Minor Aphthous Ulcers Research Articles

Intraoral digital imaging documenting recurrent aphthous ulcer healing in 2-octyl cyanoacrylate versus sham-treated lesions

Objective. A device to standardize imaging was coupled with a digital intraoral camera to investigate the efficacy of 2-octyl cyanoacrylate (OC) tissue adhesives on the healing of minor aphthous ulcers. Study design. Forty-two subjects were enrolled in a patient-blinded, sham-controlled study assessing the effects of 2-OC formulations on ulcer size and healing time. Daily images were made until ulcers were healed. Ulcer image outlines were traced by using a mouse, and ulcer areas were automatically calculated. Results. A mean difference of –0.15 mm 2 was seen between baseline and next-day measurements ( P = .48). The cumulative ulcer area was meaningfully reduced in one OC group compared with the sham group ( P = .04). Time to healing was reduced by 1.9 days in the same group compared with the sham group ( P = .02). Conclusions. The use of digital intraoral images with an integrated measurement reference enhances the accuracy and reproducibility of measurements. 2-OC adhesives hold promise as devices to promote healing of recurrent aphthous ulcers. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;89:425-31)

Oral manifestations of HIV infection in a group of predominantly ethnic Chinese.

A total of 32 HIV-infected, predominantly ethnic Chinese individuals from Hong Kong were examined for oral mucosal lesions over a period of 1 year. The commonest oral lesion found was minor aphthous ulceration (27.4%), while xerostomia (17.8%), ulceration NOS (not otherwise specified; 12.3%), hairy leukoplakia (11.0%) and erythematous candidiasis (6.9%) were less frequent; Kaposi's sarcoma was notable for its absence. When the relationship between the number of oral lesions with age, risk group, medication taken, CDC staging and CD4+ count of the study group was investigated, a significantly higher number of oral lesions was associated with use of AZT, homosexuals and CDC stage IV; in contrast, a smaller number of lesions was found in those on antiparasitics and multivitamins (all P<0.05). When compared with studies from other parts of the world, the frequency of oral lesions appeared to be less common in the current study group. However, due to a lack of similar studies from the Asian region, especially in ethnic Chinese, it is not clear whether this difference could be attributed to racial, social or geographic factors.

5% Amlexanox oral paste, a new treatment for recurrent minor aphthous ulcers: II: Pharmacokinetics and demonstration of clinical safety

The safety of 5% Amlexanox paste was demonstrated in the following clinical studies: vehicle-controlled safety and efficacy studies; dermal irritation and sensitization studies; single and multiple dose pharmacokinetic studies; and a 28-day in use safety study. Minimal adverse experiences were observed with the 991 subjects that were exposed to 5% Amlexanox paste. No significant irritation or sensitization was associated with 5% Amlexanox paste. Pharmacokinetic studies indicated that systemic levels of Amlexanox are most likely due to normal gastrointestinal absorption with only limited absorption directly through the ulcer. After a 100 mg dose of 5% Amlexanox paste the average maximum concentration of Amlexanox in the serum was 120 ng/ml, occurring 2.4 hours after application. The half-life for elimination of Amlexanox was 3.5 hours, and there was no evidence of accumulation with multiple applications. Overall, the data indicate that 5% Amlexanox paste (Aphthasol) is safe for the treatment of recurrent minor aphthous ulcers.

5% Amlexanox oral paste, a new treatment for recurrent minor aphthous ulcers: I. Clinical demonstration of acceleration of healing and resolution of pain

5% Amlexanox oral paste (Aphthasol) was studied in four vehicle-controlled, randomized, double-blind, parallel group, multicenter, clinical studies involving 1335 subjects who had 1 to 3 aphthous ulcers less than 48 hours old at enrollment. Subjects applied study pastes directly to ulcers four times a day until ulcers healed or for the duration of the study, whichever occurred first. Ulcer size was measured by the investigator and pain was evaluated by the subject; the primary determinant of efficacy was the percentage of subjects with complete healing of ulcers and complete resolution of ulcer pain. The vehicle had marginal beneficial effects as would be expected from a covering material, but statistical significance over no treatment was inconsistent. However, these studies, both individually and collectively, clearly demonstrated in a highly significant and consistent manner that in comparison to both Vehicle and No Treatment 5% Amlexanox oral paste accelerates the resolution of pain and healing of aphthous ulcers.

