Celiac disease is a common autoimmune disease triggered by gluten-containing foods (wheat, barley and rye) in genetically predisposed individuals. We present a patient with celiac disease complicated by severe aphthous stomatitis resulting in impairing swallowing, chewing and speaking. This led to weight loss, psychosocial problems as well as inability to perform her work. A variety of topical and systemic medications used resulted in either no improvement or only partial alleviation of the patient's symptoms. After informed consent, etanercept was initiated and resulted in complete remission of aphthous stomatitis, decrease in arthralgia and fatigue and considerable improvement in her quality of life. The use of newer biological agents for selected and severe manifestations of celiac disease may lead to improved morbidity in these patients, but more studies are needed to determine long-term efficacy as well as safety of these drugs in the mucosal and/or systemic complications of this disease.
... When individuals with CD ingest gluten, their immune response leads to inflammation and damage within the small intestine. This damage, known as villous atrophy, precipitates nutrient malabsorption, which can manifest as diverse symptoms, including RAS and DEDs [14]. Notably, DEDs are observed with higher frequency in individuals with CD as compared to the general population. ...
Background:
Celiac disease (CD) is a chronic immune-mediated gluten-sensitive enteropathy, affecting about 1% of the population. The most common symptoms include diarrhea, abdominal pain, weight loss, and malabsorption. Extra-intestinal symptoms include oral manifestations. This systematic review aims to catalog and characterize oral manifestations in patients with CD.
Methods:
a systematic literature review among different search engines using PICOS criteria has been performed. The studies included used the following criteria: tissues and anatomical structures of the oral cavity in humans, published in English and available in full text. Review articles and papers published before 1990 were excluded.
Results:
209 articles were identified in the initial search. In the end, 33 articles met the selection criteria. The information extracted from the articles was classified based on the type of oral manifestation. Recurrent aphthous stomatitis (34.6%), atrophic glossitis and geographic tongue (15.26%), enamel defects (42.47%), delayed dental eruption (47.34%), xerostomia (38.05%), glossodynia (14.38%), and other manifestations including cheilitis, fissured tongue, periodontal diseases, and oral lichen planus were found in the celiac subjects of the studies analyzed. The quality of articles on the topic should be improved; however, oral manifestations in CD patients are widely described in the literature and could help diagnose celiac disease.
... Actually, as stated before, CD can present with a wide spectrum of signs and symptoms that recurrent aphthous stomatitis is one of them [30]. As aphthous stomatitis might be quite severe in CD and impair CD patients' quality of life, it has attracted the great attention of researchers [31]. ...
Background
Celiac disease (CD) is a chronic immune-mediated enteropathy and a cytokine network is involved in its pathogenesis. Interleukin-2 (IL-2) has a key role in the adaptive immune pathogenesis of CD and has been reported to be one of the earliest cytokines to be elicited after gluten exposure by CD patients. This study aimed at investigating the expression level of IL-2 and functionally related genes SOCS1 and TBX21 in active and treated CD patients compared to controls.
Methods and results
Peripheral blood (PB) samples were collected from 40 active CD (ACD), 100 treated CD, and 100 healthy subjects. RNA was extracted, cDNA was synthesized and mRNA expression levels of the desired genes were investigated by Real-time PCR. The gene–gene interaction network was also constructed by GeneMANIA. Our results showed a higher PB mRNA expression of IL-2 in ACD patients compared to controls (p = 0.001) and treated CD patients (p˂0.0001). The mRNA expression level of TBX21 was also significantly up-regulated in ACD patients compared to controls (P = 0.03). SOCS1 mRNA level did not differ between active and treated CD patients and controls (p˃0.05) but showed a significant correlation with the patient’s aphthous stomatitis symptom (r = 0.37, p = 0.01). ROC curve analysis suggested that the use of IL-2 levels can reach a high specificity and sensitivity in discriminating active CD patients.
Conclusions
The PB level of IL-2 has the potential to be introduced as a diagnostic biomarker for CD. Larger cohort studies, including pediatric patients, are needed to achieve more insights in this regard.
