Systemic and local effect of oxidative stress on recurrent aphthous stomatitis: systematic review.

Recurrent aphthous stomatitis (RAS) is a chronic and recurrent inflammatory disease of the mouth. It is characterised by the appearance of painful ulcers in the oral mucosa. RAS is believed to be a multifactorial disease with genetic predisposition, environmental factors and alterations in the immune system. Oxidative stress, caused by an imbalance between free radicals and the antioxidant system, also appears to be involved in the pathogenesis of RAS. Several risk factors, such as smoking, iron and vitamin deficiency and anxiety, may contribute to the development of the disease. Understanding the underlying mechanisms may help in the prevention and treatment of RAS. We searched PubMed, Scopus and Web of Science databases for articles on oxidative stress in patients with RAS from 2000 to 2023. Studies analysing oxidant and antioxidant levels in the blood and saliva of RAS patients and healthy controls were selected. Of 170 potentially eligible articles, 24 met the inclusion criteria: 11 studies on blood samples, 6 on salivary samples and 7 on both blood and salivary samples. Multiple oxidative and antioxidant markers were assessed in blood and saliva samples. Overall, statistically significant differences were found between RAS patients and healthy controls for most markers. In addition, increased oxidative DNA damage was observed in patients with RAS. Patients with RAS show elevated levels of oxidative stress compared to healthy controls, with a significant increase in oxidative markers and a significant decrease in antioxidant defences in saliva and blood samples.

A Potential Partnership between Genetics and the Oral Microbiome in Children Displaying Periodic Fever/Aphthosis/Pharyngitis/Adenitis Syndrome.

Periodic fever/aphthosis/pharyngitis/adenitis (PFAPA) syndrome was initially described in a small cohort of American children [...].

The effect of Jiaweidaochi powder on Th1/Th2 in rats with recurrent aphthous ulcer.

OBJECTIVE: To elucidate the effect of Jiaweidaochi powder on the Th1/Th2 ratio in rats with recurrent aphthous ulcers (RAU). DESIGN: 40 Sprague-Dawley rats were included in this study, randomly divided into a control group, a model group, and three treatment groups (0.5 g/ ml, 1 g/ml, 2 g/ml Jiaweidaochi powder). The RAU model of rats was established by autoantigen injection. The effects of Jiaweidaochi powder on the expression of INFG, IL-4, TBX21, and GATA3 mRNA were detected by real-time PCR. The expression of IFN-γ, IL-4, and IFN-γ/IL-4 proteins in oral ulcer tissue and serum of rats were analyzed by Western blot and ELISA, respectively. The proportion of Th1 cells and Th2 cells in RAU rats was analyzed by flow cytometry. RESULTS: Jiaweidaochi powder reduced the number, diameter, and duration of oral ulcers in RAU rats. Real-time PCR showed that middle and high-dose Jiaweidaochi powder decreased the expression of INFG TBX21 mRNA and increased the expression of IL-4 and GATA3 mRNA in the oral tissue of RAU rats. ELISA and western blot confirmed that the expression of IFN-γ protein was significantly decreased, and the level of IL-4 protein was increased both in oral tissue and serum of RAU rats treated with middle or high doses of Jiaweidaochi powder. Flow cytometry found that the Jiaweidaochi powder decreased the proportion of Th1 cells and increased the proportion of Th2 cells in RAU rats. CONCLUSION: This study found that Jiaweidaochi powder promoted the balance of Th1/Th2 in RAU rats, contributing to the healing of RAU.

TNFRSF1A-pR92Q variant identifies a subset of patients more similar to systemic undifferentiated recurrent fever than TNF receptor-associated periodic syndrome.