Innervation of recurrent aphthous ulcers.

Specimens from nonkeratinized oral mucosa were obtained from diseased and clinically healthy mucosa from 7 patients with minor recurrent aphthous ulcers. The innervation of the specimens was visualized using antibodies to neuron-specific intermediate cytoskeletal neurofilament fiber, the cytoplasmic protein gene product 9.5 and a 38 kDa integral membrane protein of synaptic vesicles applied in avidin-biotin-peroxidase staining. Mapping with these 3 antibodies revealed dense and basically similar pattern of innervation in the specimens of the clinically healthy oral mucosa. In recurrent aphthous ulcers, all 3 general markers disclosed peripheral nerve fibers also in the lesions, apart from the necrotic area, among the inflammatory cells without signs of retraction from the diseased area. Synaptophysin staining suggested that these peripheral nerve fibers in the inflammatory areas still contained synaptic vesicles. Accordingly, they were shown to contain substance P and calcitonin gene-related peptide, which are known to be released upon stimulation of the nerve and can exert potent paracrine actions, possibly on the local inflammatory cells as suggested by a close spatial relationship between neuropeptide-containing nerves and inflammatory cells.

T-lymphocyte subsets in oral mucosa of patients with recurrent aphthous ulceration.

In the present study, the proportion of mononuclear cells and percentages of CD4+ (OKT4+) and CD8+ (OKT8+) were determined in clinically healthy buccal mucosa in patients with recurrent minor aphthous ulceration (RAU) (n = 43) during active and inactive disease as compared with RAU-free controls (n = 15). In lamina propria, the total number of mononuclear cells and subset percentages were determined histologically and immunohistochemically. Mononuclear cell counts in patient specimens were significantly lower than in the control group. CD4+ percentages were not significantly different between controls and patients. CD8+ percentages of the patients were significantly increased during active RAU, but not during inactive RAU as compared with controls. In proportion to the total number of mononuclear cells, CD4+ and CD8+ cell counts per 0.25 mm2 were significantly lower in the patients during both active and inactive disease as compared with controls. Thus, RAU seems characterized by reduced numbers of mononuclear cells, including T-lymphocytopenia in the oral mucosa as such, features that appear more pronounced during active disease than during quiescence.

Hexetidine mouthrinse in the management of minor aphthous ulceration and as an adjunct to oral hygiene

A number of compounds have been used in the management of recurrent oral ulceration, including antimicrobials. This was a double-blind placebo-controlled cross-over study to assess the value of a 0.1% hexetidine mouthwash in the management of minor aphthous ulceration and as an adjunct to oral hygiene. Forty patients with a catalogued history of ulceration took part. Patients were randomly allocated to active/placebo or vice versa order of mouthwashes, which were used as 15 ml volumes three times a day. Treatment periods were 6 weeks with a 3 week washout. During each period patients kept daily records of the number, site, and duration of ulcers, together with pain scores. Plaque and gingivitis were scored at baseline and end of treatment periods. Thirty-eight patients completed the study, with no significant treatment differences between active and placebo rinses on any ulcer parameter. Additionally, the hexetidine rinse provided no significant benefit to oral hygiene or gingival health. However, there was a significant period effect, with considerable ulcer improvements during the second period, irrespective of treatment. In conclusion, the hexetidine rinse appeared to offer no benefits to these patients, but professional supervision of ulcer treatment does appear to result in a worthwhile placebo effect.

