Exploring relief for Behçet's disease refractory oral ulcers: a comparison of TNF inhibitors versus apremilast.

OBJECTIVES: Oral and genital ulcers are the hallmark manifestation of Behçet's disease (BD), significantly impacting patients' quality of life. Our study focuses on comparing the effectiveness and safety of TNF inhibitors (TNFis) and apremilast in controlling oral ulcers of BD, aiming to provide evidence-based guidance for physicians in selecting appropriate treatment modalities. METHODS: A retrospective analysis was performed on BD patients treated between December 2016 and December 2021 with TNFis or apremilast for refractory oral ulcers. The study assessed treatment response by the absence of oral ulcers at 3 and 6 months, with additional evaluations for genital ulcers and articular involvement. RESULTS: The study included 78 patients, equally allocated between TNFis and apremilast treatments. Both groups showed significant oral ulcer reduction at 3 (p< 0.001) and 6 months (p= 0.01) with no significant difference between the treatments. Apremilast had a notable corticosteroid-sparing effect by the 3-month follow-up, persisting through 6 months. Both treatments were equally effective in reducing genital ulcers, with TNFis showing greater effectiveness in addressing articular involvement. Apremilast had a higher discontinuation rate due to gastrointestinal side effects. CONCLUSION: TNFis and apremilast are both effective for treating BD refractory oral ulcers. While TNFis may offer broader benefits for other disease manifestations, apremilast is distinguished by its corticosteroid-sparing effect, especially for patients with a milder disease phenotype. Treatment selection should consider individual disease severity and clinical features to ensure a personalized and effective management strategy.

Neutropenic ulcers in oncology: terminology, diagnosis, and management.

Neutropenic ulcerations are characterized by mucosal ulcerations which occur in the presence of neutropenia, suggesting a direct link between neutropenia and mucosal ulceration. An oral ulcer can be labeled as "neutropenic" only if the patients have primary (typically congenital) or secondary neutropenia, and neutropenia is the sole causative factor. Oral mucosal ulcers observed in patients undergoing oncologic therapy may also be termed as "neutropenic ulcers", but the pathogenesis of these oral ulcers more likely involves mucosal events related to trauma, microbial factors, and direct cytotoxicity. In cancer patients, the early appearance of oral ulcers is often attributed to oral mucositis which is a condition primarily caused by the direct mucosal cytotoxicity of chemotherapeutic agents and radiation therapy. Oral ulcers that develop later during or after active cancer therapy may result from intraoral trauma and typically manifest on non-keratinized areas of the oral mucosa which are more susceptible to mucosal damage. In patients undergoing chemotherapy, factors such as disturbances in mucosal barrier function as well as bone marrow suppression lead to reduced neutrophil count and function, and can contribute to the development of oral ulcers. While the etiology of oral ulcers in cancer therapy receiving patients can vary, it is important to emphasize that the host's response plays a crucial role in the progression and repair process of these lesions. This narrative review presents the etiopathogenesis, clinical presentation, and potential management approaches for oral ulcerations in neutropenic patients, with a particular focus on clarifying the usage of the term "neutropenic ulcer" since this term lacks diagnostic specificity and can be misleading in clinical practice regarding the underlying causes and treatment strategies.

Severe NAD(P)HX Dehydratase (NAXD) Neurometabolic Syndrome May Present in Adulthood after Mild Head Trauma.

We have previously reported that pathogenic variants in a key metabolite repair enzyme NAXD cause a lethal neurodegenerative condition triggered by episodes of fever in young children. However, the clinical and genetic spectrum of NAXD deficiency is broadening as our understanding of the disease expands and as more cases are identified. Here, we report the oldest known individual succumbing to NAXD-related neurometabolic crisis, at 32 years of age. The clinical deterioration and demise of this individual were likely triggered by mild head trauma. This patient had a novel homozygous NAXD variant [NM_001242882.1:c.441+3A>G:p.?] that induces the mis-splicing of the majority of NAXD transcripts, leaving only trace levels of canonically spliced NAXD mRNA, and protein levels below the detection threshold by proteomic analysis. Accumulation of damaged NADH, the substrate of NAXD, could be detected in the fibroblasts of the patient. In agreement with prior anecdotal reports in paediatric patients, niacin-based treatment also partly alleviated some clinical symptoms in this adult patient. The present study extends our understanding of NAXD deficiency by uncovering shared mitochondrial proteomic signatures between the adult and our previously reported paediatric NAXD cases, with reduced levels of respiratory complexes I and IV as well as the mitoribosome, and the upregulation of mitochondrial apoptotic pathways. Importantly, we highlight that head trauma in adults, in addition to paediatric fever or illness, may precipitate neurometabolic crises associated with pathogenic NAXD variants.

