Major Aphthous Ulcers Research Articles

Association of major aphthous ulcers and nicorandil

Major aphthous ulcers are generally idiopathic but can occasionally be associated with HIV infection, Behcet’s disease, or neutropenia. We report on 16 cases of major aphthous mouth ulcers after use of nicorandil, a cardiovascular drug. The patients (nine men, seven women, median age 78 years [range 64–90]) were treated with nicorandil for angina pectoris (table). The median duration of treatment at the onset of aphthous ulcers was 12 months (range 2–36). 12 patients received 40 mg/day, and four 60 mg/day. In two patients, aphthous ulcers occurred when the dose was increased from 40 mg/day to 60 mg/day. Three patients had occasional minor aphthous stomatitis before treatment by nicorandil. The lesions, one to three in number, were typical painful major aphthous ulcers of more than 1 cm in diameter, and were located on the tongue, gingiva, or cheeks. There were no extraoral signs and laboratory investigations did not show abnormalities, white blood cell, haemoglobin, and platelet counts, erythrocyte sedimentation rates, and kidney and liver functions were normal. Histopathological assessment was done for five patients and showed non-specific ulceration. Viral, bacteriological, and fungal cultures done in three cases were negative. HIV tests done in the first three patients were negative. The median duration of each major aphthous stomatitis was 3 months (range 1–36). In the first six patients, toxic aphthous ulcers were not initially diagnosed and the patients were treated with thalidomide 25–50 mg/day (n=3) or colchicine 1 mg/day (n=3) and nicorandil was continued. Aphthous ulcers healed completely in 10–15 days in all these patients, but relapsed immediately when colchicine and thalidomide were stopped. Ulcers healed completely without scars in all 16 patients 1–3 weeks after nicorandil was discontinued. No patient relapsed during a median follow-up of 12 months (range 1–17). For ethical reasons we did not test rechallenge of nicorandil after the ulcers healed. Before this series, only two isolated cases of major aphthous ulcers induced by nicorandil were reported. Our results suggest a role for nicorandil in the onset of the major aphthous stomatitis since most of these patients had never previously had aphthous ulcers, and idiopathic major aphthous stomatitis generally begin in young patients; no other aetiology of major aphthous ulcers could be detected; the patients received many different drugs but nicorandil was the only drug common to them all; transient improvement was obtained with thalidomide or colchicine, RESEARCH LETTERS

Treatment of aphthous ulcers in AIDS patients.

From 1987 to 1992, 240 acquired immunodeficiency syndrome (AIDS) patients with oral, laryngeal, and pharyngeal ulcers were evaluated. In 180 patients, ulcers resolved in less than 2 weeks without treatment. Of the 60 patients whose ulcers persisted for more than 2 weeks, 24 were culture positive for herpes simplex virus, Cryptococcus organisms, cytomegalovirus, or Mycobacterium organisms and were treated accordingly. The remaining 36 patients were diagnosed as having major aphthous ulcers. The usual sites for these ulcers were the floor of the mouth, tonsillar fossa, and epiglottis. The most common symptoms were pain and weight loss. The patients were treated with intralesional injection with triamcinolone acetonide and examined weekly. Ulcers were reinjected biweekly as needed. Response to treatment was evaluated by pain relief, ulcer healing, and weight gain. All patients reported pain relief within 2 days of initial injection. Most had marked reduction in ulcer size and subsequent weight gain, and many experienced total resolution of symptoms and complete healing.