OBJECTIVES: To describe the clinical phenotype and response to treatment of autoinflammatory disease (AID) patients with the TNFRSF1A-pR92Q variant compared to patients with tumour necrosis factor receptor-associated periodic syndrome (TRAPS) due to pathogenic mutations in the same gene and patients diagnosed with other recurrent fever syndromes including periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA) and syndrome of undefined recurrent fever (SURF). METHODS: Clinical data from pR92Q variant associated AID, classical TRAPS, PFAPA and SURF patients were obtained from the Eurofever registry, an international, multicentre registry enabling retrospective collection of data on AID patients. RESULTS: In this study, 361 patients were enrolled, including 77 pR92Q variant, 72 classical TRAPS, 152 PFAPA and 60 SURF patients. pR92Q carriers had an older age of disease onset than classical TRAPS and PFAPA patients. Compared to pR92Q variant patients, classical TRAPS patients had more relatives affected and were more likely to have migratory rash and AA-amyloidosis. Despite several differences in disease characteristics and symptoms between pR92Q variant and PFAPA patients, part of the pR92Q variant patients experienced PFAPA-like symptoms. pR92Q variant and SURF patients showed a comparable clinical phenotype. No major differences were observed in response to treatment between the four patient groups. Steroids were most often prescribed and effective in the majority of patients. CONCLUSIONS: Patients with AID carrying the TNFRSF1A-pR92Q variant behave more like SURF patients and differ from patients diagnosed with classical TRAPS and PFAPA in clinical phenotype. Hence, they should no longer be diagnosed as having TRAPS and management should differ accordingly.

What is PFAPA syndrome? Genetic clues about the pathogenesis.

PURPOSE OF REVIEW: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in childhood. Recent studies report genetic susceptibility variants for PFAPA syndrome and the efficacy of tonsillectomy in a broader cohort of patients with recurrent stereotypical fever. In this review, we highlight the findings of these studies and what they may reveal about the pathogenesis of PFAPA. RECENT FINDINGS: Newly identified genetic susceptibility loci for PFAPA suggest that it is a complex genetic disorder linked to Behçet's disease and recurrent aphthous ulcers. Patients who have PFAPA with some features of Behçet's disease have been reported. Moreover, the efficacy of tonsillectomy has now been described in patients who do not meet the full diagnostic criteria for PFAPA, although the immunologic profile in the tonsils is different from those with PFAPA. Factors that predict response to tonsillectomy are also reported. SUMMARY: These findings highlight the heterogeneous phenotypes that may be related to PFAPA due to common genetic susceptibility or response to therapy. These relationships raise questions about how to define PFAPA and highlight the importance of understanding of the genetic architecture of PFAPA and related diseases.

Association of Surfactant Protein D Single Nucleotide Polymorphisms rs721917, rs2243639, rs3088308 with Recurrent Aphthous Stomatitis in Pakistani Population.

Recurrent aphthous stomatitis (RAS) is a benign ulcerative condition, defined by the recurrent formation of non-contagious mucosal ulcers. Surfactant protein D (SP-D) is secreted frequently at surfaces exposed directly to body fluids. This study aims to investigate the association of SP-D single nucleotide polymorphisms (SNPs) with the onset of RAS. Blood samples from 212 subjects (106 cases/controls each) were collected during 2019 and genotyped for SP-D SNPs (rs721917, rs2243639, rs3088308) by polymerase chain reaction and restriction fragment length polymorphism followed by 12% polyacrylamide gel electrophoresis. Minor aphthous (75.5%) was the commonly observed ulcer type as compared to herpetiform (21.7%) and major aphthous ulcers (2.8%). A family history of RAS was reported in 70% of cases. RAS was found significantly associated with rs3088308 genotypes T/A (95% (Cl): 1.57-5.03, p = 0.0005), A/A (95% (Cl): 1.8-6.7, p = 0.0002), T-allele (95% (Cl): 1.09-2.36, p = 0.01), A-allele (95% (Cl): 1.42-3.91, p = 0.01), rs721917 genotype T/T (95% (Cl): 1.15-25.35, p = 0.03), and T-allele (95% (Cl): 1.28-3.10, p = 0.002). Female gender and obese body mass index (BMI) were significantly associated with rs3088308 genotypes T/A (95% (CI): 1.89-15.7, p = 0.001), T/T (95% (Cl): 1.52-11.9, p = 0.005), A-allele (95% (Cl): 1.65-7.58, p < 0.001), and T-allele (95% (Cl): 1.4-10.1, p <0.001) and rs721917 genotype T/T (95% (CI) = 1.3-33, p = 0.02), respectively. This study describes the association of SP-D SNPs (rs721917, rs3088308) with RAS in the Pakistani population.