... A small minority of patients have nutritional deficiencies, particularly iron, vitamin B 12 , or folate deficiency, [4][5][6] but the causal relationship is not well established. Oral aphthosis has been reported in celiac disease [7] or other immune-based conditions such as Behcet's disease [8] and AIDS (secondary aphthosis). [9] Local trauma, food allergy, hormonal changes, and emotional factors Background: Oral aphthosis is a painful ulceration of mucus membranes characterized by round or oval lesions with central necrosis and erythematous haloes. ...
Background:
Oral aphthosis is a painful ulceration of mucus membranes characterized by round or oval lesions with central necrosis and erythematous haloes. Due to unknown etiology, treatment is highly controversial and based mainly on individual experience. The aim of this study was to investigate the safety and efficacy of topical penicillin 6.3.3 for the treatment of recurrent aphthous stomatitis.
Materials and methods:
This randomized, double-blind, controlled clinical trial was done in Shahid Sadoughi Hospital Clinic in Yazd (2011-2012). Fifty patients aged 15-45 with recurrent oral aphthosis were randomly divided into two groups. After obtaining informed consents, patients in the case and control groups were treated (four times/day for a week), respectively, by topical penicillin 6.3.3 powder and placebo in similar vial. The patients who had acute-onset oral aphthae (≤48 h of appearance) with diameter ≥5 mm were included. History of sensitivity to β-lactam antibiotics and cephalosporin; spontaneous recovery during <5 days in previous episodes; concurrent systemic, infectious, or any autoimmune disorders; history of taking drugs (local or systemic) from 2 weeks prior to presentation; alcohol or drug abuse; smoking cigarette or tobacco; and poor compliance were exclusion criteria. Patients were examined in days 0, 3, 6, and 8. The main outcome measure was reduction in the median pain. Burning, pain, erythema, and inflammation were recorded as complications.
Results:
Of 25 patients receiving penicillin, 13 were female and 12 were male. Regarding the pain score (mean difference = 1.6 vs. 0.88, P = 0.012) and size of aphthus (mean difference = 9.43 vs. 1.24, P = 0.008), patients who received penicillin had significantly better results than the placebo group on day 8 after the treatment. The mean duration to healing was 3 days for penicillin group and 6 days for placebo group (P = 0.016). No topical or systemic adverse effects were observed.
Conclusion:
Our study showed a dramatic response to topical penicillin with respect to placebo. Hence, it seems that penicillin could be a safe and effective option in managing oral aphthosis.
... One study even found remission of aphthous stomatitis and improvement in quality of life in a patient with CD with the use of etanercept. 16 However, these new approaches to CD are still not standard of care; thus, a lifelong adherence to a GFD is still the mainstay of treatment. ...
... However, a faster and more sustained action was observed with only zinc sulfate [30]. [37]. One investigator recorded an increase in triglyceride level after etanercept therapy [38]. ...
Recurrent Aphthous Stomatitis (RAS) is a condition in which aphthous ulcers repeatedly occur in the oral cavity. It is prevalent
in developed countries, occurring in all ages, geographic regions and races and about 80% of people have one episode of oral
aphthous ulcers before the age of 30 years. With no laboratory procedures to confirm the diagnosis, treatment is mainly empirical
in nature and focuses on short-term symptomatic management.
Although numerous treatment modalities have been recommended, only a few are evidence based and can be considered for the
optimal management of RAS. Biologic agents are a new category of drugs which acts by blocking specific pathways associated
with the pathophysiology of neoplastic or immune-mediated diseases. These agents have targeted immunosuppressive or antiinflammatory actions. In patients of RAS who were not responding to standard therapy, etanercept, adalimumab, infliximab and
Interferon-Alpha (INF-α) were found to be useful.
The objective of this review was to propose and review a treatment protocol to be followed for the optimal management of RAS. We
reviewed several evidence-based studies and through this review we recommend topical interventions as the first-line of therapy
since they are associated with low risk of systemic side effects. Due to limitations in the number of evidence-based trials and the
insufficient data to support or refute the efficacy of the therapies prescribed, larger evidence-based clinical studies and literature
reviews are needed to further improvise the optimal methodology for the effective management of RAS.
