized, double-blind clinical trial, patients were divided into two groups. The intervention group received three daily mucosal adhesive patches to be used in the morning, afternoon, and night. The control group also did the same with a placebo. To evaluate the healing and determine the diameter of the lesions, patients were clinically examined on days zero, 3, 5, and 7. The VAS scale evaluated pain at baseline and after each meal for seven days. The Fisher's exact test, t-test, Shapiro Wilk test, Friedman test, and the Mann-Whitney test were used to analyze the data using the SPSS 20 software., Results: There was no statistically significant difference in the mean diameter of the inflammatory lesion and pain intensity in the two groups in the baseline (p > 0.05). However, the ulcer size was significantly reduced in the cinnamaldehyde group on the third, fifth, and seventh days of the study. Except for baseline, the mean pain intensity significantly decreased in the cinnamaldehyde group compared to the placebo group (p < 0.05)., Conclusion: Cinnamaldehyde mucoadhesive patches effectively reduced and improved aphthous lesions and pain intensity in patients and can be considered a treatment for RAS., Registration Number: IRCT20180312039060N2-First registration date: 20/07/2018. The present study was registered as a retrospective study., (© 2022. The Author(s).)

Objective: To describe clinical, diagnostic and therapeutic characteristics of the periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome., Data Source: Literature review in the PubMed database by using specific descriptors to identify all articles published in the English language in the last three years; 38 articles were found. After performing selection of titles and abstract analysis, 13 out of the 38 articles were fully read. Relevant studies found in the references of the reviewed articles were also included., Data Synthesis: The PFAPA syndrome (Periodic Fever, Aphthous Stomatitis, Pharyngitis and cervical Adenitis) is a medical condition grouped among the periodic fever syndromes. The etiology is uncertain, but possibly multifactorial, and its symptoms are accompanied by recurrent febrile episodes although weight and height development are preserved. It is a self-limiting disease of benign course with remission of two to three years without significant interference in the patient's overall development. Treatment consists of three pillars: interruption of febrile episodes, increase in the interval between episodes, and remission., Conclusions: Despite several attempts to establish more sensitive and specific criteria, the diagnosis of PFAPA syndrome is still clinical and reached by exclusion, based on the modified Marshall's criteria. The most common pharmacological options for treatment include prednisolone and betamethasone; colchicine may be used as prophylaxis, and surgical treatment with tonsillectomy can be considered in selected cases.

Background and Aim: Lipschutz ulcers (LU) are idiopathic genital lesions characterized by the sudden appearance of painful, usually symmetric vulvar ulcers, typically occurring in sexually inactive adolescents. LU is a diagnosis of exclusion. As these lesions heal spontaneously, in the absence of tissue scarring, the therapy is mainly symptomatic and focuses on pain relief. Recurrence of LU associated with oral ulcers describes the clinical picture of complex aphthosis, which belongs to Behçet's disease (BD) pathological spectrum. Our work aims to analyze the correct diagnostic approach to recurrent aphthous, focusing on the importance of a multidisciplinary assessment and immunogenetic investigation to identify the subjects at risk of progression towards BD.   Methods: We present the case of a 12-year-old non sexually active Italian girl who was diagnosed with LU. After 15 months, she presented recurrent reactive non sexually related acute genital ulcer associated with a history of oral aphthous. According to clinical features and anamnesis, complex aphthosis was diagnosed. For diagnostic purposes, she underwent an immunogenetic analysis that showed HLA-B51 positivity., Results: In the absence of clinical and laboratory criteria to define the risk of progression of complex aphtosis towards BD, we think that besides a strict follow-up, in pediatric patients with a suggestive clinical history, it is crucial to adopt a multidisciplinary approach, comprehensive of HLA investigation, in order to guarantee an early diagnosis and a prompt therapeutic intervention., Conclusions: In children and adolescents with genital ulcers, it is essential to consider all the possible differential diagnoses to undertake a timely and correct course of treatment.