Recurrent aphthous stomatitis

Recurrent aphthous stomatitis (RAS), also known as “canker sores,” is one of the most common diseases of the oral mucosa. It is characterized by the recurrent development of one to several discrete, painful ulcers in the mouth, often leading to difficulty in eating, drinking, and talking. RAS is world-wide in distribution and afflicts approximately 20% of the population. This disorder generally begins during adolescence, increases into adulthood, and then decreases with advancing age. Most patients are otherwise healthy. Although self-limited in nature, some individuals experience frequent and severe episodes, so that RAS may be associated with significant morbidity. Two disorders that are potentially related to RAS are “complex aphthosis” (CA) and Behçet's Disease (BD). In CA, recurrent oral and genital ulcers, or almost continuous oral ulcers (more than three), are seen. BD was originally described as the triad of oral ulcers, genital ulcers, and uveitis. However, it is now appreciated that BD is a complex multisystem disease. In both CA and BD, the mucosal ulcers are clinically and histologically indistinguishable from those that occur in RAS. For this reason, it has been suggested that these three processes present a continuum along the same disease spectrum, ranging from RAS, to CA, to BD. RAS has been divided into two forms, minor aphthous ulcers (MiAU), and major aphthous ulcers (MjAU). MiAU and MJAU, as the names imply, differ in the severity and frequency of active episodes. In both cases the clinical presentation of the oral ulcers typically progresses through four stages: premonitory, preulcerative, ulcerative, and healing. Histologic findings in RAS depend on the stage at which the biopsy was performed. Necrosis of individual epithelial cells evolves to more generalized destruction of the epithelial surface. A predominantly mononuclear inflammatory cell infiltrate is present, but vasculitis is not seen. Results of direct immunofluorescence studies have been variable and are generally considered nonspecific. The pathogenesis of RAS is unknown, despite multiple investigative studies. Possible etiologies that have been considered include genetic, nutritional, hormonal, allergic, psychological, traumatic, infectious, and autoimmune. An infectious agent and/or alteration in host immune function are considered most likely. Other disorders that may be associated with oral ulceration, and must be differentiated from RAS, include various infections (herpes simplex virus, coxsackie virus, yeast), mucocutaneous syndromes (erythema multiforme, cicatricial pemphigoid, pemphigus vulgaris, lichen planus), and certain systemic diseases (lupus erythematosus, inflammatory bowel disease, hematologic disorders). Some systemic, as well as topical, medications may also result in the development of RAS-like lesions. Unfortunately, there is currently no cure for RAS and no uniformly effective treatment. However, multiple therapeutic regimens exist that may provide significant symptomatic relief to the individuals with frequently recurrent or severe disease.

Immunomodulation by LongoVital in patients with recurrent aphthous ulceration

LongoVital (LV) (DK. Reg. No. 5178/75) is a herbal based tablet enriched with recommended doses of vitamins. Peripheral lymphocyte subsets: T-helper/CD4 (OKT4+) and T-suppressor/cytotoxic/CD8 (OKT8+) were studied quantitatively in 31 otherwise healthy patients with minor recurrent aphthous ulceration (RAU) during 6 months' daily LV intake in a double-blind, randomized, crossover 1-year study. Fourteen had had LV during the first 6 months (GrA) and 17 LV during the latter 6 months (GrB). OKT4+ percentages increased significantly during the LV period in both groups (P less than 0.05). OKT8+ percentages increased in both groups, however, only significantly in GrA (P less than 0.05). It is concluded that LV acts as an immunostimulator in patients with RAU and that the increase in T-lymphocyte subsets may account for the previously reported benefit of LV in RAU prevention.

The in vitro cytotoxic effect of leukocytes from patients with recurrent aphthous ulceration upon mouse 3T3 fibroblasts.

This study compared the in vitro cytotoxic activity against cultured NIH 3T3 mouse fibroblasts of peripheral blood leukocytes (PBL) from 13 patients with minor recurrent aphthous ulceration (RAU), 5 patients with non-aphthous oral ulceration and 23 age- and sex-matched healthy control subjects. Leukocytes from patients with RAU exerted a significantly greater degree of cytotoxicity towards the 3T3 cells than did those of control subjects. This enhanced cytotoxicity was abrogated by depletion of PBL bearing the CD5 antigen (T-lymphocytes). In contrast, PBL from patients with non-aphthous oral ulceration failed to exert an enhanced cytotoxic activity against 3T3 fibroblasts, when compared to PBL from healthy control subjects. It was concluded that PBL from patients with RAU exert a significantly enhanced cytotoxicity towards an unrelated xenogeneic target cell. This activity is a specific feature of RAU and in the assay system described appears to be mediated by T-lymphocytes.

Spontaneous migration and chemotactic activity of neutrophil polymorphonuclear leukocytes in recurrent aphthous ulceration

Chemotactic activity and spontaneous migration under agarose were assessed for peripheral blood neutrophil polymorphonuclear leukocytes from 22 patients with minor recurrent aphthous ulceration and 22 control subjects. The peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine was used as the standard chemotactic stimulus. Under the conditions of this study, no significant differences in either chemotaxis or spontaneous migration were evident between neutrophils from the patient and control groups.