Topical betamethasone and systemic colchicine for treatment of recurrent aphthous stomatitis: a randomised clinical trial.

BACKGROUND: Recurrent Aphthous Stomatitis (RAS) is painful oral ulceration frequently treated with topical steroids. There is limited published evidence for the efficacy of any treatment for RAS and there remains a need for longitudinal randomised clinical trials to evaluate and compare the effectiveness of different therapies in the management of RAS. The aim of the current project was to assess the efficacy of betamethasone mouthwash and colchicine tablets, individually and combined, for the treatment of RAS, and to establish the optimum treatment period necessary for a significant reduction in the disease severity. METHODOLOGY: A randomised, prospective, parallel-group clinical trial was conducted over one year, to compare the efficacy of three therapies in RAS. One hundred and six patients were randomized into three groups; 35 received betamethasone mouthwash, 35 had colchicine tablets and 36 received both therapies. The response was evaluated quantitatively every 3 months for 1 year, using the Ulcer Severity Score (USS). RESULTS: For all three treatment regimes, the mean USS decreased by about 30% in the first 3 months (p < 0.001). Further improvement was noted for up to 9 months. At the end of the study, the mean USS had improved by 50% from 34.9 ± 7.2 before treatment to 17.5 ± 8.9 after treatment (p < 0.001). Of included participants, 86% showed significant clinical improvement by the end of the study. There were no significant differences in outcomes between the three regimes (p < 0.05). CONCLUSIONS: This clinical trial has provided evidence for the efficacy of betamethasone mouthwash and for colchicine tablets in the treatment of RAS and has shown that at least six months of treatment may be required for optimum effect. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN3267716. Date of clinical trial registration: 15/04/2018.

Risk indicators for oral ulcers among people living with HIV during the first wave of the pandemic: a cross sectional study.

BACKGROUND: Little is currently known about HIV-related parameters that may increase the risk for oral ulcers during the COVID-19 pandemic. This study aimed to overcome this gap in research by assessing the associations between HIV viral load, antiretroviral adherence profile, co-morbidity status, SARS-CoV-2 infection and oral ulcers among people living with HIV (PLHIV). METHODS: This was a secondary analysis of data generated from 21,206 to 18 years and above, recruited from 152 countries through an online survey between July and December 2020. Data were extracted for 874 people who reported living with HIV. The dependent variable was reporting having oral ulcer. The independent variables were the viral load, adherence to antiretroviral treatment and a history of SARS-CoV-2 infection. The confounding variables were age at last birthday and sex at birth. A multivariable logistic regression analysis was conducted to determine the associations between the dependent and independent variables after adjusting for the confounding variables. RESULTS: Of the 874 participants, 99 (11.3%) reported having oral ulcers during the first wave of the COVID-19 pandemic. The odds of PLHIV having oral ulcers during the first wave of the COVID-19 pandemic was significantly higher for people who did not know their viral load than those who had undetectable viral load (AOR: 2.036; 95% CI: 1.204-3.443; p = 0.008); and people who did not adhere to the use of antiretroviral treatment than those who adhered (AOR: 4.113; 95% CI: 2.567-6.589; p < 0.001). Also, PLHIV who had SARS-CoV-2 infection had significantly higher odds of having oral ulcers than those who did not have the infection (AOR: 14.556; 95% CI: 4.500-47.078; p < 0.001). PLHIV who had co-morbidities had non-significantly higher odds of having oral ulcers than those without co-morbidities (AOR: 1.170; 95% CI: 0.656-2.085; p = 0.595). CONCLUSION: Oral ulcers may be an indicator of poor adherence to antiretroviral therapy and unsuppressed viral load among PLHIV. It may also be an indicator of SARS-CoV-2 infection and a signal to take prompt and critical care of affected individuals because of the risk for severe COVID-19 for these individuals.