Familiarity with common oral conditions allows clinicians to observe and treat patients in the primary care setting or refer to a dentist, oral surgeon, otolaryngologist, or other specialist. Recurrent aphthous stomatitis (canker sores) is the most common ulcerative condition of the oral cavity. Recurrent herpes simplex labialis and stomatitis also commonly cause oral ulcers. Corticosteroids, immunocompromise, antibiotics, and dentures can predispose patients to oral candidiasis. Benign migratory glossitis (geographic tongue) occurs in up to 3% of the population but generally lacks symptoms, although some people experience food sensitivity or a burning sensation. Hairy tongue is associated with a low fiber diet, tobacco and alcohol use, and poor oral hygiene in older male patients. Generally, hairy tongue is asymptomatic except for an unattractive appearance or halitosis. Tobacco and alcohol use can cause mucosal changes resulting in leukoplakia and erythroplakia. These can represent precancerous changes and increase the risk of squamous cell carcinoma. Mandibular and maxillary tori are common bony cortical outgrowths that require no treatment in the absence of repeat trauma from chewing or interference with dentures. Oral lichen planus occurs in up to 2% of individuals and can present as lacy reticulations or oral erosions and ulcerations. Traumatic buccal mucosal fibromas and labial mucoceles from biting can be excised.

Objectives: To evaluate the role of Helicobacter pylori and other risk factors in recurrent aphthous stomatitis (RAS)., Methods: Patients with functional dyspepsia responded to questionnaires regarding demographic and clinical data, anxiety and depression, and a specific RAS questionnaire. They underwent upper digestive endoscopy and H. pylori evaluation., Results: 476 patients were included and of the 372 evaluated for H. pylori, 65.6% were H. pylori-positive. RAS was reported by 32.6% (155/476). In the bivariate analysis of the 372 patients evaluated for gastric H. pylori status, positive subjects had a lower RAS prevalence (29.9%; 73/244) than H. pylori-negative (41.4%; 53/128) (p = .026). Smoking (p = .005) and older age (p = .034) were also associated with a lower prevalence, while female gender (p = .032) and lower income (p = .046) presented higher RAS prevalence. In the multivariate analysis, H. pylori infection (p = .017), smoking (p = .001), and older age (p = .013) were protective factors, while lower income (p = .030) and anxiety (p = .042) were risk factors. In the multivariate analysis of all patients, female gender, lower income, and more schooling years were risk factors., Conclusions: An unexpected lower prevalence of RAS was found in H. pylori-positive patients. Smoking, sex, age, income, education, and anxiety were associated with RAS., (© 2021 Wiley Periodicals LLC.)

Background: Fever is the most frequent reason for medical consultation in children, and makes up 15-25% of all consultations in primary care and emergency departments. In here we report a case of a 13 year-old girl who referred with an unusual presentation of fever and was misdiagnosed with recurrent urinary tract infection for 8 years., Case Presentation: This is a Clinical Reasoning Cycle case study. A 13 year-old girl was referred with a chief complaint of recurrent fevers from 8 years. During her first febrile episode, she had a 5-day high-grade fever associated with loss of appetite. Her physical examination at that time was unremarkable. Blood tests showed leukocytosis with a shift to the left and urine examination was in favor of pyuria. The urine culture was positive for bacterial growth. The episodes of fever were repeated every 45 days. Accordingly, the patient was diagnosed as a case of recurrent urinary tract infection. In the intervals between her febrile episodes, the patient was healthy and laboratory tests were normal. Ultrasonography, voiding cystourethrogram and dimercaptosuccinic acid scans were normal. During her last visit, the patient mentioned difficulty in swallowing and on examination cervical lymph nodes, exudative tonsillitis and painful aphthous stomatitis were detected. All antibiotics were stopped and corticosteroids were started. The patient's symptoms were relieved and the interval between her febrile episodes became longer., Conclusions: Our study shows that a patient should never be marked, particularly when the symptom and signs aren't completely justifying a patient's condition., (© 2022. The Author(s).)

Fever is a common symptom of infection in children. Periodic fever syndromes are less common but more complex. One of these Periodic fever syndromes is PFAPA (periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis) syndrome which is known as the most benign syndromes. The cause of this disease is unknown. Various factors, including environmental and genetic factors, are involved in the development of this disease. In this study, the association of rs13075270 and rs13092160 polymorphisms were investigated in CCR1 and CCR3 genes with susceptibility to this syndrome in the Chinese population. In this regard, 38 patients with PFAPA syndrome and 100 healthy individuals were selected. After DNA sampling and extraction, polymorphisms of CCR1 and CCR3 receptor genes were examined by the PCR-RFLP method. Findings were analyzed using SPSS software version 22 with a significant level of P <0.05. The frequency of T/T genotype rs13092160 polymorphism in the patient and control groups was 78.95% and 83%, respectively, C/T genotype was 21.05% and 17% (P = 0.421). The frequency of the C/C genotype was 0 in both groups. Regarding rs13075270 polymorphism, the frequency of T/T genotype in patient and control groups was 15.79% and 81%, C/T genotype was 78.95% and 18% and C/C genotype was 5.26% and 1%, respectively (P<0.05). Thus, in rs13075270 polymorphism, the C/T genotype was associated with the risk of PFAPA syndrome (P<0.05), but rs13092160 polymorphism did not show a significant difference between individuals with PFAPA syndrome and controls.