Refractory recurrent aphthous stomatitis (RRAS) manifests as severe ulcerative lesions of the oral mucosa with poor healing and a poor response to conventional therapy, with or without systemic diseases. Its treatment remains a clinical challenge owing to the lack of effective therapies. Recently, biologics have emerged as promising targeted therapies for RRAS. The biologics targeting specific inflammatory pathways involved in the pathogenesis of RRAS, including tumor necrosis factor‐alpha inhibitors and interleukin inhibitors, offer a more precise and promising therapeutic approach for RRAS. These targeted therapies have been shown to promote healing and decrease recurrence frequency in, and improve the quality of life of patients with RRAS. Herein, the types and mechanisms of biologics currently used to treat RRAS have been reviewed; furthermore, the dose, duration, therapeutic efficacy, and adverse effects of RRAS with or without certain associated systemic diseases, and the current problems and future directions have been discussed.
Introduction La maladie coeliaque (MC) est une entéropathie de nature inflammatoire qui peut avoir des manifestations digestives typiques et des manifestations extra-digestives. Les manifestations buccales de la MC font partie des signes extra-digestifs de la maladie et peuvent être à elles seules inaugurales de celle-ci. L’objectif de notre étude est d’étudier la survenue de ces manifestations bucco-dentaires liées à l’intolérance au gluten et leur distribution au sein de notre population de malades coeliaques. Patients et Méthodes : Il s’agit d’une étude épidémiologique comparative de type prospectif, réalisée au service de Pathologie et Chirurgie Buccales au cours d’une période allant de Juin 2014 à Décembre 2018 portant sur un échantillon de 108 malades coeliaques comparés à un groupe de 118 individus non coeliaques composés des apparentés du premier degré de ces malades coeliaques. Résultats et Discussion : Dans notre étude nous avons remarqué une prédominance du sexe masculin avec 51% contre 49% pour le sexe masculin. Nos résultats sont superposables à l’étude égyptienne d’EL HODHOD qui retrouve 51 ,4 % de sexe masculin contre 48,5 de sexe masculin. L’évaluation du statut bucco-dentaire nous a conduit à constater que l’hygiène bucco-dentaire est meilleure parmi les non coeliaques par rapport aux coeliaques. Un autre critère notable dans notre étude est le pourcentage élevé de malades coeliaques avec des malpositions dentaires qui représentent 66,7% contre 33,3% dans le groupe opposé. Les auteurs impliquent le retard staturo-pondéral qui entraine une cascade de troubles hormonaux se répercutant sur la croissance et l’éruption des dents. Concernant la structure dentaire nous avons remarqué la présence de dépôts noirâtres appellés black stains sur la surface dentaire chez 68,3% des malades contre 31,7% parmi les non malades. Ce critère a été identifié par des études récentes notamment celle de Majorana en 2009 qui retrouve ces dépôts chez 36% des malades coeliaques. Cette anomalie a été rattachée à un éventuel déséquilibre de la flore bactérienne orale. Pour ce qui est des anomalies de l’émail des dents, elle ont été retrouvées dans 75% des malades contre 25% parmi les non malades (P≤10-3) ce qui se rapproche des résultats de Aine en 1986 qui retrouve 96% parmi les coeliaques contre 26% dans le groupe contrôle. Quant à la distribution de ces anomalies en fonction de la classification de Aine, nous constatons que les défauts les plus sévères (grade III et VI) sont retrouvés plus dans le groupe coeliaque (7malades) que dans le groupe non malade (3sujets). Comparée aux résultats de Hastaliginin en 2009, la sévérité de ces anomalies est plus marquée dans notre échantillon. L’étude des récurrences d’aphtes montre que 8,3% des malades ont plus de 2 poussée d’ABR contre 0,8% parmi le apparentés. Ces résultats concordent avec ceux de Majorana et al. Conclusion : L’existence des manifestations bucco-dentaire dans la maladie coeliaque ne constitue plus aucun doute. Leur importance et leur valeur prédictive doit faire l’objet d’attention particulière parmi les pédiatres et odontologistes pédiatriques car elles pourraient constituer un outil de dépistage et de diagnostic précoce de la maladie coeliaque.
Conflict of interest: the authors declare that they have no conflicts of interest.
