Genetic and immunologic findings in children with recurrent aphthous stomatitis with systemic inflammation.

BACKGROUND: Recurrent aphthous stomatitis with systemic signs of inflammation can be encountered in inflammatory bowel disease, Behçet's disease (BD), Systemic Lupus Erythematosus (SLE). In addition, it has been proposed that cases with very early onset in childhood can be underpinned by rare monogenic defects of immunity, which may require targeted treatments. Thus, subjects with early onset recurrent aphthous stomatitis receiving a clinical diagnosis of BD-like or SLE-like disease may deserve a further diagnostic workout, including immunologic and genetic investigations. OBJECTIVE: To investigate how an immunologic, genetic and transcriptomics assessment of interferon inflammation may improve diagnosis and care in children with recurrent aphthous stomatitis with systemic inflammation. METHODS: Subjects referred to the pediatric rheumatologist for recurrent aphthous stomatitis associated with signs of systemic inflammation from January 2015 to January 2020 were enrolled in the study and underwent analysis of peripheral lymphocyte subsets, sequencing of a 17-genes panel and measure of interferon score. RESULTS: We enrolled 15 subjects (12 females, median age at disease onset 4 years). The clinical diagnosis was BD in 8, incomplete BD in 5, BD/SLE overlap in 1, SLE in 1. Pathogenic genetic variants were detected in 3 patients, respectively 2 STAT1 gain of function variants in two patients classified as BD/SLE overlap and SLE, and 1 TNFAIP3 mutation (A20 haploinsufficiency) in patients with BD. Moreover 2 likely pathogenic variants were identified in DNASE1L3 and PTPN22, both in patients with incomplete BD. Interferon score was high in the two patients with STAT1 GOF mutations, in the patient with TNFAIP3 mutation, and in 3 genetic-negative subjects. In two patients, the treatment was modified based on genetic results. CONCLUSIONS: Although recurrent aphthous stomatitis associated with systemic inflammation may lead to a clinical diagnosis of BD or SLE, subjects with early disease onset in childhood deserve genetic investigation for rare monogenic disorders. A wider genetic panel may help disclosing the genetic background in the subset of children with increased interferon score, who tested negative in this study.

Covid-19 and oral diseases: Crosstalk, synergy or association?

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.

Common genetic susceptibility loci link PFAPA syndrome, Behçet's disease, and recurrent aphthous stomatitis.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children. The disease appears to cluster in families, but the pathogenesis is unknown. We queried two European-American cohorts and one Turkish cohort (total n = 231) of individuals with PFAPA for common variants previously associated with two other oropharyngeal ulcerative disorders, Behçet's disease and recurrent aphthous stomatitis. In a metaanalysis, we found that a variant upstream of IL12A (rs17753641) is strongly associated with PFAPA (OR 2.13, P = 6 × 10-9). We demonstrated that monocytes from individuals who are heterozygous or homozygous for this risk allele produce significantly higher levels of IL-12p70 upon IFN-γ and LPS stimulation than those from individuals without the risk allele. We also found that variants near STAT4, IL10, and CCR1-CCR3 were significant susceptibility loci for PFAPA, suggesting that the pathogenesis of PFAPA involves abnormal antigen-presenting cell function and T cell activity and polarization, thereby implicating both innate and adaptive immune responses at the oropharyngeal mucosa. Our results illustrate genetic similarities among recurrent aphthous stomatitis, PFAPA, and Behçet's disease, placing these disorders on a common spectrum, with recurrent aphthous stomatitis on the mild end, Behçet's disease on the severe end, and PFAPA intermediate. We propose naming these disorders Behçet's spectrum disorders to highlight their relationship. HLA alleles may be factors that influence phenotypes along this spectrum as we found new class I and II HLA associations for PFAPA distinct from Behçet's disease and recurrent aphthous stomatitis.

Recurrent, Severe Aphthous Stomatitis and Mucosal Ulcers as Primary Manifestations of a Novel STAT1 Gain-of-Function Mutation.