Behçet's disease (BD) is a chronic, multi-systemic disorder of unknown aetiology typified by recurrent oral and genital mucocutaneous lesions, uveitis and vasculitis. Innate and adaptive immune system dysregulation has been implicated in pathogenesis with alterations in serum cytokine profiles. Few studies have investigated salivary cytokines in BD, despite more than 90% of BD patients first presenting with oral ulceration. The aim of this pilot study was twofold; firstly to investigate whether cytokine levels in matched serum and saliva samples show a differential profile in BD (with and without oral ulcers), recurrent aphthous stomatitis (RAS) and healthy controls (HCs), and secondly, to explore if any differential profiles in serum and/or saliva could provide a panel of cytokines with diagnostic and therapeutic potential for BD. Concentrations of 12 cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IFN-γ, TNF-α, TNF-β) were measured using the Human Th1/Th2 11-Plex FlowCytomix™ kit with IL-17A, in BD (N=20), RAS (N=6) and HCs (N=10). A differential range of cytokines was detected in serum and saliva with the majority of cytokine levels higher in saliva. The most prevalent salivary cytokines were IL-1β, IL-2, IL-8, IL-10 and TNF-α present in all samples in contrast to serum where the most prevalent cytokine detected was IL-8 (91.9%). The least abundant cytokine was IFN-γ in both saliva (43.2%) and serum (2.7%). After normalizing saliva for protein content, BD patients with oral ulcers (BD-MA) had significantly higher levels of salivary IL-1β (p=0.01), IL-8 (p=0.02), TNF-α (p=0.004) and IL-6 (p=0.01) than HCs. Notably, BD patients without oral ulcers (BD-MQ) also had significantly higher salivary IL-1β, IL-8 and TNF-α (p ≤ 0.05) than HCs. During relapsed (BD-RE) and quiet (BD-Q) systemic episodes, salivary IL-β and TNF-α were also significantly increased with IL-8 significantly higher only in BD-Q (p=0.02). BD oral ulcers signify a potential reactivation of systemic inflammation. Identifying cytokines released during asymptomatic episodes and oral ulceration might lead to targeted drug therapy to prevent recurrent oral ulcers and possible disease relapse. This is the first study to report salivary cytokine levels in BD. The detectable levels suggests cytokine profiling of BD saliva may provide an alternative, less invasive, sensitive procedure for frequent monitoring of disease activity and progression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Novak, Hamedi, Bergmeier, Fortune and Hagi-Pavli.)

Cyclic neutropenia has been rarely associated with chronic inflammation and development of reactive AA amyloidosis. We report a family with cyclic neutropenia with associated renal and thyroid amyloid. A 12-year-old female presented with thyromegaly, recurrent aphthous ulcers, severe neutropenia, and renal failure. Renal and thyroid biopsies revealed abundant amyloid deposition. Presence of a heterozygous ELANE c.358 A>T gene mutation p.I120F variant with autosomal dominant inheritance confirmed the diagnosis of cyclic neutropenia. The patient's father also had neutropenia and amyloidosis with renal failure. We started filgrastim to attenuate neutropenia and thereby reduce chronic inflammation and minimize further amyloid deposition., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The coronavirus disease 2019 (Covid-19) is a viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that clinically affects multiple organs of the human body. Cells in the oral cavity express viral entry receptor angiotensin-converting enzyme 2 that allows viral replication and may cause tissue inflammation and destruction. Recent studies have reported that Covid-19 patients present oral manifestations with multiple clinical aspects. In this review, we aim to summarise main signs and symptoms of Covid-19 in the oral cavity, its possible association with oral diseases, and the plausible underlying mechanisms of hyperinflammation reflecting crosstalk between Covid-19 and oral diseases. Ulcers, blisters, necrotising gingivitis, opportunistic coinfections, salivary gland alterations, white and erythematous plaques and gustatory dysfunction were the most reported clinical oral manifestations in patients with Covid-19. In general, the lesions appear concomitant with the loss of smell and taste. Multiple reports show evidences of necrotic/ulcerative gingiva, oral blisters and hypergrowth of opportunistic oral pathogens. SARS-CoV-2 exhibits tropism for endothelial cells and Covid-19-mediated endotheliitis can not only promote inflammation in oral tissues but can also facilitate virus spread. In addition, elevated levels of proinflammatory mediators in patients with Covid-19 and oral infectious disease can impair tissue homeostasis and cause delayed disease resolution. This suggests potential crosstalk of immune-mediated pathways underlying pathogenesis. Interestingly, few reports suggest recurrent herpetic lesions and higher bacterial growth in Covid-19 subjects, indicating SARS-CoV-2 and oral virus/bacteria interaction. Larger cohort studies comparing SARS-CoV-2 negative and positive subjects will reveal oral manifestation of the virus on oral health and its role in exacerbating oral infection., (© 2021 John Wiley & Sons Ltd.)