Absence of circulating IgG immune complexes in minor recurrent aphthous ulceration.

A monoclonal rheumatoid factor binding assay has been employed to detect IgG type immune complexes in sera from 21 patients with minor recurrent aphthous ulceration and 31 control subjects. In only one of the ulcer group patients was there a marginal elevation of immune complexes above the normal range, with no statistically significant difference between the patient and control groups. Assays of intrinsic serum rheumatoid factor and serum IgG, IgM and IgA levels also showed no significant differences between patient and control groups, with all mean values falling within the normal ranges.

DETECTION OF RNA COMPLEMENTARY TO HERPES-SIMPLEX VIRUS IN MONONUCLEAR CELLS FROM PATIENTS WITH BEHÇET'S SYNDROME AND RECURRENT ORAL ULCERS

Viral DNA probes were used in in-situ hybridisation to detect the complementary RNA in mononuclear cells from the blood of normal subjects and patients with Behçet's syndrome and recurrent oral ulcers. Hybridisation of 125I-labelled DNA probes was detected by means of autoradiography and quantitated with a video image-analysis technique. Hybridisation between herpes-simplex virus type 1 (HSV-1) DNA and the complementary RNA in mononuclear cells was significantly greater in 10 of 20 patients with Behçet's syndrome than in controls. Consistently, mononuclear cells from fewer patients showed significant hybridisation with the HSV-2 probe, and the grain counts were also lower. Control DNA probes from adenovirus 2, bacteriophage lambda, and Micrococcus lysodeikticus did not show significant hybridisation. Further separation of the patients into the four types of Behçet's syndrome revealed that mononuclear cells in 8 of 10 patients with the ocular or arthritic types showed significant hybridisation of RNA to the HSV-1 DNA probe, compared with 2 of 10 patients with the mucocutaneous or neurological types. Mononuclear cells from 4 of 8 patients with minor but not major aphthous ulcers also showed significant RNA hybridisation to HSV-1 DNA. The results suggest that at least part of the HSV genome is present and transcribed in peripheral-blood mononuclear cells—probably lymphocytes—of patients with the ocular and arthritic types of Behçet's syndrome and minor aphthous ulcers. The immunopathogenesis of these diseases might therefore be associated with HSV-1.

Salivary immunoglobulin A levels in normal subjects, tobacco smokers, and patients with minor aphthous ulceration

There seems to be no relationship between time of day and SlgA concentration in pooled unstimulated saliva. Such concentrations are more accurately expressed as a range of normal. A selected group of tobacco smokers showed a decrease in SlgA concentrations when compared with a matched control group, and a group of patients with minor aphthous ulcerations showed no deviation from the control range. The significance of the decrease in SlgA concentrations in chronic tobacco smokers is discussed in the light of this being due to an immunosuppressive effect of the combustion products of tobacco and the possibility of the incidence of intraoral neoplastic disease being increased in tobacco smokers by this effect.

Premonitory stages of recurrent aphthous stomatitis. I. Histological and enzyme histochemical investigations.

Biopsy specimens were repeatedly excised from 10 patients with minor and major recurrent aphthous ulcers (RAS). All lesions represented premonitory stages of RAS. The histological and enzyme histochemical investigations were indicative of an early degeneration of individual, suprabasal epithelial cells. The metabolically negative, vacuolated cells were surrounded by cells with normal enzyme activity. No inflammatory reactions were recorded in the connective tissue at this stage. At more advanced stages of the disease the distribution of vacuolated cells within the oral epithelium increased and at the same time an inflammatory reaction in the connective tissue appeared. The vacuolated cells seemed to coalesce and form minor, intraepithelial vesicles. The findings of early intraepithelial degeneration of individual cells in stratum spinosum are compatible with both a viral and an immunological etiology of RAS.

Possibility of a viral etiology in recurrent aphthous ulcers and Behçet's syndrome.

The clinical signs, laboratory data, and histological features of recurrent aphthous ulcers (RAU) and Behçet's syndrome suggest a viral etiology. In fact, there are reports of adenovirus isolations in herpetiform oral ulcers and on the isolation of a filterable agent in sporadic cases of Behçet's syndrome. However, isolation studies on the major and minor aphthous ulcers and more recent studies on Behçet's syndrome have been negative. A review of the literature on the role of viruses and autoimmunity in RAU and Behçet's syndrome is presented. Biopsy specimens of ulcerative lesions were grown in vitro for up to 300 days. Those cultures, along with leukocytes and body fluids, were examined by a variety of techniques for the presence of virus or viral antigens. Although a persistent or latent virus was not detected, these negative studies cannot exclude a viral etiology. In fact, the hypothesis of an infectious and viral etiology is still reasonable.