Behcet's disease in a patient with primary sclerosing cholangitis: a case report and literature review.

Behçet's disease (BD) is a rare, chronic multisystem disease of unknown aetiology. Clinically, it presents with ulceration located on the oral and genital mucosa, skin, uveitis, arthritis and neurological disorders. Most commonly, the disease affects men in the second and third decades of life and occurs endemically. The vast majority of cases have been reported in Asia and the Mediterranean area. The diagnosis of this disease is difficult, especially because of its rare occurrence in Central Europe. In this report, we present the case of BD in a 56-year-old man with primary sclerosing cholangitis, followed by a literature review covering current insights into BD aetiology, diagnostics and treatment.

Platelet-rich fibrin a new approach in management of persistent oral ulcers in blistering skin diseases.

The present study designed to evaluate the healing power of platelet-rich fibrin (PRF) in terms of pain control and mucosal repair. A randomised, controlled, pilot clinical trial was conducted on 16 patients randomly distributed with 1:1 allocation ratio into two groups. The treatment group received PRF minced and mixed with orabase and the control group received clobetasol propionate 0.05% mixed with orabase. Pain reduction was evaluated as primary outcome along with mucositis healing as secondary outcome. A statistically significant difference in pain reduction was observed between the two groups (p ≤ 0.05). The clinical results at Day 7 has shown that PRF group had 100% pain reduction while, CP group had 32.5% reduction from base line. PRF offered superior clinical results providing rapid pain alleviation and accelerated ulcer healing compared to corticosteroids.

Photodynamic antimicrobial chemotherapy using indocyanine green in experimentally induced intraoral ulcers in rats.

BACKGROUND: Photodynamic antimicrobial chemotherapy (PACT) is a promising modality for eradication of microorganisms from the wound. This study aimed to investigate the effectiveness of PACT using indocyanine green (ICG) for reduction of bacterial load of oral ulcers in rats and its impact on the healing process. METHODS: In this experimental study, 50 adult male Sprague Dawley rats were recruited. Oral ulcers were surgically made on the left cheek mucosa, and animals were randomly assigned into five groups (n = 10). Wound site in groups 1, 2, and 3 was irrigated with the sterile saline (0.9%), chlorhexidine (CHX; 0.2%), and ICG solutions (1 mg/mL), respectively. Group 4 was exposed to laser irradiation using 810 nm diode laser on continuous-wave mode for 30 seconds (fluence: 55 J/cm2 , power: 300 mW, spot size: 4.5 mm). In group 5, PACT was performed using topical application of ICG followed by laser irradiation in the same way as the previous group. Bacterial load of oral ulcers was assessed before and after each treatment modality. Besides, rats were sacrificed on the 5th day post ulceration and histological features of healing were evaluated. RESULTS: Bacterial load was significantly reduced merely in the PACT-ICG-treated group by one log (P < .0001). Animals in the PACT-ICG-treated group also showed an accelerated healing in comparison with others on the 5th day of an experiment. CONCLUSION: Photodynamic antimicrobial chemotherapy using topical application of ICG has a potential to reduce the bacterial load of oral ulcers and accelerate wound repair. Therefore, it can be considered as an alternative to currently available modalities for wound management.

The effect of indocyanine green-mediated photodynamic therapy in healing of experimentally induced oral mucosal traumatic ulcer in rat.