Abstract: The relationship between recurrent aphthous stomatitis (RAS), a common mucosal lesion, and cancer has not been demonstrated. This study investigated the risk for developing cancer in patients with RAS, based on data from Korea's National Health Insurance Sharing Service (NHISS). Nationwide population-based cohort data from 2005 to 2009 provided by the NHISS was used. The group diagnosed with RAS for 5 years and an undiagnosed control group were constructed through 1:1 propensity score matching (PSM). The experimental design compared the incidence rate of a cancer diagnosis from 2010 to 2015 between these 2 groups. After identifying 13,808 people that met our inclusion criterion from a 1 million cohort group, 13,808 controls were included in the study through PSM. Among all cancers, pancreatic cancer had an adjusted hazard ratio of 1.26 (95% confidence interval: 1.01-1.57, P < .041). For the rest of the cancers, there was no significant incidence rate. RAS was associated with an increased risk of pancreatic cancer in the analysis using large population-based cohort data. Further long-term follow-up studies are needed., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome is the most common cause of periodic fever in childhood. This study aimed to investigate sleep patterns and possible factors that are associated with sleep disturbances among children with PFAPA syndrome., Methods: Sixty-two patients with PFAPA and 68 age and sex matched healthy controls were enrolled in the study. Patients who had an attack during the former 2 weeks were not included. Demographic and anthropometric data, duration of fever episodes, laboratory results, and clinical manifestations of patients were recorded. The Children`s Sleep Habits Questionnaire was administered., Results: The total sleep scores of patients with PFAPA were significantly higher than the control group (49.6 ± 10.7 vs. 38.3 ± 7.5, p = 0.002 ). Children with PFAPA had significantly higher scores regarding sleep-onset delay, sleep anxiety and night wakening (p=0.003, p=0.007, and p=0.014, respectively). Total sleep durations were similar between children with PFAPA and the control group. There was a significant positive correlation between the total sleep score and disease duration (r=0.425, p=0.002). Also there was a significant positive correlation between disease duration and sleep onset delay (r=0.561, p < 0.001) and night wakening (r=0.327, p=0.003)., Conclusion: This study showed for the first time that patients with PFAPA have significantly disturbed sleep when compared to otherwise normal children. This study emphasized the need to assess sleep problems in children with PFAPA.

There is currently a lack of effective drugs to cure recurrent aphthous stomatitis. This study aimed to evaluate the efficacy of probiotics alone or as an adjunct in recurrent aphthous stomatitis (RAS) patients. Seven randomized controlled trials (RCTs) were included, of which three were included in quantitative analysis. Of five studies evaluating the efficacy of probiotics alone compared with placebo or Oracure gel, two reported no significant difference in relieving oral pain, while probiotics exhibited a higher capacity for decreasing oral pain in the other three. A significant decrease in ulcer severity was found in one, while no significant difference was found in the other four. The remaining two studies demonstrated that probiotics, as an adjunct to steroids or anaesthetic antiseptic gel, significantly reduced the ulcer severity and oral pain. The meta-analysis showed a significant decrease in oral pain (- 1.72, P = 0.0001) with probiotics compared with placebo. In conclusion, probiotics alone were capable of relieving oral pain but not effective in reducing ulcer severity. A combination of probiotics and steroids or anaesthetic antiseptic gel was more effective than steroids or anaesthetic antiseptic gel alone in RAS patients. Probiotics are promising for the treatment of recurrent aphthous stomatitis.

Objective: To assess the efficacy and safety of an oral mucoadhesive film containing chitosan for the treatment of recurrent aphthous stomatitis (RAS). Methods: Seventy-two subjects with RAS were recruited to this randomized, parallel-controlled, double-blind clinical trial. The participants were randomly allocated to the test group or the control group. Demographic data were recorded at baseline. The use of the film was demonstrated. Pain score (visual analog scale), adverse effects, ulcer size were recorded on day 1 (baseline), day 2, day 4, and day 6. Results: The reduction in ulcer size was significantly greater ( p <.05) in the treatment group (2.91 ± 3.66) than in the control group (1.10 ± 2.26) between days 4 and 6. There was no significant difference between the treatment and control groups in the pain score, ulcer size, or reduction in the pain score ( p >.05). No obvious adverse effects were observed. Conclusions: The oral mucoadhesive film containing chitosan promotes oral ulcer healing and can be used as a drug carrier in treating oral ulcers. Trial registration number: ChiCTR-IOR-16008970.