NLRP3 gene variants and serum NLRP3 levels in periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome.

OBJECTIVES: Although most of the autoinfammatory disorders have a confirmed genetic cause, periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome still has an unknown genetic background. However, familial cases of PFAPA syndrome have been reported suggesting a genetic its basis. PFAPA syndrome may also be considered an infammasome disorder as variants in infammasome-associated genes such as CARD8, NLRP3, and MEFV have been reported to contribute to the disease. METHODS: Polymerase chain reaction (PCR)/Sanger sequencing analysis was performed for the detection of the variations in 71 PFAPA patients and 71 healthy controls. NLRP3 concentrations in serum were measured in 71 PFAPA patients and 71 healthy controls. RESULTS: No statistically significant differences were observed in the allele or genotype frequencies of the NLRP3 polymorphisms between the controls and patients (P > 0.05). We found no significant differences for NLRP3 serum levels between PFAPA patients and controls (p > 0.05). Mutations in the MEFV gene were detected in 32.5% of our patients (13/40). CONCLUSIONS: It seems that the synergistic effect of different genes plays a role in the formation of PFAPA syndrome. For this reason, it may be useful to examine the presence of mutations in genes such as NLRP3, MEFV, and CARD8 together while investigating the genetics of PFAPA syndrome. Key points • Familial cases of PFAPA syndrome have been reported suggesting a genetic basis for this syndrome. • Elevated serum or plasma levels of IL-1ß, IL-6, and IL-18 have been demonstrated during PFAPA flares in several studies. • It seems that the synergistic effect of different genes plays a role in the formation of PFAPA syndrome.

Characterization of immune landscape and development of a novel N7-methylguanine-related gene signature to aid therapy in recurrent aphthous stomatitis.

OBJECTIVES: Recurrent aphthous stomatitis (RAS) is the most common inflammatory disease of the oral mucosa resulting in an impaired life quality and even leading to tumors in susceptible populations. N7-Methylguanine (m7G) plays a vital role in various cellular activities but has not yet been investigated in RAS. We aimed at picturing the immune landscape and constructing an m7G-related gene signature, and investigating candidate drugs and gene-disease association to aid therapy for RAS. METHODS: For our study, m7G-related differentially expressed genes (DEGs) were screened. We outlined the immune microenvironment and studied the correlations between the m7G-related DEGs and immune cells/pathways. We performed functional enrichment analyses and constructed the protein-protein interaction (PPI) and multifactor regulatory network in RAS. The m7G-related hub genes were extracted to formulate the corresponding m7G predictive signature. RESULTS: We obtained 11 m7G-related DEGs and studied a comprehensive immune infiltration landscape, which indicated several immune markers as possible immunotherapeutic targets. The PPI and multifactor regulatory network was constructed and 4 hub genes (DDX58, IFI27, IFIT5, and PML) were identified, followed by validation of the corresponding m7G predictive signature for RAS. GO and KEGG analyses revealed the participation of JAK-STAT and several immune-related pathways. Finally, we suggested candidate drugs and gene-disease associations for potential RAS medical interventions. CONCLUSIONS: The present study pictured a comprehensive immune infiltration landscape and suggested that m7G played a vital role in RAS through immune-related pathways. This study provided new insight for the future investigation of the mechanisms and therapeutic strategies for RAS.

Does having MEFV gene sequence variants affect the clinical course and colchicine response in children with PFAPA syndrome?