Oral manifestations associated with HIV-related disease as markers for immune suppression and AIDS

Background. Oral lesions are common findings in HIV-related disease, but little is known about their significance in predicting immune suppression among a representative group of HIV-infected persons. Methods. Oral examinations were performed on 454 patients who came to an outpatient dental clinic for dental care. CD4+ cell counts were obtained within 2 months of the examination. Results. In persons with a specific lesion and a CD4+ cell count below 200 cells/mm 3 the corresponding mean CD4+ cell counts and predictive values were 149.5 cells/mm 3 and 69.9% for candidiasis, 143.3 cells/mm 3 and 70.1% for oral hairy leukoplakia, 126.0 cells/mm 3 and 69.4% for xerostomia, 51.8 cells/mm 3 and 95.1% for necrotizing ulcerative periodontitis, 98.7 cells/mm 3 and 87.0% for long-standing herpes simplex virus infections, 66.6 cells/mm 3 and 93.6% for Kaposi's sarcoma, and 33.7 cells/mm 3 and 100% for major aphthous ulcers. The mean CD4+cell count declined with increased numbers of different concurrent lesions. Conclusion. The presence of specific oral manifestations and the number of different concurrent intraoral lesions among HIV-infected persons are associated with severe immune suppression and AIDS. Oral examinations are an essential component for early recognition of disease progression and comprehensive evaluation of HIV-infected patients.

Major aphthous ulcers in patients with HIV disease

Major aphthous ulcers are associated with a high degree of morbidity in patients infected with human immunodeficiency virus. A large representative cohort intected with human immunodeficiency virus was examined to evaluate the prevalence of major aphthous ulcers, demographic data of patients with major aphthous ulcers, and the usage of major aphthous ulcers as a marker for immune deterioration. The effects of tobacco smoking and the use of specific antibiotics, trimethoprim/sulfamethoxalazole or dapsone, on the development of major aphthous ulcers was also investigated. In a population of 767 persons infected with human immunodeficiency virus, major aphthous ulcers were found at a prevalence rate of 3.1% (24 patients). This type of lesion did not show any predilection for human immunodeficiency virus transmission category, ethnic group, or gender. Persons who received trimethoprim/sulfamethoxalazole or dapsone or had a history of tobacco smoking showed a decreased prevalence of major aphthous ulcers. All patients (100%) with major aphthous ulcers had CD4+ cell counts below 100 cells/mm 3, but only 50% had a previous acquired immunodeficiency syndrome defining illness. Major aphthous ulcers in persons infected with human immunodeficiency virus are suggestive of severe immune suppression and may serve as a marker for human immunodeficiency virus disease progression.

Alternative Therapies For Major Aphthous Ulcers in Aids Patients

treatments for recurrent aphthous ulcers in HIV-infected patients are explored in Alternative Therapies for Major Aphthous Ulcers and AIDS Patients, by Drs. Michael Glick and Brian C. Muzyka. Two alternate therapies for resistant major recurrent aphthous ulcers in patients with significant immune deficiency are presented.

Common lesions of the oral mucosa. A guide to diseases of the lips, cheeks, tongue, and gingivae.

Canker sores and cold sores are common, relatively banal diseases of the oral mucosa and lips, occurring most often in young persons. Some otherwise healthy patients may have a more severe variant, such as major aphthous ulcers, recurring lesions of aphthous stomatitis, or acute herpetic gingivostomatitis. Other patients may present with severe recurrent herpes simplex labialis or chronic oral candidiasis, and in these patients an immunodeficiency state must be considered.

Recurrent aphthous ulcers in association with HIV infection: Diagnosis and treatment

Recurrent aphthous ulcers in patients with HIV infection can cause significant morbidity, which makes successful diagnosis and treatment imperative. We have found that the diagnostic paradigm for recurrent aphthous ulcers in HIV-seronegative patients, which is based on the uclers' clinical appearance, location, absence of other ulcer-causing pathogens or pathogenic processes, and response to therapy, may be successfully applied to recurrent aphthous ulcers in HIV-infected patients. However, one must be alert for ulcers with uncommon causes as well as ulcers with common causes that have atypical clinical appearances that may mimic recurrent aphthous ulcers. The topical glucocorticoids, which are used to treat recurrent aphthous ulcers in HIV-seronegative patients, proved very effective in HIV-infected patients for treatment of herpetiform and minor ulcers and most major ulcers and were without notable side effects. A few severe cases of major recurrent aphthous ulcers required treatment with systemic prednisone, and some side effects were encountered.