A variety of acute oral lesions may be encountered in the scope of dermatology. Oral lesions may be single or multiple; may arise secondary to infectious, immune, congenital, medication use, or idiopathic causes; and may take a variety of forms. A thorough evaluation of the oral cavity is required to assess patients with oral lesions. Affected patients may be monitored, treated, or referred to an appropriate specialist for further management as needed. Many acute oral lesions are self-limiting in nature and patients may require only assessment and reassurance. Several common acute oral lesions are discussed in this article., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Context: Monoclonal antibody therapies have revolutionized the treatment of autoinflammatory-immune/genetic disease including spondylarthritis, asthma and rheumatoid arthritis. Behcet's disease (BD) is a multi-systemic vasculitis, which is generally recurrent aphthous lesions (RAL) as well as ocular and skin lesions. Today, the immunohistopathogenesis of BD is mostly unknown., Method: Omalizumab (Anti-IgE humanized monoclonal antibody) therapy is given for severe persistent allergic asthma, and unintentionally it had effect on RAL. Our patient has received omalizumab treatment for 3 years. The steroid treatment was completely discontinued a month later and the systemic-steroid dependent diabetes mellitus was healed. The IL-1 β, IL-6, IL-8, IL-33, IL-25, IL-10, IL-23, and IL-17A levels were measured using an Enzyme-Linked Immunosorbent Assay (ELISA) kit., Results: After a long-term omalizumab treatment administered, the levels of WBC, d-dimer, IL-33, IL-6, IL-25 and IL-1 β decreased. The patient's hsCRP decreased from 3 to 0.1 and Eosinophil Cationic Protein (ECP) levels decreased from 78 to 21. A significant improvement was noticed in the RAL, the asthma symptoms (cough, shortness of breath), the number of emergency admissions, and the average length of stay of the patient within the days following the initiation of the omalizumab treatment., Conclusions: Here, for the first time, we introduce omalizumab treatment of a patient diagnosed with BD and the examination of the treatment for the clinical manifestations and the cytokines/coagulant protein levels. A significant improvement is observed in the patient's RAL following the initiation of omalizumab. There is strong evidence that the serum proinflammatory cytokines/coagulant factors could also play an important role in the relationship between RAL and IgE-dependent vascular autoinflammation.

Background: Periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome is a cyclic autoinflammatory disease generally diagnosed in childhood. There have been studies suggesting a relationship between menstruation and other autoinflammatory syndromes such as familial Mediterranean fever (FMF), but not PFAPA specifically., Case: This case describes a patient with a diagnosis of PFAPA who experienced complete resolution with tonsillectomy only to have recurrence of symptoms with onset of menstruation. She experienced symptom control with initiation of oral contraceptives., Summary and Conclusion: Prior to this case report, there had been no evidence in the literature suggesting a relationship between PFAPA and menstruation despite the observed association in other autoinflammatory syndromes. Onset of menses may be a trigger in PFAPA., (Copyright © 2020 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)

Background: Despite to PFAPA syndrome is considered a benign and self-limited condition in childhood its impact on patients and families can be remarkable in many cases. Currently, the therapeutic options for managing are non-specific and no consensus exists about the best treatment to use. Pidotimod has been suggested as a new potential treatment in PFAPA syndrome for its immunodulatory effects. We conducted a preliminary, prospective, controlled, open, cross-over trial to assess the efficacy and the safety of Pidotimod in the treatment of children with PFAPA syndrome., Methods: 22 children with PFAPA syndrome were randomly allocated to treatment with pidotimod (with 2 vials of 400 mg daily) in combination with betamethasone 0.5-1 mg on need, based on parents/caregivers' decision (group A) or betamethasone 0.5-1 mg on need, based on parents/caregivers' decision (group B). Each treatment period was for 3 months (Phase 1), after that patients were switched to the other arm for other 3 months (Phase 2). Efficacy was expressed in terms of number of episodes of fever, pharyngitis, or aphthous stomatitis, as well as the additional use of betamethasone on need. Safety and tolerability of the Pidotimod were evaluated on the basis of the number and type of adverse events (AEs) recorded during the treatment., Results: Patients receiving Pidotimod and use betametasone showed a significant decrease in frequency of fevers (p = 0.002); number of episodes of pharyngitis (p = 0.049); aphthous stomatitis (p = 0.036) as well as the betamethasone use on need (p = 0.007). Overall, 19/22 (86.4%) showed benefits from Pidotimod administration. The safety profile of Pidotimod was excellent as no serious adverse events have been reported in the treated groups., Conclusions: We firstly showed that high dosage of Pidotimod could be an effective and safe to reduce the PFAPA attacks in children.