The primary aim of this study was to document the treatment modalities used in periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome and look for the efficacy and safety of colchicine in the treatment of PFAPA patients. The secondary aim was to search for whether having MEFV (Mediterranean fever) gene sequence variants affect the clinical course and response to colchicine. The study was conducted in 2 pediatric rheumatology centers. The patients that have been diagnosed with PFAPA syndrome between December 2017 and December 2021 were evaluated retrospectively. The study included 157 patients with PFAPA syndrome (54.8% boys and 45.2% girls). The median follow-up duration was 18 (IQR: 12-30) months. One hundred and fifty-five patients (98.7%) had exudative pharyngitis, 120 patients (76.4%) had aphthous stomatitis, and 82 patients (52.2%) had cervical lymphadenitis during the attacks. Clinical features during attacks were not affected by the presence or absence of the MEFV gene sequence variants. Corticosteroid treatment during attacks was given to 152 patients (96.8%). The frequency of fever attacks did not change in 57 patients (37.5%), increased in 57 patients (37.5%), and decreased in 38 patients (25%) after corticosteroid use. Colchicine was given to 122 patients (77.7%) in the cohort. After colchicine treatment, complete/near-complete resolution of the attacks was observed in 57 patients (46.7%). Colchicine led to partial resolution of the attacks in 59 patients (48.4%). In only 6 patients (4.9%), no change was observed in the nature of the attacks with colchicine treatment. The median duration of the attacks was 4 (IQR: 4-5) days before colchicine treatment, and it was 2 (IQR: 1-2.5) days after colchicine treatment. Also, a significant decrease in the frequency of the attacks was observed before and after colchicine treatment [every 4 (IQR: 3-4) weeks versus every 10 (IQR: 8-24) weeks, respectively, (p < 0.001)]. The overall response to colchicine was not affected by MEFV sequence variants. It was seen that the frequency of fever attacks decreased dramatically in both groups, and children with MEFV variants had significantly less attacks than children without MEFV variants after colchicine treatment (every 11 weeks vs every 9.5 weeks, respectively, p: 0.02). CONCLUSION: Colchicine seems to be an effective and safe treatment modality in PFAPA treatment. It led to a change in the nature of the attacks either in the frequency, duration, or severity of the attacks in 95.1% of the patients. This study has shown that having MEFV gene sequence variants did not affect the clinical course or response to colchicine. We recommend that colchicine should be considered in all PFAPA patients to see the response of the patient, irrespective of the MEFV gene mutations. WHAT IS KNOWN: • Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome is the most common periodic fever syndrome in the world. Familial Mediterranean fever (FMF) is the most common cause of periodic fever syndrome in Turkey. • Colchicine has become a new treatment option in PFAPA. WHAT IS NEW: • Some PFAPA patients have Mediterranean fever (MEFV) gene variants, and it is speculated that PFAPA patients with MEFV gene mutations respond better to colchicine. • The aim of this study was to look for this hypothesis. We have seen that the clinical phenotype and colchicine response of PFAPA patients were not affected by MEFV gene sequence variants.

Gene polymorphisms and serum levels of mannose-binding lectin in Czech patients with recurrent aphthous stomatitis: A case-control study.

BACKGROUND: Recurrent aphthous stomatitis is one of the most prevalent oral mucosal immunological diseases. A recent case-control study in the Egyptian population suggested that single nucleotide polymorphism Gly54Asp (rs1800450) of the mannose-binding lectin 2 gene might affect the mannose-binding lectin serum level and recurrent aphthous stomatitis development. The aim of this study was to determine the distribution of six functional mannose-binding lectin 2 gene polymorphisms and analyse their role in recurrent aphthous stomatitis susceptibility in the Czech population. METHODS: The study included 227 subjects; 137 healthy people and 90 patients with recurrent aphthous stomatitis. Six mannose-binding lectin 2 gene polymorphisms (rs11003125, rs7096206, rs7095891, rs5030737, rs1800450, rs1800451) were analysed by the SNaPshot assay method, mannose-binding lectin serum levels were determined by enzyme-linked immunosorbent assay (ELISA) method in a subgroup of subjects (N = 87). RESULTS: No significant differences in mean of mannose-binding lectin serum levels between healthy controls and patients with recurrent aphthous stomatitis were observed (383 ng/ml ± 249 standard deviation (SD) vs. 316 ng/ml ± 177 SD in remission phase vs. 343 ng/ml ± 254 SD in active phase; p > 0.05), also the allele and genotype frequencies of the studied mannose-binding lectin 2 polymorphisms did not differ significantly between the two groups (p > 0.05, odds ratio (OR): 0.75-1.23). Moreover, the distribution of mannose-binding lectin 2 haplotypes and haplogenotypes was similar in the healthy subjects and patients with recurrent aphthous stomatitis (p > 0.05, OR: 0.75-1.23). CONCLUSIONS: This study did not confirm the previously reported association of the mannose-binding lectin 2 Gly54Asp gene variant and low mannose-binding lectin serum level as the risk factors for susceptibility to recurrent aphthous stomatitis. In addition, no significant relationships between mannose-binding lectin 2 functional haplotypes or haplogenotypes and recurrent aphthous stomatitis were observed.

