World Workshop on Oral Medicine VII: Oral adverse effects to biologic agents in patients with inflammatory disorders. A scoping review.

BACKGROUND: Biologic agents are rapidly emerging as an effective therapy to treat autoimmune and other chronic diseases. The use of these agents is poorly characterized, resulting in a lack of guidance for dental practitioners. Case reports of oral adverse events have begun to emerge. However, their scope and frequency have not been summarized and analysed to date. The objective of this review was to characterize the literature on oral adverse effects associated with biological therapy when used for autoimmune and inflammatory disorders. METHODS: This review was developed in accordance with scoping review recommendations. Search strategies were developed and employed for six databases. Studies were selected using a systematic search process but with broad inclusion of study types given the paucity of information available. Reports of oral adverse events were analysed descriptively according to agent, mechanism of action, underlying disease, and oral adverse effect observed. RESULTS: Our search returned 2080 articles and 51 met our inclusion criteria, of which most were case reports. The most frequent adverse effects included angioedema, oral lichenoid lesions, osteonecrosis of the jaw, and oral infections. There were also cases of oral malignancies associated with use of biologic agents. Less common effects such as pigmentation were also described. CONCLUSIONS: Oral adverse events have been reported in patients on biologic therapy, albeit in small numbers to date. This limits the generalizability of these results, which should not be used to generate a clinical guideline as they are based primarily on case reports. However, this study presents the first review characterizing the adverse effects observed. Large multi-center studies will be necessary to further define the oral and dental complications caused by biologic agents.

Competencies for the new postdoctoral Oral Medicine graduate in the United States.

Oral Medicine is primarily a nonsurgical dental discipline that includes management of (1) oral mucosal and salivary gland diseases; (2) temporomandibular disorders and orofacial pain; (3) oral complications of systemic disease; and (4) dental management of medically complex patients within its scope of practice. In the United States, the American Academy of Oral Medicine (AAOM) is the professional organization that primarily supports Oral Medicine education, research, and patient care. This document informs the knowledge, skills, and behaviors of beginning Oral Medicine graduates in the United States in three domains: Diagnosis and primarily nonsurgical management of oral mucosal and salivary gland disorders. Diagnosis and primarily nonsurgical management of temporomandibular, orofacial pain, and neurosensory disorders. Management of the medically complex patient. Each domain is subsequently expanded with major competencies and supporting competencies.

Epigallocatechin-3-gallate modulates anti-oxidant defense enzyme expression in murine submandibular and pancreatic exocrine gland cells and human HSG cells.

Sjogren's syndrome (SS) and type-1 diabetes are prevalent autoimmune diseases in the USA. We reported previously that epigallocatechin-3-gallate (EGCG) prevented and delayed the onset of autoimmune disease in non-obese diabetic (NOD) mice, a model for both SS and type-1 diabetes. EGCG also normalized the levels of proteins related to DNA repair and anti-oxidant activity in NOD.B10.Sn-H2 mice, a model for primary SS, prior to disease onset. The current study examined the effect of EGCG on the expression of anti-oxidant enzymes in the submandibular salivary gland and the pancreas of NOD mice and cultured human salivary gland acinar cells. NOD mice consuming 0.2% EGCG daily dissolved in water showed higher protein levels of peroxiredoxin 6 (PRDX6), a major anti-oxidant defense protein, and catalase, while the untreated NOD mice exhibited significantly lowered levels of PRDX6. Similarly, pancreas samples from water-fed NOD mice were depleted in PRDX6 and superoxide dismutase, while EGCG-fed mice showed high levels of these anti-oxidant enzymes. In cultured HSG cells EGCG increased PRDX6 levels significantly, and this was inhibited by p38 and JNK inhibitors, suggesting that the EGCG-mediated increase in protective anti-oxidant capacity is regulated in part through mitogen-activated protein kinase pathway signaling. This mechanism may explain the higher levels of PRDX6 found in EGCG-fed NOD mice. These preclinical observations warrant future preclinical and clinical studies to determine whether EGCG or green tea polyphenols could be used in novel preventive and therapeutic approaches against autoimmune diseases and salivary dysfunction involving oxidative stress.