Photodynamic therapy (PDT) is a promising approach for the healing of ulcerative lesions. This study aimed to investigate the effect of PDT using indocyanine green (ICG) in the healing of the experimentally induced oral mucosal traumatic ulcer in rat. Sixty adult male Sprague-Dawley rats were recruited in this experimental study. The ulceration was surgically made in the left cheek mucosa, and the rats were randomly assigned into four equal groups (n = 15). Oral ulcers in groups 1 and 2 were treated with the sterile saline solution (0.9%) and ICG (1 mg/ml). In group 3, laser irradiation was applied using the 810 nm diode laser in the continuous-wave mode for 30 s (light dose: 55 J/cm2, power: 300 mW, spot size: 4.5 mm). Following the topical application of ICG (1 mg/ml) in group 4, laser irradiation was performed in the same way as the previous group. After 24 h, treatments were repeated once more in all groups. The healing process was histopathologically assessed at the 3rd, 7th, and 14th days after ulceration. Wound healing was significantly accelerated in the ICG-mediated PDT group in comparison to the control group at all sampling time points (p < 0.005). However, the other groups displayed a similar healing rate (p > 0.05). Data suggest that ICG-mediated PDT has the potential to accelerate wound healing and prevent clinical infection in oral mucosal traumatic ulcers. However, further studies are required to confirm whether our results can be generalized to other wounds.

Clinical characteristics and risk factors of major oral ulcers in the mandibular retromolar region in children.

OBJECTIVES: To describe the characteristics of major aphthous ulcers (MjOU) in children and analyze its potential risk factors. MATERIALS AND METHODS: Data were collected from the National Clinical Research Center for Oral Diseases of China between 2012 and 2017. Children younger than 15 years old, who had a giant mucosa ulcer (≥ 1 cm in diameter) and met the diagnostic criteria for MjOU were included in this study. Differences were compared between two subgroups of patients based on the location of the ulcerous lesions. A measurement of ratio (TBR) between the length of the mandibular second molar tooth germ and the height of the mandible was performed in children with MjOU lesions located in the mandibular retromolar pad region (MjOU-P) and their age- and sex-matched controls. RESULTS: A total of 1067 children were diagnosed with oral ulcers during the study period, of which 125 (11.7%, 95% CI: 9.8%-13.7%) met the diagnostic criteria for MjOU. More than half (n = 64, 51.2%) of the MjOU cases were MjOU-P, which had a male predilection (n = 52, 81.3%) with a significant majority at 7 to 9 years of age (n = 43, 67.2%). In comparison to the MjOU located in other regions, MjOU-P lasted longer in duration and had more comorbidities. Logistic regression analysis showed that MjOU-P was statistically significantly associated with TBR controlling age and gender. CONCLUSIONS: MjOU-P is a predominant form of MjOU in children and is a distinct subgroup of major ulcers that is likely associated with the development of the mandibular second molars. CLINICAL RELEVANCE: This study is the first to describe the demographic and clinical features of MjOU in children, which may facilitate the identification and treatment of these patients.

Efficacy and safety of apremilast for 3 months in Behçet's disease: A prospective observational study.

OBJECTIVE: To determine the real-world short-term efficacy and safety of apremilast for Behçet's disease (BD). METHODS: The study included patients who received apremilast for refractory oral ulcers in addition to meeting International Study Group criteria for BD or the revised International Criteria for Behçet's Disease. To assess the efficacy of apremilast, Behçet's disease current activity form (BDCAF) and patients' self-perception of their disease activity were monitored for three months. The disease phenotypes, laboratory data, concomitant medication use, and adverse events were also investigated. RESULTS: Fourteen BD patients were included in the study. Concomitant drug use were as follows: colchicine 92.9%, prednisolone 21.4%, immunosuppressants 28.6%, and tumor-necrosis inhibitor 14.3%. Oral ulcers and BDCAF scores at 3 months showed significant improvement compared to baseline. Adverse events during the study were diarrhea (n = 3, 21.4%), nausea (n = 3, 21.4%), music hallucination (n = 1, 7.1%), and branch retinal vein occlusion (n = 1, 7.1%). Apremilast was discontinued in 1 patient (7.1%) due to nausea. CONCLUSION: Significant improvement in oral ulcer and BDCAF with apremilast was confirmed in real-world BD patients after 3 months. The combination of colchicine and apremilast appears to be well tolerated in BD in the short-term.