Network pharmacology and bioinformatics analyses identify the intersection genes and mechanism of Huang Bai for recurrent aphthous stomatitis.

Recurrent aphthous stomatitis (RAS) are complex inflammatory diseases caused by multi-factors, which severely impact patient quality of life. However, there is still no effective treatment method for RAS without side effects. Traditionally, Cortex Phellodendri known as "Huang Bai" was used to treat RAS for antibacterial and anti-inflammatory properties in China. Network pharmacology methods and bioinformatics analysis were utilized to search and fish incorporating target. Network analysis and silico validation were used to discover the pharmacological mechanisms of "Huang Bai" for the treatment of RAS. A total of 25 active ingredients in HB, 200 drug targets, and 578 differentially expressed genes (DEGs) between Recurrent aphthous stomatitis and normal samples were obtained. The Gene Ontology enrichment analysis revealed that the immune response was the most significantly enriched term within the DEGs. The KEGG pathway analysis identified 60 significant pathways, most of which involved in the inhibition of inflammation and regulation of immunological response. The functions are dependent on a multi-pathway, particularly the TNF signaling pathway and the HIF-1 signaling pathway. We identified six hub genes in the PPI network, most of which were validated as highly expressed in oral ulcers by DiseaseMeth databases. In addition, molecular docking displayed that the primary molecule combined well with the key targets. "Huang Bai" contains potential anti-RAS active compounds. This study reflects the multi-component multi-target multi-pathway action characteristics of "Huang Bai." Our study provides potential biomarkers or treatment targets for further research.

IL-10 and TGF-beta1 gene polymorphismsin Greek patients with recurrent aphthous stomatitis

Background: Recurrent aphthous stomatitis (RAS) is one of the most frequent inflammatory disorders of theoral mucosa. Cytokines, which play an important role in RAS pathogenesis, participate directly or indirectly innormal, immunological and inflammatory processes and are secreted from cells belonging to innate and adaptiveimmunity as a consequence of microbial and antigenic stimuli. Gene polymorphisms in specific cytokines maypredispose to RAS development. The aim of this study was the investigation and association of IL-10 and TGF-β1gene polymorphisms with RAS.Material and Methods: Study’s cohort consisted of 60 Greek patients diagnosed with RAS, including 40 patientswith minor, 10 patients with major and 10 with herpetiform aphthous ulcers. Forty age- and sex-matched controlsubjects were included in this study. DNA was extracted from whole blood samples of all patients and sequencespecific primers (SSP)-based polymerase chain reaction (PCR) was used for genotyping. Gene polymorphisms forcytokines IL-10 at loci -592 and -819 and for TGF-β1 at codon 10 were detected.Results: Significant differences between patients with minor RAS and healthy controls were recorded for IL-10genotypes distribution at position -592 (p=0.042) and -819 (p=0.045) with predominance of C/A and C/T genotypes in RAS patients, respectively. Also, in patients with minor and herpetiform aphthous ulcerations, heterozygousTGF-β1 genotype C/T at codon 10 was associated with increased risk of RAS (p=0.044 and p=0.020, respectively).Conclusions: These data provide evidence that genetic predisposition for RAS and possibly its specific clinical variants is related with the presence of gene polymorphisms for specific cytokines, including IL-10 and TGF-β1, which,in turn, may vary according to geographic origin and genetic background. (AU)

Colchicine versus cimetidine: the better choice for Periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome prophylaxis, and the role of MEFV gene mutations.