Epigallocatechin-3-gallate prevents autoimmune-associated down- regulation of p21 in salivary gland cells through a p53-independent pathway.

The submandibular salivary glands of non-obese diabetic (NOD) mice, a model for Sjogren's syndrome and type-1 diabetes, show an elevated level of proliferating cell nuclear antigen (PCNA), a protein involved in cell proliferation and repair of DNA damage. We reported previously that epigallocatechin-3-gallate (EGCG), the most abundant green tea catechin, normalizes the PCNA level. PCNA's activity can be regulated by the cyclin-dependent kinase inhibitor p21, which is also important for epithelial cell differentiation. In turn, expression of p21 and PCNA are partially regulated by Rb phosphorylation levels. EGCG was found to modulate p21 expression in epithelial cells, suggesting that EGCG-induced p21 could be associated with down-regulation of PCNA in vivo. The current study examined the protein levels of p21 and p53 (which can up-regulate p21) in NOD mice fed with either water or EGCG, and the effect of EGCG on p21 and p53 in cell line models with either normal or defective Rb. In NOD mice, the p21 level was low, and EGCG normalized it. In contrast to HSG cells with functional Rb, negligible expression of p21 in NS-SVAC cells that lack Rb was not altered by EGCG treatment. Inhibition of p53 by siRNA demonstrated that p21 and p53 were induced independently in HSG cells by a physiological concentration range of EGCG, suggesting p53 could be an important but not conditional factor associated with p21 expression. In conclusion, PCNA and p21 levels are altered inversely in the NOD model for SS and in HSG cells, and warrant further study as candidate new markers for salivary dysfunction associated with xerostomia. Induction of p21 by EGCG could provide clinically useful normalization of salivary glands by promoting differentiation and reducing PCNA levels.

Epigallocatechin-3-gallate modulates antioxidant and DNA repair-related proteins in exocrine glands of a primary Sjogren's syndrome mouse model prior to disease onset.

The autoimmune disorder primary Sjogren's syndrome (SS) is associated with xerostomia and xerophthalmia. SS pathogenesis involves both genetic/epigenetic and environmental factors. A major potential contributor is oxidative stress associated with damage to cellular components, including DNA. We reported previously that the green tea polyphenol epigallocatechin-3-gallate (EGCG) normalizes the elevated levels of proliferating cell nuclear antigen (PCNA), a key component of DNA repair, in the NOD mouse model for SS and type 1 diabetes. The current study examined levels of the antioxidant enzymes peroxiredoxin 6 (PRDX6), catalase and superoxide dismutase (SOD), as well as PCNA, in NOD.B10.Sn-H2 mice, a model for primary SS, and determined the effect of EGCG on their expression. PCNA elevation was detected in the submandibular gland and pancreas by 8 weeks of age in water-fed mice, and increased through 14 weeks of age, prior to overt onset of symptoms. This early PCNA elevation was followed by a decline of peroxiredoxin 6 protein. In contrast, EGCG-fed mice exhibited normal levels of PCNA and peroxiredoxin 6, comparable to healthy untreated BALB/c mice. Similar patterns were observed in the pancreas, even though these mice do not develop diabetes. Thus, elevated PCNA is an early biomarker for exocrine glandular dysfunction associated with SS-like autoimmune disease, accompanied subsequently by decreased PRDX6 antioxidant enzyme levels that could further contribute to oxidative stress, and these changes precede inflammatory cell infiltration. Importantly, EGCG consumption normalizes the expression of these biomarkers in this model. These observations could lead to early diagnosis and intervention of autoimmune disorders.