Efficacy and safety of apremilast for Behçet's syndrome: a real-life single-centre Italian experience.

OBJECTIVES: To evaluate the efficacy and safety of apremilast in treating oral ulcers (OUs), the cardinal and high-disabling feature of Behçet's disease (BD). METHODS: Twelve consecutive patients affected by BD with recurrent/relapsing OUs resistant and/or intolerant to conventional therapy were enrolled and prospectively followed. The primary endpoint was the number of OUs at week 12. Secondary endpoints were modification from baseline to week 12 in Behçet's Syndrome Activity Score (BSAS), Behçet's Disease Current Activity Form (BDCAF) score, Behçet's Disease Quality of Life (BDQOL) scale and pain of OUs, as measured by a visual analogue scale (VAS). All adverse events (AEs) were recorded during follow-up. Non-parametric tests (Wilcoxon rank test) were used and a P-value <0.05 was considered statistically significant. RESULTS: After 12 weeks of apremilast, there was a significant reduction in the number of OUs [0.58 (s.d. 0.67) vs 3.33 (s.d. 1.45) at baseline, P = 0.02] that was paralleled by improvement in disease activity: BSAS was 16.8 (s.d. 9.1) [from 45.9 (s.d. 19.6) at baseline] (P = 0.02), BDCAF score was 0.72 (s.d. 0.65) [vs 2.45 (s.d. 1.0) at baseline] (P = 0.04) and the VAS score for pain decreased to 23.3 (s.d. 13.7) [vs 67.9 (s.d. 17.2) at baseline] (P = 0.02). Consistently, an improvement of BDQOL was assessed (P = 0.02). Clinical improvement led to complete steroid discontinuation in six patients and a tapering of the prednisone dose in two patients (P = 0.016). Colchicine was discontinued in six of nine patients (P = 0.031). AEs related to apremilast occurred in four patients (mainly due to gastrointestinal AEs), leading to drug discontinuation in all of them. CONCLUSION: Our preliminary real-world data support the use of apremilast as an effective therapeutic strategy against BD-related recurrent OUs resistant or intolerant to first-line therapy.

Behçet: the syndrome.

Behçet's syndrome (BS) is a systemic vasculitis characterized by a relapsing and remitting course. It can involve the skin, mucosa, joints, vessels (arteries and/or veins), eyes, and nervous and gastrointestinal systems, and so is referred to as a syndrome rather than as a unique and nosologically distinct condition. These involvements may present alone or co-exist in the same patient. Although all the possible combinations of the above-mentioned manifestations may occur, clusters of commonly co-existing involvements (also referred to as 'disease phenotypes') have been suggested, namely 'mucocutaneous and articular', 'peripheral vascular and extra-parenchymal neurological' and 'parenchymal neurological and ocular' phenotypes have been described. Patient-specific demographic and genetic features have been described as positively or negatively associated with specific disease phenotypes. This review will focus on the different clinical features of Behçet's syndrome, summarizing current evidence on the distinct disease manifestations as well as the major phenotypes.

Value of colchicine as treatment for recurrent oral ulcers: A systematic review.

BACKGROUND: In oral medicine, colchicine is a therapeutic alternative for idiopathic recurrent aphthous stomatitis (RAS), Behçet disease (BD), periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome, and mouth and genitals ulcers with inflamed cartilage (MAGIC) syndrome. The present review aims to evaluate reliability of colchicine against recurrent oral ulcers. METHODS: A systematic review was conducted, with the following PICO (Patient, Intervention, Control, Outcome) question: "In populations with idiopathic or secondary recurrent oral ulcers, is colchicine more effective in improving pain and accelerating healing, compared to other intervention or placebo?" RESULTS: Seven RCTs and 3 OCTs were considered eligible. Four RCTs focused on BD, two RCTs and three OCTs on RAS, and one RCT on PFAPA syndrome. Heterogeneity between RCTs prevented from meta-analysis. Regarding BD, no significant difference between colchicine and placebo was found in two of three placebo-controlled RCTs, whereas the third RCT showed benefit. A comparative RCT found ciclosporin more effective than colchicine for oral lesions of BD. One open-label RCT showed promising but partial results on colchicine in reducing PFAPA attacks, when compared to corticosteroids. Concerning RAS, colchicine appeared less effective than clofazimine, thalidomide and dapsone, and with outcomes similar to low-dosage corticosteroids but higher gastric discomfort than prednisolone. One OCT reported positive results compared with no treatment but a RCT found no difference with placebo. CONCLUSION: Role of colchicine as treatment for idiopathic or secondary recurrent oral ulcers is still controversial. Further standardized RCTs and crossover trials are needed.