BACKGROUND: During childhood, the most common periodic fever is periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. The effective treatment and prevention of febrile attacks improve these patients' and their families' quality of life. However, there is no single strategy or evidence-based guideline to manage this syndrome, and most of them are based on consensus treatment plans. METHODS: This randomized controlled trial was carried out on 67 PFAPA patients referred to three tertiary centers of pediatric rheumatology. The patients were divided into two groups, including group 1 (n = 36) receiving prednisolone plus colchicine and group 2 (n = 31) receiving prednisolone plus cimetidine. Demographic characteristics and the number of febrile episodes were compared between the two groups before and after the intervention. RESULTS: In both groups, the number of febrile episodes after the treatment decreased (P ≤ 0.001). Statistical Analysis showed no significant difference between the two groups (P = 0.88). Moreover, 44 patients from both groups were checked for the MEFV gene. There were no statistical differences between MEFV positive and negative subgroups in response to colchicine (P = 1). CONCLUSION: This study showed that both drug regimens are significantly effective in preventing febrile attacks in PFAPA syndrome, and the presence of a MEFV gene mutation might not be the only significant risk factor for a response to colchicine. TRIAL REGISTRATION: IRCT, IRCT20191222045847N1. Registered 23 October 2019, https://fa.irct.ir/search/result?query=IRCT20191222045847N1.

The rs13075270 and rs13092160 polymorphisms of CCR1 and CCR3 genes on oral aphthous-like lesions in PFAPA syndrome.

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.

IL-10 and TGF-ß1 gene polymorphisms in Greek patients with recurrent aphthous stomatitis.

BACKGROUND: Recurrent aphthous stomatitis (RAS) is one of the most frequent inflammatory disorders of the oral mucosa. Cytokines, which play an important role in RAS pathogenesis, participate directly or indirectly in normal, immunological and inflammatory processes and are secreted from cells belonging to innate and adaptive immunity as a consequence of microbial and antigenic stimuli. Gene polymorphisms in specific cytokines may predispose to RAS development. The aim of this study was the investigation and association of IL-10 and TGF-ß1 gene polymorphisms with RAS. MATERIAL AND METHODS: Study's cohort consisted of 60 Greek patients diagnosed with RAS, including 40 patients with minor, 10 patients with major and 10 with herpetiform aphthous ulcers. Forty age- and sex-matched control subjects were included in this study. DNA was extracted from whole blood samples of all patients and sequence-specific primers (SSP)-based polymerase chain reaction (PCR) was used for genotyping. Gene polymorphisms for cytokines IL-10 at loci -592 and -819 and for TGF-ß1 at codon 10 were detected. RESULTS: Significant differences between patients with minor RAS and healthy controls were recorded for IL-10 genotypes distribution at position -592 (p=0.042) and -819 (p=0.045) with predominance of C/A and C/T genotypes in RAS patients, respectively. Also, in patients with minor and herpetiform aphthous ulcerations, heterozygous TGF-ß1 genotype C/T at codon 10 was associated with increased risk of RAS (p=0.044 and p=0.020, respectively). CONCLUSIONS: These data provide evidence that genetic predisposition for RAS and possibly its specific clinical variants is related with the presence of gene polymorphisms for specific cytokines, including IL-10 and TGF-ß1, which, in turn, may vary according to geographic origin and genetic background.

Role of genetic polymorphisms in recurrent aphthous stomatitis: A systematic review and meta-analysis.