Chronic mucocutaneous candidiasis (CMC) characterized by persistent and recurrent Candida infection of the skin, nails, and the mucosa membranes has been proposed as the major infectious phenotype in patients with gain-of-function mutation of signal transducer and activator of transcription 1 (STAT1) 1. However, viral infections caused mostly by herpesviruses, and a broad range of autoimmune disorders may also be part of the clinical phenotype. We report here on a 31 years old female patient suffering from severe mucosal aphthous mucositis and ulcers and recurrent herpes simplex for decades. We found a previously unknown heterozygous sequence variant in STAT1 (c.1219C>G; L407V) affecting the DNA-binding domain of the protein in the patient and her 4 years old daughter. We found this mutation gain-of-function (GOF) by using immunoblot and luciferase assays. We detected low proportion of IL-17A-producing CD4+ T cell lymphocytes by using intracellular staining and flow cytometry. Candida-induced secretion of IL-17A and IL-22 by mononuclear cells from the patient was markedly decreased compared to controls. These data suggest that the novel mutant allele may result in impaired differentiation of CD4+ T cells to CD4+/IL-17+ cells. The clinical phenotype of the disease in this patient was unique as it was dominated primarily by severe aphthous stomatitis and ulcerative esophagitis and only partly by typical CMC resulting in diagnostic delay. We suggest that patients with severe recurrent aphthous stomatitis and esophagitis should be evaluated for STAT1 GOF mutation. Based on the broad clinical spectrum of the disease, we also suggest that CMC and CMC disease may not be an appropriate term to define clinically STAT1 GOF mutation.

Long-term Stabilization of Aqueous Doxycycline Formulations, in Mucoadhesive Hydrogels for Treatment of Oral Mucosal Conditions.

BACKGROUND: The main aim of this work was to develop stable (>2 years) doxycycline formulation, at clinically relevant concentrations and using clinically relevant formulation. Doxycycline has a MMP- inhibitory effects that is important for the treatment of various oral mucosal conditions. Therefore, protecting doxycycline from degradation in aqueous formulation requires halting or prevention of oxidation and epimerisation of the active compound. METHODS: Stabilizing excipients were intuitively put together to enhance the stability as a cumulative effort. A total of 30 hydrogels were compared with different types and concentrations of stability enhancing excipients, pH, storage temperatures (4, 25 and 40°C) and mucoadhesive polymers. The duration of the study was from day 1 and up to 58 months. The gelation temperature was adjusted below the actual body temperature. The complexation efficiency between the doxycycline and HPßCD was studied using the DSC, FTIR and XRPD. RESULTS: The majority of formulations at 4°C were highly stable by the end of 58 months and their stabilities were improved at all 3 temperatures. CONCLUSION: In conclusion, it is possible to prevent doxycycline from both oxidation and epimerization in an aqueous formulation, for up to 5 years.

The immunology of the periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome; what can the tonsils reveal. A literature review.

OBJECTIVES: Tonsillectomy (TE) or adenotonsillectomy (ATE) may have a beneficial effect on the clinical course in children with the periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome. However, an immunological reason for this effect remains unknown. This literature review summarizes the current knowledge regarding the immunological role of the tonsils in the PFAPA syndrome. METHODS: We searched PubMed, Medline, EMBASE and Cochrane for papers written in English dated from 1 January 1987 to 30 April 2019. The search included all studies reporting histological, immunological or microbiological workup of tonsil specimens from children aged 0-18 years with PFAPA. RESULTS: Thirteen articles reported histological, immunological or microbiological workup of tonsil specimens in children with PFAPA. The histology of tonsil specimens from children with PFAPA displayed chronic tonsillar inflammation with lymphoid hyperplasia. No uniform immunological pattern was identified, but some studies found fewer B-lymphocytes and smaller germinal centers in PFAPA compared to controls. A difference in tonsillar microbiota between PFAPA and controls was found in one study. CONCLUSION: A uniform immunological or microbiological pattern explaining the clinical effect of TE in children with PFAPA has not been revealed. Future targeted immunological studies of tonsils in PFAPA patients could possibly illuminate the understanding of the immunology in this disease.

Immune Dysregulation in the Tonsillar Microenvironment of Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) Syndrome.

