Complex aphthosis and Behçet's disease

Complex aphthosis is a disorder in which patients develop recurrent oral and genital aphthous ulcers or almost constant, multiple oral aphthae, without manifestations of systemic disease. Beh?et's disease is a multisystem disease characterized clinically by oral and genital aphthae, arthritis, cutaneous lesions, and ocular, gastrointestinal, and neurologic manifestations. This article reviews both disorders, including their clinical and histologic presentations, factors in pathogenesis, and includes an overview of therapeutic modalities.     

Complex aphthosis: A forme fruste of Behçet's syndrome?

The evaluation of the rare patient who presents with oral and genital aphthae or almost constant, multiple (greater than 3) oral aphthae, but no systemic signs or symptoms (i.e., complex aphthosis), is difficult because no laboratory test is available to exclude Beh?et's syndrome. Six patients with complex aphthosis were evaluated. In addition, patients with simple aphthosis, those with seronegative arthritis, and normal controls were assessed for circulating immune complexes (CIC) by in vitro and in vivo assays and for neutrophil migration by subagarose methods, since these tests have given significant results in patients with Beh?et's syndrome. Patient 1, with complex aphthosis, had Raji cell evidence for CIC (51.2 mg aggregated human gamma globulin Eq/ml), C1q, and C3 in dermal blood vessels 4 hours post intradermal histamine injection and had a Sweet's syndrome-like vasculitis 24 hours post histamine injection. In addition, her serum enhanced the migration of patient neutrophils (3.6 +/- 0.6 to 4.6 +/- 0.5; N = 6, p less than or equal to 0.01). All other test and control patients had negative or normal CIC and neutrophil migration determinations. Sixteen-month clinical follow-up has confirmed that Patient 1, but not Patients 2 to 6, has developed overt manifestations of Beh?et's syndrome.     

Therapy of recurrent oral aphthae with thymopoetin pentapeptide

Five patients suffering from recurrent oral aphthae and one patient with Beh?et's disease were treated with thymopoetin pentapeptide injections for 6 weeks. Although some immune parameters showed a tendency toward normalization no clinical improvement was observed.     

Clinical aspects and treatment of recurrent aphthous ulcers

Recurrent aphthous ulcers are the most common inflammatory lesions of the oral mucosa, occurring in up to 10% of the population and even more common in children. The history, morphological characteristics, predilection sides and typical stages of aphthae help to distinguish them from other diseases that may exhibit aphthous-like lesions. Underlying diseases should be excluded. The main goals of therapy are to minimize pain and functional disabilities as well as decrease frequency and severity of recurrences. Topical symptomatic relief is the standard of care for simple cases of recurrent aphthosis. In cases of major aphthosis or systemic involvement, topical therapies are still useful but should be combined with systemic therapy, such as colchicine, pentoxifylline or prednisolone. In case of Adamantiades-Beh?et disease, systemic immunomodulatory drugs can inhibit the development of new lesions. This overview summarizes morphological and presentation forms of aphthae, differential diagnoses and evidence-based therapeutic possibilities.     

Neutrophilic eccrine hidradenitis in a patient with Behçet's disease

Patients with Beh?et's disease may develop multiple mucocutaneous manifestations, several of which are mediated by neutrophils. These include aphthous ulcers, pseudofolliculitis, acneform lesions, and pathergy. We report another neutrophil-mediated disorder, neutrophilic eccrine hidradenitis (NEH), in a patient with Beh?et's disease. NEH should be added to the list of mucocutaneous lesions that may be seen in patients with Beh?et's disease.     