Recurrent aphthous stomatitis (RAS) is one of the most common oral ulcerative diseases with unknown etiology. Identifying the genetic markers can improve medical care and prevention of RAS. Genetics variants inflammatory agents are associated with the risk of RAS. Thus, this meta-analysis aimed to investigate the genetic polymorphisms in RAS. Electronic literature search was carried out on Scopus, PubMed, and Web of Science (WOS). The references of relevant reviews were also manually checked. The observational studies till the end of 2020 were included. Odds ratio (OR) was estimated by fixed and random effect model. Seventeen polymorphisms in 23 studies were included in analysis. Pooled analysis performed for 12 polymorphisms (IL-2+166, IL-2-330, IL-4-590, IL-4 RA1902, IL-6-597, TNF-α-308, NLRP3(rs4612666, rs10754558), MMP2- rs2285053, MMP9- rs11697325, MMP9- rs3918242, MMP9- rs17576, IL-1a-889, IL-10-819, and IL-12+1188). The meta-analyses carried out for six polymorphisms (IL-1ß-511, IL-1ß+3954, IL-6-174, IL-10-592, IL-10-1082, and serotonin transporter). There were following significant results for IL-10, 819 in allelic:1.46(1.04-2.05) and homozygote: 1.61(1.08-2.39) models, serotonin Transporter in allelic:0.53(0.40-0.71), recessive:0.56(0.35-0.90), dominant:0.35(0.22-0.57) and homozygote:0.30(0.17-0.54) models. IL-1ß-511 in dominant 0.69(0.50-0.95) and overdominant 0.73(0.55-0.96) models, IL-1ß+3954 in allelic 1.25(1.05-1.50), homozygote 1.67(1.05-2.63) and dominant 1.26(1.01-1.57) models, IL-6-174 in dominant 2.24(1.36-3.67), IL-10-592 in homozygote 0.41(0.23-0.72) and dominant 0.55(0.33-0.93), IL-10-1082 in allelic 1.19(1.01-1.39) and dominant 1.29(1.02-1.64). In conclusion, serotonin transporter(L/S), IL-10-819(T/C), IL-10-592(C/A), IL-10-1082(G/A), IL-1ß-511(C/T), IL-6-174(G/C), and IL-1ß+3954 (T/C) polymorphisms are associated with susceptibility to RAS. These variants could be potential predictors of RAS and could be used for the developing clinically effective genetic panel for RAS.

Association of the angiotensin I converting enzyme (ACE) gene polymorphisms with recurrent aphthous stomatitis in the Czech population: case-control study.

BACKGROUND: Recurrent aphthous stomatitis (RAS) is multifactorial disease with unclear etiopathogenesis. The aim of this study was to determine distribution of the angiotensin I converting enzyme (ACE) gene polymorphisms and their influence on RAS susceptibility in Czech population. METHODS: The study included 230 subjects (143 healthy controls and 87 patients with RAS) with anamnestic, clinical and laboratory data. Five ACE gene polymorphisms (rs4291/rs4305/rs4311/rs4331/rs1799752 = ACE I/D) were determined by TaqMan technique. RESULTS: The allele and genotype distributions of the studied ACE I/D polymorphisms were not significantly different between subjects with/without RAS (Pcorr > 0.05). However, carriers of II genotype were less frequent in the RAS group (OR = 0.48, 95% CI = 0.21-1.12, P = 0.059). Stratified analysis by sex demonstrated lower frequency of II genotype in women (OR = 0.33, 95% CI = 0.09-1.17, P < 0.035, Pcorr > 0.05, respectively) than in men with RAS (P > 0.05). Moreover, the frequency of AGTGD haplotype was significantly increased in RAS patients (OR = 13.74, 95% CI = 1.70-110.79, P = 0.0012, Pcorr < 0.05). In subanalysis, TGD haplotype was significantly more frequent in RAS patients (P < 0.00001) and CGI haplotype was less frequent in RAS patients (P < 0.01), especially in women (P = 0.016, Pcorr > 0.05). CONCLUSIONS: Our study indicates that while the AGTGD and TGD haplotypes are associated with increased risk of RAS development, CGI haplotype might be one of protective factors against RAS susceptibility in Czech population.

Combined signatures of serum proteome and transcriptome in patients with recurrent aphthous ulcer.