Dear Editor,
Recurrent aphthous stomatitis (RAS) is a common cause of painful oral ulcer, can be a part of systemic disease such as Behçet syndrome, inflammatory bowel disease, reactive arthritis, coeliac disease, cyclic neutropenia, HIV infection, MAGIC (mouth and genital ulcer with inflamed cartilage) syndrome, PFAPA (periodic fever, aphthous ulcer, pharyngitis, cervical adenitis) syndrome, bullous disorders and vitamin deficiencies (B1, B2, B12, folate).¹ Treatment for RAS includes systemic steroids, immunosuppressive drugs and apremilast¹,² and, in refractory cases, etanercept, a tumour necrosis factor (TNF)‐α inhibitor.³
A 38‐year‐old woman presented with a 12‐year history of RAS. She had 8–10 lesions every week, which caused excruciating pain and discomfort; each episode lasted about 2 weeks with exacerbations during emotional stress and before her menstrual periods. She reported no association with food or alcohol intake, and there was no history of oral trauma, genital ulcers, red eyes, skin lesions, chronic diarrhoea, weight loss, fever or arthralgia.
Antitumor necrosis factor (anti-TNF) alpha agents have become critical in the treatment of multiple dermatologic diseases. Initially, and still primarily, used for the treatment of psoriasis, multiple other conditions, including psoriatic arthritis and hidradenitis suppurativa have anti-TNF therapy, as a central therapeutic option. This chapter will review the potential benefits, as well as adverse effects of anti-TNF therapy, as well as cover the expanding targets for these treatments.
To evaluate the efficacy and safety of systemic interferon alfa treatment in patients with Adamantiades-Behçet disease.
Reports and abstracts published in 1986 through 1997 in all languages were identified by the MEDLINE database, the Reference Index Related to Behcet's Disease, the Behçet disease conference proceedings, and abstract booklets. The indexing terms used Behçet and interferon.
Twenty-two reports identified were included to estimate the efficacy of interferon alfa on mucocutaneous, ocular, and joint manifestations. Responses of individual mucocutaneous signs were evaluated in 8 reports. Adverse effects were sufficiently documented in 12 reports. All patients met the criteria of the Behçet Syndrome Research Committee of Japan or those of the International Study Group for Behçet's Disease.
Data were extracted and evaluated according to the following criteria: complete remission, disappearance of all manifestations during treatment; partial remission, greater than 50% decrease in the number, severity, duration and/or frequency of recurrence of the lesions; stable disease, less than 50% change in the manifestations; and progressive disease, greater than 50% deterioration of existing manifestations or/and the development of new ones.
Systemic interferon alfa has been administered in 144 patients with Adamantiades-Behçet disease by subcutaneous or intramuscular injections of 3 to 18 x 10(6) units of interferon alfa-2a (70 patients) or 3 to 5 x 10(6) units of interferon alfa-2b (74 patients) daily or 3 times per week for 1 to 60 months. Seventy-four percent (92/124) of patients with mucocutaneous manifestations, 95% (37/39) of patients with uveitis, and 93% (51/55) of patients with arthropathy/arthritis exhibited a partial or complete response. Interferon alfa-2a regimens were more effective than interferon alfa-2b ones on mucocutaneous (47% vs 7% complete response) and ocular (67% vs 8% complete response; P < .001) manifestations. Mucocutaneous and ocular manifestations responded within 1 to 4 months after initiation of therapy. Thirty-eight percent (20/52) of patients with mucocutaneous lesions, 73% (8/11) of patients with uveitis, and 88% (21/24) of patients with arthropathy/arthritis experienced recurrences immediately or up to 7 months after discontinuation of treatment. Mild adverse effects were generally recorded; transient influenza-like symptoms (87% vs 63%; P < .05) and reversible leukopenia (24% vs 4%; P < .05) occurred more often under interferon alfa-2a regimens, while reversible mild alopecia was more common in patients receiving interferon alfa-2b (2% vs 28%; P < .01).
Systemic interferon alfa treatment is reasonable for Adamantiades-Behçet disease. A 3-month high-dose regimen (9 x 10(6) units 3 times per week) followed by a low maintenance dose (3 x 10(6) units 3 times per week) is recommended.