Periodic Fever, Aphthous stomatitis, Pharyngitis and Adenitis (PFAPA) syndrome is an inflammatory disorder of childhood classically characterized by recurrent fevers, pharyngitis, stomatitis, cervical adenitis, and leukocytosis. While the mechanism is unclear, previous studies have shown that tonsillectomy can be a therapeutic option with improvement in quality of life in many patients with PFAPA, but the mechanisms behind surgical success remain unknown. In addition, long-term clinical follow-up is lacking. In our tertiary care center cohort, 62 patients with PFAPA syndrome had complete resolution of symptoms after surgery (95.3%). Flow cytometric evaluation demonstrates an inflammatory cell population, distinct from patients with infectious pharyngitis, with increased numbers of CD8+ T cells (5.9% vs. 3.8%, p < 0.01), CD19+ B cells (51% vs. 35%, p < 0.05), and CD19+CD20+CD27+CD38-memory B cells (14% vs. 7.7%, p < 0.01). Cells are primed at baseline with increased percentage of IL-1ß positive cells compared to control tonsil-derived cells, which require exogenous LPS stimulation. Gene expression analysis demonstrates a fivefold upregulation in IL1RN and TNF expression in whole tonsil compared to control tonsils, with persistent activation of the NF-κB signaling pathway, and differential microbial signatures, even in the afebrile period. Our data indicates that PFAPA patient tonsils have localized, persistent inflammation, in the absence of clinical symptoms, which may explain the success of tonsillectomy as an effective surgical treatment option. The differential expression of several genes and microbial signatures suggests the potential for a diagnostic biomarker for PFAPA syndrome.

Clinical features and new diagnostic criteria for the syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis.

AIM: The syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is a common inflammatory disease that presents with periodic fever. We aimed to establish more specific diagnostic criteria for PFAPA based on the clinical characteristics of PFAPA patients in our directory. METHOD: The clinical, laboratory, genetic, and family history details of 257 Japanese PFAPA patients treated at our and other affiliated hospitals between April 2000 and April 2018 were analyzed along with quantitative measurements of the number of CD64 molecules on neutrophils, and the levels of serum inflammatory cytokines. The sensitivity and specificity of the criteria were calculated for several diseases. RESULTS: Because recurrent fevers were crucial findings, they were defined as the required criterion. Tonsillitis/pharyngitis with white moss were important accompanying signs. Other symptoms associated with febrile episodes were cervical lymphadenitis with tenderness, aphthous stomatitis, sore throat, vomiting, and headache but not cough. A total of 159 (62%) patients had a family history of recurrent fevers, indicating autosomal dominant inheritance. C-reactive protein levels were extremely elevated during febrile attacks but normal in attack-free periods. Serum immunoglobulin D levels were high in 72 of the 199 tested patients. Oral glucocorticoid and cimetidine were extremely effective in all and 51.6% of the patients, respectively. We defined the above as supportive criteria. These criteria were sensitive and specific enough to distinguish PFAPA from other recurrent fever diseases. Raised serum interferon-γ levels and remarkable CD64 expression on neutrophils during flare-ups were recognized, indicating they contributed to diagnosis. CONCLUSION: Our new criteria are useful for diagnosing PFAPA.

Genome wide analysis for mouth ulcers identifies associations at immune regulatory loci.

Mouth ulcers are the most common ulcerative condition and encompass several clinical diagnoses, including recurrent aphthous stomatitis (RAS). Despite previous evidence for heritability, it is not clear which specific genetic loci are implicated in RAS. In this genome-wide association study (n = 461,106) heritability is estimated at 8.2% (95% CI: 6.4%, 9.9%). This study finds 97 variants which alter the odds of developing non-specific mouth ulcers and replicate these in an independent cohort (n = 355,744) (lead variant after meta-analysis: rs76830965, near IL12A, OR 0.72 (95% CI: 0.71, 0.73); P = 4.4e-483). Additional effect estimates from three independent cohorts with more specific phenotyping and specific study characteristics support many of these findings. In silico functional analyses provide evidence for a role of T cell regulation in the aetiology of mouth ulcers. These results provide novel insight into the pathogenesis of a common, important condition.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome: main features and an algorithm for clinical practice.

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.

Celiac disease-specific and inflammatory bowel disease-related antibodies in patients with recurrent aphthous stomatitis.