HLA antigens in recurrent oral ulceration.

Recurrent oral ulceration (ROU) is the most common disease that affects the oral mucosa, and more than 10% of the population may be affected. 1 Much of the recent evidence suggests that ROU is associated with autoimmune responses to oral mucosa or to some cross-reacting antigens. 2-5 This evidence and the frequency of a family history of ROU 6 raised the possibility that susceptibility to ROU may be associated with HLA antigens. A series of 100 patients with ROU was studied, and these patients were subdivided into three groups, according to the following criteria that were published previously 7 : minor aphthous ulcers (MiAU), major aphthous ulcers (MjAU), 8 and herpetiform ulcers (HU). 9 The results were compared with those obtained in 100 unaffected adult controls who gave no history of ROU. Preliminary family studies were performed to explore the possibility that susceptibility to ROU might segregate with HLA haplotypes. Results

Haematological features and differentiation of recurrent oral ulceration

A prospective study was carried out over a period of 4 years to determine the role of anaemia, vitamin B 12 folate or iron deficiency in the pathogenesis of minor, major and herpetiform ulcers. A series of 193 patients with recurrent oral ulceration (ROU) was examined clinically and haematologically and the results were compared with those from 80 patients with other types of oral ulcers, 204 patients with non-ulcerative oral diseases and 100 controls. A small number of patients with ROU were found to be anaemic due to iron deficiency (4·7 per cent), vitamin B 12 deficiency (0·5 per cent) or folate deficiency (2·1 per cent). The low prevalence suggests that anaemia does not play a primary aetiological role in ROU. Subnormal serum iron levels without anaemia (sideropenia) were found in 20 per cent of patients with ROU, but also in 20 per cent of those with other oral ulcers, in 13 per cent with other oral diseases and 5 per cent of the controls. The findings of an increased prevalence of sideropenia in both ROU and in patients with other oral ulcers, a correlation between severity of ulceration and sideropenia and a failure by most patients to respond clinically to iron therapy, suggest that sideropenia is secondary to the oral ulceration. Patients with minor aphthous ulcers did not show an increased prevalence of any haematological deficiency in comparison with controls. In a small number of patients ROU was associated with systemic diseases and iron deficiency or macrocytic anaemia; these ulcers could be distinguished from minor, major and herpetiform ulcers by careful clinical and haematological assessment and are termed pseudominor, pseudo-major and pseudo-herpetiform ulcers.

Immune complexes in Behcet's syndrome and recurrent oral ulceration.

Seventeen patients with Behçet's syndrome, 11 with recurrent oral ulceration, and eight controls were studied in an investigation of the part possibly played by immune complexes in the transition from focal oral ulceration to the multifocal syndrome. Changes in the distribution of C3 within the first peak of Sephadex G200 fractionated plasma were found in nine of the 17 patients with Behçet's syndrome (55%), three of the 11 patients with recurrent oral ulcers, and none of eight controls. These findings provide indirect evidence that immune complexes are found in the plasma of these patients. Immune complexes were more common in patients with the neuro-ocular type of Behçet's syndrome than in those with the mucocutaneous type, and in those with herpetiform ulcers than in those with major or minor aphthous ulcers. Immune complexes were also associated with active disease. These findings support the hypothesis that the formation of immune complexes is an important step in the pathogenesis of Behçet's syndrome.

Herpetiform ulceration

The rationale for the clinical existence of a less commonly found form of recurrent oral ulceration, herpetiform ulceration (HFU), is presented, illustrated by six clinical cases. The clinical and laboratory features that separate it from recurrent herpetic ulceration (RHU) and recurrent minor aphthous ulceration (RAU) are discussed. Although a viral cause has been proposed for this condition, based on the finding of intranuclear bodies, electron microscopic and other laboratory investigations by the authors indicate that there is insufficient evidence at present to confirm this. Since HFU does have a significant number of histologic and immunologic features in common with recurrent aphthous ulceration, it is thought that it should be considered to be a variant of this condition until the true cause of it is revealed.