Celiac disease (CD) is one of the most common diseases, resulting from both environmental (gluten) and genetic factors [human leukocyte antigen (HLA) and non-HLA genes]. The prevalence of CD has been estimated to approximate 0.5%-1% in different parts of the world. However, the population with diabetes, autoimmune disorder or relatives of CD individuals have even higher risk for the development of CD, at least in part, because of shared HLA typing. Gliadin gains access to the basal surface of the epithelium, and interact directly with the immune system, via both trans- and para-cellular routes. From a diagnostic perspective, symptoms may be viewed as either "typical" or "atypical". In both positive serological screening results suggestive of CD, should lead to small bowel biopsy followed by a favourable clinical and serological response to the gluten-free diet (GFD) to confirm the diagnosis. Positive anti-tissue transglutaminase antibody or anti-endomysial antibody during the clinical course helps to confirm the diagnosis of CD because of their over 99% specificities when small bowel villous atrophy is present on biopsy. Currently, the only treatment available for CD individuals is a strict life-long GFD. A greater understanding of the pathogenesis of CD allows alternative future CD treatments to hydrolyse toxic gliadin peptide, prevent toxic gliadin peptide absorption, blockage of selective deamidation of specific glutamine residues by tissue, restore immune tolerance towards gluten, modulation of immune response to dietary gliadin, and restoration of intestinal architecture.
In summary, research in immunogenetics, protein chemistry, and molecular biology is leading to a greater understanding of the contribution of genetic, environmental, and immunologic factors to the etiopathogenesis of celiac disease. Taken together, the findings discussed in this article suggest that understanding of the contribution of a major genetic factor to celiac disease susceptibility is closer at hand. Thus, the pathogenesis of celiac disease appears to involve an interaction between the gene products of the HLA class II D region on chromosome 6 and the gliadin proteins, possibly because of their homology with an intestinal viral protein. A logical extension of these findings would predict that T cells, particularly CD4 T cells, play a key role in the pathogenesis of celiac disease by virtue of their recognition of a gliadin or viral peptide in conjunction with the HLA class II D-region gene products.
Nonetheless, the precise mechanisms by which the HLA class II genes and their products contribute to celiac disease is not known. Further, the precise peptide sequence in gliadin that interacts with the relevant HLA class II D-region molecule is not known. Finally, the role of CD4 T cells in the pathogenesis of celiac disease, either directly or indirectly by their ability to regulate other T-cell subsets and antibody-producing B cells, remains to be defined. The lessons learned and to be learned from celiac disease will substantially increase our underStanding of the mechanisms that are important in this disease as well as in other intestinal and HLA-associated autoimmune diseases.
Celiac disease (gluten sensitive enteropathy) is a common disorder affecting both children and adults. As many people with celiac disease do not present with the classic malabsorptive syndrome, delays in diagnosis are common. Dental enamel defects and recurrent aphthous ulcers, which may occur in patients with celiac disease, may be the only manifestation of this disorder. When dentists encounter these features, they should enquire about other clinical symptoms, associated disorders and family history of celiac disease. In suspected cases, the patient or family physician should be advised to obtain serologic screening for celiac disease and, if positive, confirmation of the diagnosis by intestinal biopsy. Dentists can play on important role in identifying people who may have unrecognized celiac disease. Appropriate referral and a timely diagnosis can help prevent serious complications of this disorder.
Using a multistep polymerase chain reaction method, we have produced a construct in which a cDNA sequence encoding the extracellular domain of the human 55-kD tumor necrosis factor (TNF) receptor is attached to a sequence encoding the Fc portion and hinge region of a mouse IgG1 heavy chain through an oligomer encoding a thrombin-sensitive peptide linker. This construct was placed downstream from a cytomegalovirus promoter sequence, and expressed in Chinese hamster ovary cells. A secreted protein, capable of binding TNF and inactivating it, was produced by the transfected cells. Molecular characterization revealed that this soluble version of the TNF receptor was dimeric. Moreover, the protein could be quantitatively cleaved by treatment with thrombin. However, the monovalent extracellular domain prepared in this way has a greatly reduced TNF inhibitory activity compared with that of the bivalent inhibitor. Perhaps because of its high affinity for TNF, the chimeric protein is far more effective as a TNF inhibitor than are neutralizing monoclonal antibodies. This molecule may prove very useful as a reagent for the antagonism and assay of TNF and lymphotoxin from diverse species in health and disease, and as a means of deciphering the exact mechanism through which TNF interacts with the 55-kD receptor.