Direct immunofluorescence in recurrent aphthous ulcers and Beh?et's disease

Direct immunofluorescence (IF) investigations in oral aphthae were performed in 17 patients with recurrent aphthous ulcers (RAU) and in 9 patients with Beh?et's disease (BD). In addition, cutaneous hyperreactivity lesions from 2 BD patients were examined. The results were compared to direct IF findings in 28 patients with nonaphthous oral diseases. There was no difference between direct IF on oral aphthae in RAU compared to BD. Deposition of C3 in vessel walls of the subepithelial connective tissue was observed in 13 of 17 patients with RAU and in all patients with BD. IgM deposits in vessel walls were found in 5 RAU and 3 BD patients. Deposition of C1q or C4 was not present. By contrast, IgG and/or IgM, C1q, C3 and C4 were detected in dermal vessel walls of skin hyperreactivity lesions from 2 BD patients. This finding is considered to be a true immune complex vasculitis. Compared to nonaphthous oral lesions, oral aphthae of BD and RAU were characterized by C3 deposition in the subepithelial vessel walls.     

The pathogenesis of lesions in Beh?et's disease.

Current concepts incriminate a cell-mediated mechanism in the pathogenesis of mucocutaneous lesions of Beh?et's disease. However, such a mechanism alone fails to explain various aspects of hyperreactivity response which is a unique feature manifested with lesions similar to those occurring spontaneously in the disease. 19 patients with active Beh?et's disease have been investigated for possible mechanisms other than cell mediated which may be involved in the process. Beside cell-mediated mechanisms there were indications that polymorphonuclear leucocytes and mast cells may play part in the process. Further study of these two aspects may open a new approach in the understanding and possibly in the treatment of this disease.     

Colchicine and benzathine penicillin in the treatment of Behçet disease: a case comparative study

Beh?et disease is a chronic relapsing disease characterized by multiple signs and symptoms such as recurrent orogenital ulceration, eye involvement, skin manifestations, and other systemic involvement. Multiple therapeutic modalities have been used to treat Beh?et disease. These agents act through different mechanisms and are associated with a variety of side effects. We performed a case-comparative study to evaluate efficacy of combined colchicine and benzathine penicillin in the treatment and prophylaxis of Beh?et disease. Sixty-six patients who fulfilled the international study group criteria for diagnosis of Beh?et disease were included. The patients were divided into three groups: group 1 (20 patients) received 1.2 Mu benzathine penicillin injection monthly; group 2 (21 patients) received two tablets of colchicine daily (each tablet contained 0.5 mg); and group 3 (25 patients) received both 1.2 Mu benzathine penicillin injection monthly and two tablets of colchicine daily. Each patient was followed up monthly for 5 months, 4 months on treatment and 1 additional month followup. The clinical manifestation index (CMI), the numerical sum of the clinical features, was calculated for each patient initially and then monthly. Pathergy test was performed for each patient monthly. The CMI was reduced by colchicine and benzathine penicillin treatment, and the reduction was highly significant. The reduction in the CMI remains satisfactory and good for 1 month after stopping the treatment. When each colchicine and benzathine Penicillin are used alone the index is also reduced significantly, but this reduction is much less than when both drugs are used together and there is also rapid and earlier relapse. Based on our findings, the combination of colchicine and benzathine penicillin appears to be of greater efficacy in the treatment of Beh?et disease than the use of either drug alone.     

Current therapy in Behcet's disease

Beh?et's disease is an inflammatory disorder of unknown cause. There is often involvement of the gastrointestinal system, the central nervous system and large vessels, which can be life-threatening. As well, ocular lesions can cause blindness. Mucocutaneous symptoms are self-limiting but more frequent. Almost all the patients have recurrent oral aphthous ulcers, and more than 70% of the patients have genital ulcers and skin symptoms, which include erythema nodosum, pseudofolliculitis, papulopustular lesions, acneiform nodules and a positive pathergy test. The pathergy test is felt to reflect cutaneous hypersensitivity. In general, topical treatment using corticosteroids is satisfactory for these mucocutaneous lesions unless eye and vital organs are involved.     