The oral-medical disease connection: pregnancy, cardiovascular disease, and diabetes.

There is considerable perplexity regarding the oral-systemic connection. Existing research, including epidemiologic findings, interventional studies, and a smaller number of reports seeking to elucidate mechanisms of action, have been somewhat contradictory. Of importance to the practicing clinician is how to gain understanding of this abundance of emerging scientific evidence, synthesize it, and integrate it into clinical practice. In essence, clinicians need to be able to authoritatively respond to their patients' inquiries regarding relationships between oral and systemic disease. This article seeks to provide insights to this issue with regards to pregnancy, cardiovascular disease, and diabetes.

Superficial mucoceles in chronic graft-versus-host disease: a case report and review of the literature.

Graft-versus-host disease (GVHD) is a common complication among allogeneic hematopoietic cell transplant recipients. Chronic GVHD (cGVHD) has numerous clinical manifestations and the oral cavity is almost always involved. Common oral manifestations include diffuse mucosal erythema and atrophy, lichenoid lesions, pain, and xerostomia. This article reports the case of a 40-year-old man with a history of allogeneic hematopoietic cell transplantation who developed cGVHD. In addition to diffuse oral mucosal erythema and lichenoid-appearing lesions, he also developed numerous persistent painful superficial mucoceles. The superficial mucoceles were refractory to treatment with topical steroids; however, subsequent treatment with triamcinolone intra-lesional injections decreased their quantity, size, and symptoms.

The anesthetic efficacy of 4 percent articaine 1:200,000 epinephrine: two controlled clinical trials.

OBJECTIVE: The authors conducted two double-blinded, randomized, multicenter clinical trials to determine the efficacy and clinical anesthetic characteristics of 4 percent articaine hydrochloride (HCl) with 1:200,000 epinephrine (A200) as compared with those of 4 percent articaine HCl with 1:100,000 epinephrine (A100) and 4 percent articaine HCl without epinephrine (Aw/o). METHODS: During separate testing sessions, members of the authors' research team used three articaine study formulations to induce either inferior alveolar nerve block anesthesia (Trial 1) or maxillary infiltration anesthesia (Trial 2). In each trial, subjects received, in a randomized sequence, each of the three formulations to determine efficacy (success rate) and anesthetic characteristics (onset time and duration). The authors evaluated pulpal anesthesia via subjects' response to electric pulp testing (EPT). RESULTS: A total of 126 subjects were enrolled in the two studies (63 subjects in each trial). In both mandibular and maxillary trials, the success rates for inducing profound anesthesia (EPT score > 80), the mean onset times and the mean durations of anesthesia were similar for both epinephrine-containing formulations (A200 and A100). In subjects who received the formulation containing no epinephrine (Aw/o), the success rate for profound anesthesia was significantly less. CONCLUSION: These studies demonstrated that the inclusion of epinephrine in 4 percent articaine anesthetic formulations is essential for achieving profound anesthesia. The authors found that the A200 formulation provided a level of pulpal anesthesia comparable with that of the A100 formulation.

A review of adverse oral reactions to systemic medications.

There is no debate that oral health and general well-being are inextricably bound. Many commonly prescribed medications have associated dental and oral manifestations that often are nonspecific and can vary in significance. This article reviews many common oral manifestations of systemic drugs, including the clinical manifestations, diagnosis, and treatment of these conditions.

A study of benzocaine gel dosing for toothache.