The etiology of recurrent aphthous stomatitis (RAS) remains unknown. RAS can be presented as primary, idiopathic condition and as a secondary RAS, which is associated with a systemic disease. The aim of our study was to evaluate the presence and concentrations of antibodies specific for celiac disease (CeD) and antibodies related to inflammatory bowel diseases (IBD) in patients with RAS without gastrointestinal symptoms. Antibodies against tissue transglutaminase (anti-tTG), deaminated gliadin peptides (DGP), deaminated gliadin-analogous fragments (anti-GAF-3X) and Saccharomyces cerevisiae (ASCA) were determined by ELISA and antineutrophil cytoplasmic antibodies (ANCA) by indirect immunoflurescence (IIF) in 57 patients with RAS and 60 control subjects. The prevalence of CeD specific antibodies did not differ between RAS patients and controls. However, the concentrations of IgA anti-tTG, IgA anti-GAF-3X antibodies in patients with RAS were significantly higher compared to controls (p = 0.002 and p = 0.04 respectively). Histological changes consistent with CeD were confirmed by duodenal biopsy in one RAS patient with highly positive IgA anti-tTG, anti-GAF-3X and anti-DGP antibodies. Higher prevalence along with higher concentrations of IgG ASCA were found in RAS patients compared to controls (p < 0.01). Patients with positive IgG ASCA in the absence of clinical symptoms decided not to pursue any further testing. Dysfunction of oral mucosa and the exposure to various antigens might be a reason for the loss of tolerance resulting in increased production of autoantibodies. It seems likely that antibodies are markers of aberrant immune response, rather than key effectors involved in the pathogenesis of the disease.

INTERMEDIATE UVEITIS ASSOCIATED WITH PERIODIC FEVER, APHTHOUS STOMATITIS, PHARYNGITIS, AND CERVICAL ADENITIS SYNDROME.

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.

Establishment of Role of IL-2, IL-10 and IL-12 in Patients with Recurrent Aphthous Stomatitis-A Clinical Study.

BACKGROUND: Recurrent aphthous stomatitis is a vesiculobul-lous disease characterized by painful ulcers in the oral cavity. The role of interleukins such as IL-2, IL-10 and IL-12 in initiating disease demands careful assessment. The present study was conducted to determine the level of IL-2, IL-10 and IL-12 in patients with recurrent aphthous stomatitis. MATERIALS AND METHODS: The present study was conducted on 40 patients diagnosed with recurrent aphthous stomatitis. An equal number of age and gender-matched subjects (40) was included as a control. They were divided into 2 age groups from 20 to 40 years and 40 to 60 years. All were made to sit comfortably on a dental chair, and 1 ml of unstimulated saliva was collected in a sterile tube to assess the level of IL-2, IL-10 and IL-12 using ELISA. The level of IL-2, IL-10 and IL-12 was measured in pg/mL. RESULTS: Each group had 10 males and 10 females. The difference was non-significant (P-1). Age group 20-40 years comprised of 14 patients in group I (eight males and six females) and 12 in group II (five males and seven females). Age group 40-60 years had six patients in group I (two males and four females) and 8 patients in group II (five males and three females). The difference was significant (p < 0.05). The most common form was minor (82%) followed by herpetiform (13%) and major (5%). In group I, the mean value of IL-2 level was 32.24 pg/mL, IL-10 was 1.24 ± 0.6 and IL-12 was 28.34 ± 4.04 and in group II, mean value of IL-2 level was 12.10 pg/mL, IL-10 was 2.56 ± 1.12 and IL-12 was 23.16 ± 4.16. The difference was significant (p < 0.05). CONCLUSION: Age group 20 to 40 years showed higher prevalence. The level of IL-2 and IL-12 is highly increased while IL-10 is decreased in patients. CLINICAL SIGNIFICANCE: Role of interleukins as a precipitating factor along with stress is well established. With the thorough knowledge of the disease process, the newer treatment modality specific against interleukins may be proven useful in controlling the disease.

Recurrent aphthous stomatitis and gene variability in selected interleukins: a case-control study.

Genetic factors, especially those related to immune system functioning, have been intensively studied to determine their role in the development of recurrent aphthous stomatitis (RAS). The aim of the present study was to analyze gene variability in interleukin (IL)2, IL4 (and its receptor α, IL4Rα), IL10, and IL13, which were selected based on literature review and/or their functional relevance, in Czech patients with RAS and in healthy controls. In total, 252 subjects (178 controls and 74 patients with RAS) were enrolled in this case-control study, and their detailed anamnestic, clinical, and laboratory data were obtained. Nine polymorphisms in the genes encoding interleukins were determined using PCR techniques. There were no significant differences in allele or genotype frequencies of the IL2, IL4, IL4Rα, IL10, and IL13 polymorphisms rs2069762/rs2069763, rs2243250/rs79071878, rs1801275, rs1800896, and rs1800925, respectively, between controls and patients with RAS. The minority alleles rs1800871 and rs1800872, which encode variants of IL10, were associated with a statistically significantly higher risk of RAS, as confirmed by the results of genotype and haplotype analyses. We suggest that variability in the IL10 gene may play an important role in the development of RAS in the Czech population.