Clinical presentation and diagnostic delay in pemphigus vulgaris: A prospective study from Turkey.

BACKGROUND: To evaluate the diagnostic patterns and factors that may influence delays in the diagnosis of pemphigus vulgaris (PV) with oral involvement. MATERIALS AND METHODS: In this prospective cohort study, 36 newly diagnosed PV patients with oral involvement were clinically examined and interviewed about the natural history of the oral lesions, number of medical consultations (Med consultation), medical treatment history, and diagnostic delay time (DD time). RESULTS: Thirty (83%) PV patients presented initially with oral mucosal involvement (OMI) and 6 (17%) presented initially with skin involvement (SI). The mean DD time was 6.19 ± 3.82 months, and the mean number of Med consultation was 5.8 (n = 36). The means of all the parameters were significantly higher for the OMI patients than for the SI patients (P < .05). All of the patients with OMI had been misdiagnosed. The DD time was significantly longer in patients who presented initially with desquamative gingivitis (8.25 ± 3.81) than patients who presented with ulcers and erosions (4.78 ± 1.11) (P < .05). There was a statistically significant positive correlation between DD time and Med consultation (r = 0.91). CONCLUSION: Even with the high frequency of oral involvement and easy access to the oral cavity, diagnostic delays are still common for patients with oral PV. This underlines the need for education to improve healthcare providers' awareness and knowledge of the clinical oral presentation of PV.

A nonspecific ulcer on upper lip presented as the first and sole sign of syphilis.

Syphilis, a sexually transmitted disease, can be categorized as acquired syphilis and congenital syphilis, manifesting diverse lesions involving multiple sites. Oral manifestations at the primary stage of acquired syphilis are usually characterized by its short period and non-specific varied presentations. And oral ulcers as initial and the only presentation of syphilis oral lesions are infrequent and occur in less than 2% of patients. Because of its transient nature and variable manifestations which could mimic other oral ulcerative lesions, oral syphilis presenting as sole ulceration at early stage can be easily neglected and rather difficult to diagnose. Herein, we report a 35-year-old female patient manifested a sole atypical ulceration on her upper lip for approximately 1 month. We highlighted the importance of early and accurate diagnosis, focused on the characteristics of oral chancre, and gave an insight to the differential diagnoses, which would be enlightening and useful in clinical practice.

Persistent Palatal Ulcerations. A Potential Manifestation of Juvenile Systemic Lupus Erythematosus.

Oral ulcerations in children and adolescents is a common occurrence and affects about 20-30% of this population. This case report describes a unique and serious autoimmune condition that presented with distinct oral findings that significantly supported the differential diagnosis of Juvenile Systemic Lupus Erythematosus in a 15 year-old female. Pediatric and general dentists should familiarize themselves with the condition to facilitate diagnosis with collaborative efforts with the medical team.

Citric acid treatment of oral ulcers refractory to conventional treatment: a case study.

OBJECTIVE: Oral ulcers are painful sores that appear in the mouth. Most of them are usually harmless and clear up on their own. Sometimes, they are non-responsive and difficult to manage. This report describes the case of an 80-year-old female patient with chronic oral ulcers of three years duration and which were refractory to conventional therapy. The ulcers were subsequently treated using 3% citric acid as a sole topical agent, applied three times a day that resulted in complete healing of oral ulcers by day 10 of treatment. The findings of this case report suggest that topical citric acid is a possible alternative treatment for chronic oral ulcers unresponsive to conventional treatment.