OBJECTIVE: This pilot study evaluated subject compliance with a proposed OTC label with improved dosing directions for self-application of a 20% benzocaine gel for toothache pain, and assessed the methodology for evaluating efficacy in a future pivotal study of benzocaine gel. It was hypothesized that > or = 75% of subjects would apply < or = 400 mg of product (80 mg benzocaine). Exploratory analyses of efficacy were also performed. METHODOLOGY: Thirty patients with spontaneous pain of moderate or severe intensity from a single tooth due to caries, a lost restoration, or a fracture entered this randomized, parallel group, double-blind study. Before self-applying 20% benzocaine gel or placebo, patients read a label containing new dosing directions, including a picture of how much product to apply to their tooth and the surrounding gingival tissues. The amount applied was determined by weighing the tube before and after dosing. Following dosing, pain intensity and relief were recorded every five minutes through 30 minutes, then every ten minutes through 120 minutes. Responders were defined as those subjects who experienced at least a one-unit reduction in pain intensity from baseline at two consecutive time points within the first 20 minutes. Onset of meaningful relief was recorded using a stopwatch. The percentage of responders was compared using the Mantel-Haenszel test. ANOVA was employed to test for differences in Pain Relief Combined with Pain Intensity Difference (PRID), and the areas under the curve at 30, 60, 90, and 120 minutes for this measure (SPRID). Median onset and duration times were compared using the Cox proportional hazards model. Adverse events were recorded if and when they occurred. RESULTS: It was found that 86.7% of the subjects (26/30) applied < or = 375 mg of product (mean +/- SD = 327.7 +/- 276.8 mg). The benzocaine group had a significantly higher (p = 0.022) responder rate (86.7%) than the placebo group (46.7%). Significant differences in favor of the benzocaine group were also recorded for PRID at 10, 15, and 30 minutes (p < 0.05) and SPRID-30 (p = 0.037). Median onset and duration times were 8.3 minutes and > 115 minutes for the benzocaine group, >120 minutes and 5 minutes for the placebo group. There were no adverse events recorded in the study. CONCLUSION: The improved dosing directions resulted in a high percentage of subjects self-applying an appropriate amount of benzocaine gel or matching placebo. The label and study methodology appear suitable for a pivotal dose-response study in subjects with toothache pain. While the current study was not statistically powered to make firm efficacy conclusions, 20% benzocaine gel appeared more efficacious than placebo, providing a rapid onset of pain relief and a relatively long duration of action.

Lichen planus, lichenoid drug reactions, and lichenoid mucositis.

Lichen planus is a common mucocutaneous disease affecting a significant portion of the general population. This article reviews the most current concepts on the epidemiology, etiology, pathogenesis, clinical presentations, and treatment of oral lichen planus, lichenoid drug reactions, and lichenoid mucositis.

The management of oral human papillomavirus with topical cidofovir: a case report.

Cidofovir, a purine nucleotide analog of cytosine, has showed significant promise against a number of DNA viruses. In 1997, the US Food and Drug Administration approved the use of cidofovir intravenously in the treatment of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome. Recent studies and reports suggest that a topical form of cidofovir may be useful for treating viral cutaneous lesions recalcitrant to traditional treatments. We report the case of a 36-year-old man with human immunodeficiency virus (HIV) and recalcitrant human papillomavirus (HPV) lesions on the gingiva that were successfully treated with cidofovir gel 1%.

Desquamative gingivitis: early presenting symptom of mucocutaneous disease.

Desquamation of the gingiva is a sign that may be encountered in clinical practice. Various diseases can affect the gingival tissues. Mild desquamation that is localized may be associated with mechanical irritation or induced by trauma. Moderate to severe generalized desquamation associated with ulceration and erythema may be indicative of a more serious systemic condition. Although often overlooked, mucocutaneous diseases frequently present with gingival desquamation as an early presenting symptom. The most common mucocutaneous diseases that affect the oral cavity are lichen planus, pemphigus, and mucous membrane pemphigoid. This article reviews the etiology, signs and symptoms, and therapies for these disorders. Increased knowledge of mucocutaneous diseases can help the clinician recognize these disorders and enable the patient to receive appropriate therapy.

Mucous membrane pemphigoid. Update for the general practitioner.