Treating Recurrent Aphthous Ulcers in Patients with AIDS

A patient with AIDS had two outbreaks of major aphthous ulcers the first ulceration responded to topical corticosteroid therapy, and the second ulceration required systemic corticosteroid treatment. A patient with AIDS had two outbreaks of major aphthous ulcers the first ulceration responded to topical corticosteroid therapy, and the second ulceration required systemic corticosteroid treatment.

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.

Mechanisms of depressed natural killer cell activity in recurrent aphthous ulcers

Natural killer (NK) cell activity was studied serially in the peripheral blood obtained from 35 patients with recurrent aphthous ulcers (RAU) and from 46 age/sex-matched normal healthy controls. The NK cell activity was assayed by a 4-hr 51Cr release assay using K562 cells as targets. The results showed that the patients in remission (2 weeks of convalescence) had normal NK cell activity compared to that of normal controls. Four stages of evolution (early, exacerbation, postexacerbation, and convalescence) in these patients were further evaluated. Increased NK cell activity in the exacerbation of major aphthous ulcer was noted. In contrast, depressed NK cell activity in postexacerbation and in 1 week of convalescence was found at different effector/target ( E T ) ratios. The depressed NK cell activity was interpreted as temporary and a secondary phenomenon in the immunopathogenesis of this disease. Partial restoration of depressed NK cell activity by adding recombinant interleukin-2 (rIL-2) suggests that other factors are also involved in the process or that IL-2 deficiency exists in RAU patients. However, no deficiency of plasma IL-2 and interferon-γ (IFN-γ) was noted. The percentage of large granular lymphocytes (LGL, NK K ) was correlated with NK cell activity, with both parameters being depressed in the postexacerbation of RAU patients. NK cell activity of RAU patients was still depressed after the depletion of plastic adherent cells. Surprisingly, in contrast to the remission stage, unresponsiveness to rIL-2 of normal NK cell activity in the exacerbation stage was found. The discrepancy was not associated with different subpopulations of NK heterogeneous cells. Immunopathogenesis of RAU on the NK-IFN-IL-2-IL-2R system needs further clarification.

Major aphthous-like ulcers in patients with AIDS

This report describes persistent, painful oral ulcers that occurred in nine patients with the acquired immunodeficiency syndrome (AIDS). These ulcers resembled major aphthous ulcers in clinical appearance and response to therapy. They occurred less frequently in patients with AIDS than those caused by herpes simplex and were found in 4 of 346 (1.1%) patients with AIDS at one medical center. Lesions were typically painful. Identification and treatment with topical tetracycline and steroids led to resolution with relief of symptoms. Further study is necessary to understand the etiology and pathogenesis of these ulcers.

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.

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

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.

Immunoglobulin estimation of blood and saliva in human recurrent oral ulceration

Immunoglobulin estimations by an immunochemical method were performed in serum and saliva of 120 subjects; 70 patients with recurrent oral ulceration, 20 with lichen planus and 30 normal controls. Raised levels of serum IgA and IgG were found in patients with recurrent oral ulcers, as compared with normal controls, but the 5 per cent level of significance was reached only in patients, with major aphthous ulcers. In lichen planus, however, serum IgG concentration was significantly depressed, although IgA was slightly raised. Salivary IgA concentration showed little variation between the controls and patients and depressed IgA clearance was found only in herpetiform ulceration. Although IgG was not detectable by this method in parotid saliva, it was found in almost all samples of whole saliva. Serum IgM was normal in all groups of patients and IgM was not detected in any of the samples of saliva. Recurrent oral ulceration is not associated with immunoglobulin deficiency in serum or saliva. The raised serum IgG and IgA levels are consistent with those found in some autoimmune disorders. Immunoglobulin transport into saliva is discussed.