Objectives: Recurrent aphthous stomatitis (RAS) represents a dysfunction in focal inflammatory processes. With the emerging anti-inflammatory roles of vitamin D (VD), we wanted to investigate the association between the onset and severity of RAS and serum VD level., Methods: Fifty-two RAS cases and sex and age-matched controls were screened for serum iron, B 12 , folic acid, VD and red cell indices. Variables were compared using independent samples t test and chi square. Binary logistic regression was used to assess the association between the severity of RAS and various hematinic deficiencies., Results: VD was deficient in 53% of the study population with no statistically significant difference between the RAS patients and healthy controls (53.6 versus 51.5 nmol/l, respectively). In comparison with controls, RAS patients had lower means of iron (81.0 versus 89.3 μg/dl), vitamin B 12 (368.5 versus 412.7 pg ml) and most of the red cell indices; however, these differences were not statistically significant. No correlations were seen between RAS severity assessed by ulcer diameter, number of ulcers and their frequency and hematinic deficiencies. However, logistic regression showed a significant association between the number of ulcers (single or multiple) and VD deficiency (OR 4.978; 95% CI 1.204-20.576; p value = 0.027), adjusted for age, sex and other hematinics., Conclusions: VD deficiency appears to have a role in aggravating RAS ulcerative episodes, but not their onset., Clinical Relevance: Multiple aphthous ulcers might represent a subcategory of RAS lesions in which VD deficiency plays a role in aggravating the oral ulcerative condition.

Objectives: Data on the adult-onset periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome are scarce. European studies reported that unlike pediatric-onset PFAPA, tonsillectomy is ineffective for adult-onset PFAPA. The aims of this study were (1) to assess the response to tonsillectomy in a cohort of Japanese adult-onset PFAPA patients and (2) to evaluate the histologic appearance of tonsils in adult-onset PFAPA patients and to compare them with those of tonsils from age- and sex-matched controls with chronic tonsillitis., Methods: In this retrospective cohort study, 5 adults with PFAPA and 15 controls who had undergone tonsillectomy were recruited. The size of the tonsil germinal centers was measured by hematoxylin and eosin staining, and the number and density of B and T lymphocytes in germinal centers were measured by immunohistochemistry, using CD3, CD4 and CD8 as T cell markers and CD20 as B cell marker., Results: All patients had complete remission of the symptoms after surgery. PFAPA patients had significantly smaller germinal center areas than controls. The number and density of CD8+ cells in germinal centers were significantly lower in tonsils from PFAPA compared with controls. No differences were found between the two groups in CD3+, CD4+, and CD20+ cells. These results are compatible with the tonsillar features of pediatric-onset PFAPA., Conclusion: Our report demonstrates that tonsillectomy might be effective for adult-onset PFAPA and that tonsils of adult- and pediatric-onset PFAPA share the same histological features. These results suggest that the pathogenic mechanisms of adult- and pediatric-onset PFAPA are identical., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Recurrent aphthous stomatitis (RAS) is a common oral disease with unknown molecular pathogenesis. Our preliminary microarray analysis revealed the altered expression of lncRNA Cancer Susceptibility Gene 2 (CASC2) in RAS. We therefore analyzed the role of CASC2 in RAS., Methods: In this study, plasma samples were obtained from RAS patients and healthy participants. Plasma levels of CASC2 were measured by RT-qPCR. Plasma levels of IL-6 and IL-18 were measured by enzyme-linked immunosorbent assay (ELISA). A follow-up study was performed to analyze the role of CASC2 in the recurrence of RAS., Results: In the present study, we found that lncRNA Cancer Susceptibility Gene 2 (CASC2), as well as pro-inflammatory factors interleukin 6 (IL-6) and interleukin 18 (IL-18), were upregulated in plasma of RAS patients compared with healthy participants. Plasma levels of lncRNA CASC2 were positively correlated with plasma levels of IL-6 and IL-18 in RAS patients but not in healthy participants. Compared with pre-treatment levels, plasma levels of lncRNA CASC2, IL-6 and IL-18 were reduced after recovery. A follow-up study showed that patients with high levels of lncRNA CASC2 had a significantly higher recurrence rate., Conclusion: LncRNA CASC 2 is upregulated in RAS and predicts the recurrence.

The periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is an auto-inflammatory condition characterized by recurrent episodes of fever accompanied by aphthosis, cervical adenitis, and pharyngitis. Diagnosis of PFAPA could be challenging due to clinic overlap with familial Mediterranean fever (FMF). An international consensus has been established recently, to define a new set of classification criteria for PFAPA syndrome. We aimed to evaluate the performance of recently proposed PFAPA criteria, to assess their utility in FMF regions. Patients diagnosed with PFAPA syndrome, FMF, and juvenile idiopathic arthritis (JIA) were included. Two investigators blindly evaluated all of patients for the newly proposed PFAPA criteria. A total of 542 patients (322 with PFAPA syndrome, 118 FMF and 102 JIA) were evaluated. Mean age of patients was 6.6 ± 2.81, 12.75 ± 3.9, and 12.42 ± 4.8 years for PFAPA, FMF, and JIA, respectively. We found quite high sensitivity (89.7%) but insufficient specificity of newly proposed PFAPA criteria (69.5%). When applied to control patients separately, specificity was found to be 61% and 79.4% for FMF and JIA patients, respectively. Positive predictive value was 81%, while negative predictive value was 82%. Recently proposed PFAPA criteria have satisfactory sensitivity, but its specificity is still under expectation. There is a need for a distinctive criterion between PFAPA syndrome and FMF, in FMF endemic regions, e.g., cryptic tonsillitis rapidly responsive to single dose of glucocorticoids. Further studies with higher patients' number in different regions are needed.

Small supernumerary marker chromosomes (sSMCs) are characterized as additional centric chromosome fragments which are too small to be classified by cytogenetic banding alone and smaller than or equal to the size of chromosome 20 of the same metaphase spread. Here, we report a patient who presented with slight neutropenia and oral aphthous ulcers. A mosaic de novo sSMC, which originated from 5 discontinuous regions of chromosome 8, was detected in the patient. Formation of the sSMC(8) can probably be explained by a multi-step process beginning with maternal meiotic nondisjunction, followed by post-zygotic anaphase lag, and resulting in chromothripsis. Chromothripsis is a chromosomal rearrangement which occurs by breakage of one or more chromosomes leading to a fusion of surviving chromosome pieces. This case is a good example for emphasizing the importance of conventional karyotyping from PHA-induced peripheral blood lymphocytes and examining tissues other than bone marrow in patients with inconsistent genotype and phenotype., (© 2020 S. Karger AG, Basel.)

Background/purpose: To report two novel cases of intermediate uveitis associated with Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis syndrome., Methods: Observational case reports and review of the literature., Results: Both patients in this report had an established diagnosis of Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis syndrome before the onset of ocular inflammation. Infectious and noninfectious systemic conditions known to be associated with intermediate uveitis were excluded. Intermediate uveitis was confirmed clinically in both patients by the presence of vitritis, snowballs, and peripheral snowbanks in the region of the pars plana. Both cases had a course characterized by recurrent inflammation; in which systemic steroid treatment, and in one case, immunomodulatory therapy was necessary., Conclusion: Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis syndrome is an auto-inflammatory fever disorder in childhood. Although other auto-inflammatory disorders such as, Blau syndrome, Muckle-Wells syndrome, and Behcets disease have been associated with various forms of uveitis, Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis has never been reported to be associated with any type of ocular inflammation. We describe for the first time, two cases of Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis syndrome presenting with intermediate uveitis.