OBJECTIVES: Recurrent aphthous ulcer (RAU) is a common oral disease with unclear mechanism. This study aimed to explore the serum signatures of RAU patients via proteomic and transcriptomic analysis. METHODS: This study was based on clinical observation. Part of serum was used for clinical tests, while the rest was processed for isobaric tags for relative and absolute quantitation (ITRAQ) labeling coupled with two-dimensional liquid chromatography-tandem mass spectrometry (2D LC-MS/MS) combined with microRNA (miRNA) microarrays. Bioinformatic analysis was then used to obtain significant signatures, which was verified by ELISA, qRT-PCR, and dual-luciferase reporter gene assays. RESULTS: Clinical data showed that triglyceride level, white blood cell count, and neutrophils percentage were increased in RAU group, while lymphocytes percentage was decreased. ITRAQ-2D LC-MS/MS identified 22 upregulated and 33 downregulated proteins in RAU group. Simultaneously, miRNA microarrays identified 64 upregulated and 31 downregulated miRNAs. After integrative bioinformatic analysis and verification, three miRNA-protein pairs, mainly involved in oxidative stress and inflammation responses, were obtained. Additionally, the interaction network indicated the crucial role of complement and coagulation cascade pathway in RAU. CONCLUSIONS: Our study revealed that complement and coagulation cascade pathway, oxidative stress, and inflammation responses may act as vital factors in pathogenesis of RAU.

Making a diagnosis of periodic fever syndrome: Experience from a single tertiary centre.

AIM: This study aims to evaluate the utility of genetic testing of patients diagnosed with periodic fever syndromes and to assess the validity of existing scoring criteria. METHODS: This study retrospectively reviewed the clinical history of patients diagnosed with periodic fever syndromes at Queensland Children's Hospital between November 2014 and June 2018. RESULTS: Forty-three patients were diagnosed with periodic fever syndromes. Diagnoses in the cohort included periodic fever, adenitis, pharyngitis and aphthous stomatitis (10), tumour necrosis factor receptor-associated periodic syndrome (9), cryopyrin-associated periodic syndrome (6), mevalonate kinase deficiency (4) while 14 remained unspecified. No presenting symptoms were uniquely associated with any particular diagnosis. Genetic testing of between 1 and 26 genes was performed in 26 (60%) patients. Two (7.7%) patients had pathogenic variants identified. Variants of uncertain significance which were insufficient to confirm a monogenic disorder were identified in a further 7 (27%) patients. The Eurofever classification criteria correlated with clinical diagnosis for patients diagnosed with cryopyrin-associated periodic syndrome (P = 0.046) and tumour necrosis factor receptor-associated periodic syndrome (P = 0.025) but not for patients diagnosed with mevalonate kinase deficiency (P = 0.47); however, the Eurofever classification criteria were often positive for more than one diagnosis in these patients. CONCLUSION: The European classification criteria can form a potentially useful tool to guide diagnosis; however, clinical judgement remains essential, because the score is often positive for multiple diagnoses. The diagnostic yield of genetic testing in this cohort was low and genetic testing may be more useful to confirm a strong clinical suspicion than to clarify a diagnosis for patients with less clear symptoms.

Mannose-binding lectin serum levels and (Gly54asp) gene polymorphism in recurrent aphthous stomatitis: A case-control study.

Objectives: Dysregulation of the immune response appears to play a significant role in recurrent aphthous stomatitis (RAS) development. The main objective of this case-control study is to investigate the blood levels of mannose-binding lectin (MBL) and the frequency of the MBL2 gene (gly54asp) polymorphism in RAS patients, including 40 RAS patients and 40 healthy controls. Methods: Serum MBL levels were determined by ELISA, while the PCR-restriction fragment length polymorphism was used in MBL2 genotyping. Results: The median serum MBL level was significantly lower in the RAS group than in the control group (975 ng/mL (545-1320) vs. 1760 ng/mL (1254-2134); p≤ 0.001). The MBL levels were significantly lower in the BB genotype, whereas they were significantly higher in the wild type AA with a median of 525 and 1340 ng/mL, respectively (p =0.005). The B allele was expressed in significantly higher percentages of RAS patients than in controls. There was no significant association between MBL serum levels (p=0.685) or MBL2 codon 54 genotypes (p=0.382) with the type of ulcers. Conclusion: There was an association between low MBL serum levels and the variant allele B of the MBL2 (gly54asp) gene, and the susceptibility to RAS. As a result, potential novel therapeutic options for RAS patients with MBL deficiency should be investigated.