Celiac disease results from the interplay of genetic, environmental, and immunologic factors. An understanding of the pathophysiology of celiac disease, in which the trigger (wheat, rye, and barley) is known, will undoubtedly reveal basic mechanisms that underlie other autoimmune diseases (eg, type 1 diabetes) that share many common pathogenic perturbations. This review describes seminal findings in each of the 3 domains of the pathogenesis of celiac disease, namely genetics, environmental triggers, and immune dysregulation, with a focus on newer areas of investigation such as non-HLA genetic variants, the intestinal microbiome, and the role of the innate immune system.
Overview:
Celiac disease is a T-cell-mediated, autoimmune, genetic illness that targets the small intestine and typically resolves with removal of gluten from the diet. More widespread serologic testing indicates that celiac disease affects 0.5% to 1% of the U.S. population, but presentation is highly variable and diagnosis is often missed or delayed. Strict adherence to a gluten-free diet remains the only treatment but can be challenging. This article outlines the pathophysiology of celiac disease, discusses signs and symptoms and the four disease types, describes testing, and addresses treatment and nursing implications.
To describe the clinical characteristics, histopathologic features, and outcomes of patients in whom vasculitis developed in association with use of tumor necrosis factor-α (TNF-α) inhibitors.
This is a retrospective review of patients evaluated at Mayo Clinic, Rochester, Minnesota, from January 1, 1998, through March 31, 2011, with a diagnosis of vasculitis induced by anti-TNF-α therapy.
Of 8 patients with vasculitis associated with anti-TNF-α therapy (mean age, 48.5 years), 6 (75%) were female. Four (50%) had rheumatoid arthritis, 1 (13%) had Crohn disease, and 3 (38%) had ulcerative colitis. Five (63%) were treated with infliximab, 2 (25%) with etanercept, and 1 (13%) with adalimumab. The mean duration of treatment before development of vasculitis was 34.5 months. The skin was the predominant organ affected (5 patients [63%]), with the most common cutaneous lesion being palpable purpura (4 of 5 [80%]). Two organs involved in systemic vasculitis were the peripheral nervous system (4 patients [50%]) and kidney (1 patient [13%]). All cases of vasculitis were histopathologically confirmed. Seven of 8 patients improved with discontinuation of therapy (mean time to resolution, 6.9 months) and adjuvant treatment (all 8 received prednisone; another agent was also used in 7); rechallenge with anti-TNF-α therapy was not attempted in any patient. At last follow-up, no patients had experienced a recurrence of vasculitis after therapy discontinuation.
Cutaneous small-vessel vasculitis was the most common finding, but systemic vasculitis, including peripheral nerve and renal vasculitis, was also frequently observed.
In this update on etanercept (ETN) in psoriatic arthritis (PsA) we analyze this drug's mechanism of action, clinical efficacy/effectiveness, optimal dosage, disease-modifying antirheumatic drugs (DMARD) association, radiological progression, safety, switching aspects, and pharmacoeconomy. The efficacy/effectiveness of ETN in PsA has been demonstrated in randomized placebo-controlled trials as well as in observational studies representing routine clinical practice. At 1 and 2 years, ETN inhibited radiographic disease progression, assessed by the modified total Sharp score. ETN (generally at a dosage of 50 mg/weekly) can be used either in monotherapy or in combination with DMARD such as methotrexate. A systematic search of randomized, placebo-controlled trials of ETN to treat adults with plaque psoriasis or PsA suggests that the short-term risk/benefit ratio is favorable. Longterm studies, such as observational studies, confirmed this safety profile of ETN. A variable percentage of patients withdrew anti-tumor necrosis factor-α (TNF-α) inhibitor treatment owing to inefficacy or poor tolerability. Observational studies showed that in the case of treatment failure with 1 agent, switching to the other agent may also be useful in patients with PsA because of the different molecular structures and targets of available TNF-α blockers. The clinical effect of ETN is associated with favorable pharmacoeconomic considerations.