Interleukin-4 and Interleukin-4 Receptor Alpha Gene Polymorphisms in Recurrent Aphthous Stomatitis.

BACKGROUND: Recurrent aphthous stomatitis (RAS) is a common oral condition with a major impact on the quality of life. The condition is thought to be due to the overexpression of T helper-1(Th1)-related cytokines. Since interleukin-4 (IL-4) and its receptor (IL-4Rα) are antagonistic to Th-1 pathways, polymorphisms in their genes may also be involved in the pathogenesis of aphthous stomatitis. METHODS: Sixty-four patients diagnosed with minor RAS and 141 (age- and sex-matched) healthy controls were assessed for 3 single-nucleotide polymorphisms (SNPs) within the promoter region of the IL-4 gene (-1098G/T, -590C/T, and -33C/T), and 1 SNP in IL-4Rα gene (+1902 A/G). RESULTS: No significant differences were detected between the patient and the control group regarding IL-4 allele frequencies. However, the patient group demonstrated a higher frequency of IL-4 -590 CC genotype and a lower rate of IL-4 -590 TC genotype. The TCT, GTT, GCT, and GTC haplotypes of the IL-4 gene (-1098, -590, -33) were significantly more frequent in the patients and the GCC, and TTT haplotypes were more common in healthy controls. No significant differences were found in IL-4Rα gene polymorphism between the 2 groups. CONCLUSIONS: Certain polymorphisms of IL4 gene could predispose individuals to RAS.

[Clinical and genetic analysis of 11 cases with periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome].

Objective: To investigate the clinical, inflammatory and genetic characteristics of cases with periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome. Methods: Clinical and inflammatory manifestations and gene sequencing of 11 cases with PFAPA were retrospectively analyzed. Inflammatory markers including white blood cell (WBC) , C reactive protein (CRP) , and serum amyloid A (SAA) were compared between febrile period and intermittent period. Fifteen normal children were taken as healthy controls. The levels of plasma inflammatory cytokines including interleukin(IL)1ß, IL-6, IL-17, tumor necrosis factor(TNF)-α, interferon (IFN)-γ, and granulocyte-colony stimulating factor(G-CSF) were compared between febrile period and intermittent period with paired-sample t test, and compared between febrile cases and healthy controls with independent t test. Results: A total of 11 cases (7 females and 4 males) were included. The median onset age was 24 (3-60) months, and the median age of diagnosis was 69 (11-151) months. The median febrile duration was 4 (1-8) days, and the intermittent period lasted 1 to 8 weeks. All the cases had periodic fever and pharyngitis/tonsillitis, 7 of whom had combined lymphadenitis, and 5 of whom suffered from oral ulcers. Compared to intermittent-period-status,WBC ((14.7±4.1) ×10(9)/L vs. (8.4±1.9) ×10(9)/L, P<0.05), CRP((24.2±21.1) vs. (3.3±2.1)mg/L, P<0.05), SAA ((136.4±47.7) vs. (7.1±1.1)mg/L, P<0.05) were significantly elevated in febrile period. Compared to intermittent-period-status and healthy controls, plasma levels of IL-6 ((38±10) vs. (8±4) and (8±5)ng/L, t=6.514 and 6.830 respectively, P<0.05), IFN-γ ((132±43) vs.(49±21) and (53±21)ng/L, t=4.069 and 4.276 respectively, P<0.05), G-CSF ((403±12) vs. (175±90) and (121±49)ng/L, t=4.219 and 9.047 respectively, P<0.05) were significantly higher in febrile period, while no differences were found in levels of IL-1ß, IL-17 and TNF-α. Gene sequencing found MEFV gene heterozygous variation in 8 cases. Conclusions: PFAPA often manifests as periodic fever, pharyngitis, tonsillitis, aphthous stomatitis and adenitis. Gene sequencing analysis, detection of inflammation markers and cytokines could help with the diagnose of this disease.

Oral manifestations of inflammatory bowel disease.

Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, have important extraintestinal manifestations, notably in the oral cavity. These oral manifestations can constitute important clinical clues in the diagnosis and management of IBD, and include changes at the immune and bacterial levels. Aphthous ulcers, pyostomatitis vegetans, cobblestoning and gingivitis are important oral findings frequently observed in IBD patients. Their presentations vary considerably and might be well diagnosed and distinguished from other oral lesions. Infections, drug side effects, deficiencies in some nutrients and many other diseases involved with oral manifestations should also be taken into account. This article discusses the most recent findings on the oral manifestations of IBD with a focus on bacterial modulations and immune changes. It also includes an overview on options for management of the oral lesions of IBD.

Immune system and zinc are associated with recurrent aphthous stomatitis: an assessment using a network-based approach

OBJECTIVE: The aim of this research was to identify genes, proteins and processes from the biomedical information published on recurrent aphthous stomatitis (RAS) using network-based foci. METHODS: The clinical context was defined using MeSH terms for RAS and biomarkers, combined with words associated with risk. A set of protein coding genes was prioritized using the Génie web server and classified with PANTHER. For defining biologically relevant proteins, protein-protein interaction networks were constructed using Reactome database and Cytoscape. Top 20 proteins were then subjected to functional enrichment using STRING. RESULTS: From 1,075,576 gene-abstract links, 1,491 genes were prioritized. Proteins were related to signaling molecule proteins (n=221), receptor proteins (n=221) and nucleic acid binding proteins (n=169). The network constructed with these proteins included 3,963 nodes and functional analysis showed that main processes involved immune system and zinc ion binding function. CONCLUSIONS: For the first time, bioinformatics tools were used for integrating pathways and networks associated with RAS. Molecules and processes associated with immune system recur robustly in all analyzed information. The molecular zinc ion binding function could be an area for exploring more specific and effective therapeutic interventions

Immune response of patients with recurrent aphthous stomatitis challenged with a symbiotic.

BACKGROUND: There are indications that Th1 polarization of immune response plays an important role in the pathogenesis of recurrent aphthous stomatitis (RAS), and that the use of probiotics can stimulate immune regulatory activity, influencing the course of the disease. The aim of this study was to characterize the initial immune profile of RAS patients and evaluate clinical and serological response following a challenge with symbiotic treatment containing fructooligosaccharide, Lactobacillus, and Bifidobacterium. METHODS: The immune responses of the 45 patients with RAS, submitted to symbiotic or placebo for 120 days, in relation to 30 RAS-free controls, were evaluated over a period of 6 months. Peripheral blood was collected from all patients at 0 (T0), 120 (T4), and 180 days (T6) after the start of treatment and Th1 (IL12-p70, IFN-γ), Th2 (IL-4), Treg (IL-10), Th17 (IL-17A), inflammatory (TNF-α, IL-6)-associated cytokines, and clinical parameters were quantified. RESULTS: At T0, significant differences were found in the serological levels of the IFN-γ, IL-4, and IL-6 cytokines of the RAS patients in comparison with the controls. It was observed that the cytokine profile of the RAS group was comprised of 2 distinct clusters: a pure Th2 and a Mixed (Th1/Th2) subtype and that symbiotic treatment induced an improvement in pain and an increase in IFN-γ levels, producing a reduction in Th2 response. CONCLUSIONS: In RAS, symbiotic treatment based on a fructooligosaccharide, Lactobacillus, and Bifidobacterium composition produced an alteration in the Th2 serological immune profile in the direction of Th1 and improved pain symptomatology.

Unraveling the pathogenesis of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis through genetic, immunologic, and microbiologic discoveries: an update.

PURPOSE OF REVIEW: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is considered the most common periodic fever syndrome of childhood. Although it was first described three decades ago, the pathogenesis has been poorly understood. Recent studies on the heritability and immunology of the disorder have begun to shed light into the mechanisms of this autoinflammatory disorder. This review will focus on the pathogenesis of PFAPA, especially as it pertains to the genetic susceptibility, tonsillar immunology, and the role of the microbiome. RECENT FINDINGS: Recent literature provides insights into the heritability, potential genetic modifiers, and the immunologic and microbiological profile of the tonsils in this syndrome. SUMMARY: Evidence is mounting that PFAPA is inherited as a complex genetic disease. Furthermore, tonsillectomy is curative in the majority of patients, including those who do not meet the complete clinical criteria for PFAPA. The tonsils in PFAPA patients may exhibit unique immunologic and microbiological features. The goal of this review is to outline these new developments.