A common patient complaint that may be encountered in practice is desquamation of oral tissue. Moderate-to-severe, generalized oral desquamation associated with ulceration and erythema could be associated with systemic mucocutaneous disease. Systemic mucocutaneous diseases that affect the oral cavity include lichen planus, pemphigus and mucous membrane pemphigoid. This article will review the etiology, clinical presentation and management of mucous membrane pemphigoid.

Epithelioid blue nevus of the oral mucosa: a rare histologic variant.

Epithelioid blue nevus (EBN) is an extremely rare histologic variant of blue nevus that has only recently been identified. Unlike other variants of blue nevus, which primarily are composed of pigmented, spindle-shaped melanocytes, EBN is characterized by large, well-defined, heavily-pigmented polygonal or epithelioid-shaped melanocytes intermixed with less densely pigmented epithelioid- and fusiform-shaped melanocytes. Furthermore, in contrast to other benign melanocytic proliferations, the lesional cells in EBN exhibit little or no maturation as they extend deeper into the underlying tissue. Blue nevi are the second most common form of nevus in the oral cavity. However, to our knowledge, the epithelioid variant has not been previously identified in the mouth. Only 6 examples of EBN have been identified in the skin of the head and neck. We now report the first documented case of EBN involving the oral mucosa. A brief review of the clinical and histopathologic features of EBN is also presented.

Pemphigus: update for the general practitioner.

Pemphigus is a dermatologic disease that can affect both the skin and mucous membranes. Pemphigus affects the oral cavity; the most common form of the disease that is observed clinically is pemphigus vulgaris. Oral lesions may precede skin lesions; therefore, it is imperative that clinicians are aware of the clinical signs and symptoms of this disorder. This article will review the etiology, symptomatology, diagnostic tools, and treatments available to diagnose and manage this disease.

Oral lichen planus. Update for the general practitioner.

There are a variety of dermatologic disorders that commonly present in the oral cavity. Among these is lichen planus which may affect the oral mucous membranes. Dentists need to be familiar with the clinical presentations of this disease. This article will review the common signs and symptoms of oral lichen planus, and will discuss the tools and criteria used to diagnose this disorder. We will also described the modalities available to clinicians to treat this disease.

Burning mouth syndrome. A retrospective analysis of clinical characteristics and treatment outcomes.

Burning mouth syndrome is a condition characterized by burning sensations of the oral cavity in the absence of physical abnormalities of the mucosa or a detectable underlying medical disorder. It is a multifactorial disorder with unclear etiology, affecting predominatly middle-aged women. Multiple approaches to treatment have been described in the literature, with few controlled clinical trials regarding their efficacy. The objectives of this retrospective study were to: 1. determine the epidemiologic characteristics of BMS patients referred to an oral medicine practice; 2. determine if BMS classification correlates with response to treatment; 3. determine the efficacy of a variety of known therapies for BMS. A database was constructed from the charts of 150 consecutive patients diagnosed with BMS; and these charts were reviewed. Patients were classified according to previously published criteria for BMS. Presumed etiologies were grouped into depression/anxiety-associated; hematinic deficiencies, including iron, folate and vitamin B complex; oral habits: and idiopathic BMS. Treatment approaches were divided into seven categories: soft desensitizing appliance; tricyclic antidepressants (TCA); benzodiazepines (BZD); topical analgesics; hematinic supplements; habit awareness counseling; and multi-modal therapy (combining two or more of the above). Improvement was recorded using a zero to 100% VAS scale and classified as no relief (0%); mild (0-40%); meaningful/moderate (41-80%); and profound relief (81-100%). Burning mouth syndrome without any identifiable cause (idiopathic) was diagnosed in 33 patients (46.6%). Patients were followed up at one month (4 weeks) after the initial visit. Nine patients (12.7%) reported profound relief; 17 patients (23.9%) reported meaningful relief; 39 patients (54.9%) reported mild relief. This retrospective review showed no significant correlation between classification of BMS and response to therapy. The most effective treatment modalities were habit awareness, followed by TCAs.