Aim: Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is the most common cause of a periodic fever in childhood. The exact pathogenesis and the aetiology of PFAPA are still unknown., Methods: We conducted a non-systematic review of published articles about PFAPA syndrome and summarised the evidence for diagnostic criteria and treatment options for PFAPA., Results: The first proposed diagnostic criteria for PFAPA, in addition to periodic fever, included aphthous stomatitis, pharyngitis or cervical lymphadenitis in children younger than five years at the beginning of the symptoms. C-reactive protein (CRP) levels and leucocyte counts increase in most patients during episodes. Recent research reveals that tonsillectomy provides an immediate and long-lasting cure for PFAPA, even in the absence of classic criteria of aphthous stomatitis, pharyngitis or cervical adenitis and in children older than five years., Conclusion: We suggest that PFAPA can be diagnosed in children with at least five regularly occurring fever episodes without any other explanation, even in the absence of aphthous stomatitis, pharyngitis or cervical lymphadenitis and also in children older than five years., (©2019 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is a recurrent fever syndrome of early childhood with increasing number of adult-onset cases. Although it is a self-limited disease, it may negatively affect the quality of life. The aim of this review is to present a detailed analysis of PFAPA syndrome and an algorithm for diagnosis, therapeutic options, and evaluation of outcome. A comprehensive literature search was conducted through the Cochrane Library, Scopus, and MEDLINE/PubMed databases. The main topics covered are the epidemiology, clinical manifestations, diagnosis, differential diagnosis, etiopathogenesis, genetics, management, disease course and prognosis, disease in adults, unsolved issues, and unmet needs in PFAPA. The diagnosis of PFAPA is mainly based on clinical classification criteria. The most relevant hypothesis for pathogenesis is that dysregulated immune system in a genetically predisposed individual responds to a yet unidentified trigger in an exaggerated way. The pedigree analyses suggest a genetic background for the disease with an autosomal dominant pattern of inheritance. For management, single-dose corticosteroids during attacks and tonsillectomy remain the most effective therapies, while colchicine is a promising option to decrease attack frequency. There remain unsolved issues in PFAPA such as the exact etiopathogenesis and genetic background, the reason why the inflammation is restricted to the oropharyngeal lymphoid tissue, reasons for clock-work regularity of attacks, and self-limited disease course. There is need for a valid diagnostic criteria set with a high performance for both children and adults and consensus on management of PFAPA.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is a recurrent fever syndrome for which tonsillectomy is a therapeutic option curing the disease in most patients. Recurrence after remission with tonsillectomy is extremely rare. Increasing number of reports on diverse disease manifestations in PFAPA could give us clues about the disease etiopathogenesis. We aimed to describe a patient with recurrence of PFAPA syndrome after tonsillectomy and to review the previous studies including similar cases. We report a 17-year-old boy with PFAPA syndrome who experienced remission for 3 years after tonsillectomy and was later found to harbor an MEFV mutation when the disease relapsed. He responded well to colchicine treatment at relapse. The literature review revealed 14 articles describing 24 similar PFAPA patients. The therapeutic options include single-dose corticosteroids and nonsteroidal anti-inflammatory drugs during attacks, cimetidine, and resurgery. The presented case was the only one heterozygous for an MEFV mutation and treated with colchicine at disease relapse. Albeit rare, the reoccurrence of PFAPA after tonsillectomy could occur. The presence of such patients opposes with the hypothesis that the trigger or immune dysregulation in PFAPA pathogenesis resides in tonsils.

Painful oral vesiculoerosive diseases (OVD) include lichen planus, pemphigus vulgaris, mucous membrane pemphigoid, erythema multiforme, and recurrent aphthous stomatitis. OVD lesions have an immunopathic cause. Treatment is aimed at reducing the immunologic and the following inflammatory response. The mainstay of OVD management is topical or systemic corticosteroids to include topical triamcinolone, fluocinonide, and clobetasol, whereas systemic medications used in practice can include dexamethasone, prednisone, and prednisolone. Oral herpetic lesions can be primary or recurrent. If management is desired, they can be treated by topical or systemic antiviral drugs. Topical antiviral creams include prescription acyclovir, penciclovir and over-the-counter docosanol., (Published by Elsevier Inc.)

Background: Diagnosis of Periodic Fever, Aphthous stomatitis, Pharyngitis and Cervical Adenitis (PFAPA) syndrome is currently based on the modified Marshall's criteria, but no validated evidence based classification criteria for PFAPA has been established so far., Methods: A multistep process, based on the Delphi and Nominal Group Technique was conducted. After 2 rounds of e-mail Delphi survey involving 21 experts in autoinflammation we obtained a list of variables that were discussed in an International Consensus Conference. Variables reaching the 80% of consensus between participants were included in the new classification criteria. In the second phase the new classification criteria and the modified Marshall's criteria were applied on a cohort of 80 pediatric PFAPA patients to compare their performance., Results: The Delphi Survey was sent to 22 participants, 21 accepted to participate. Thirty variables were obtained from the survey and have been discussed at the Consensus Conference. Through the Nominal Group Technique we obtained a new set of classification criteria. These criteria were more restrictive in respect to the modified Marshall's criteria when applied on our cohort of patients., Conclusion: Our work led us to identify a new set of classification criteria for PFAPA syndrome, but they resulted to be too restrictive to be applied in daily clinical practice for the diagnosis of PFAPA.