Behçet''s Disease

Beh?et's disease is a multisystem disease featuring mucocutaneous, ocular, intestinal, articular, vascular, urogenital, and neurologic involvement. While classically intermittent in its manifestations, the disease can stabilize and become chronic in a given organ system. The diagnosis of Beh?et's disease is based on clinical criteria. Recurrent aphthous ulcerations in the mouth, skin lesions, eye lesions, and genital ulcerations must be present during the course of the disease for a diagnosis of Beh?et's disease to be made unequivocally. A nonspecific skin hyperreactivity called pathergy is said to be helpful in the diagnosis. There are no pathognomonic laboratory findings, but biopsy usually shows a venulitis. The pathogenesis of the disease is unknown. No virus has been satisfactorily isolated to date. There is evidence of an increased frequency of HLA-B5 and HLA-B12. Humoral and cellular immunity seem to play a major part in the pathogenesis of the various manifestations of the disease. The treatment of Beh?et's disease is difficult to evaluate because of the many spontaneous exacerbations and remissions during the clinical course of the disease. Topical corticosteroids for orogenital ulcers and ocular inflammation are helpful. Intralesional injections for affected joints and retrobulbar tissues are useful in some cases. Systemic corticosteroids have appeared to be helpful for all manifestations of the disease. It is customary to use 60 mg of prednisone by mouth daily during acute exacerbations, then to taper as the condition improves. Chlorambucil has been shown to be safe and effective for various manifestations of Beh?et's disease; often it is used in combination with corticosteroids.(ABSTRACT TRUNCATED AT 250 WORDS)     

Behçet disease

Beh?et's disease is a multisystem inflammatory disorder of unknown origin, characterized by recurrent oral and genital ulcerations, ocular and cutaneous lesions, arthritis, central nervous system, and vascular disease. There is no pathognomonic laboratory test, but there are clinical criteria to assist in establishing the diagnosis. Beh?et's is most common along the Silk Road. It is particularly common among persons who have the HLA-B51 major histocompatibility type. Cutaneous lesions include pustules, erythema nodosum-like lesions, Sweet's-like lesions, pyoderma gangrenosum-ike lesions, and pathergy. The major cutaneous findings may be classified as neutrophilic vascular reactions. There is considerable morbidity resulting from Beh?et's disease, most notably a high risk of blindness from ocular involvement. Mortality may occur as a result of neurologic or vascular disease or gastrointestinal perforation.     

Beh?et's disease and complex aphthosis

Beh?et's disease is a complex disorder that causes considerable morbidity and occasional mortality. Increasing understanding of the pathogenesis of this disorder will, we hope, lead to better treatment modalities. Patients with complex aphthosis, a recently described entity, appear to be at risk for development of Beh?et's disease and require close observation.     

Behçet's disease

A 29-year-old man presented with oral and genital ulcers, erythematous papules and pustules on his back and chest, and deep vein thrombi. A diagnosis of Beh?et disease was made. Beh?et disease is a relapsing disorder that affects the mucocutaneous surfaces. It presents usually as ulcers on the orogenital mucosae, but can also present as an acneiform eruption. The International Study Group on Beh?et disease has established criteria that consist of oral and genital lesions, ocular involvement, skin findings, and a pathergy. Treatment of choice is colchicine or prednisone.     

Nicotine and biochanin A, but not cigarette smoke, induce anti-inflammatory effects on keratinocytes and endothelial cells in patients with Behçet's disease

During periods of smoking, patients with Beh?et's disease have less oral aphthae than in abstinence. To elucidate this observation, human keratinocytes and dermal microvascular endothelial cells (HMEC-1) were incubated with serum of 20 patients with Beh?et's disease and 20 healthy controls for 4 hours. Maximum non-toxic concentrations were determined and the cells were further treated with 6 microM nicotine, 3.3% cigarette smoke extract (CES), 100 microM biochanin A, and 6.25/12.5 microM pyrrolidine dithiocarbamate alone and in combinations for 24 hours. Serum IL-8 levels of patients were significantly lower than those of controls. However, after 4 hours incubation with patients' sera, IL-8 release by both cell types was markedly increased when compared with the corresponding serum levels. The levels of IL-6 and vascular endothelial growth factor (VEGF) release were after 4 hours similar with the corresponding levels in serum. IL-1 was not detected. Nicotine significantly decreased IL-8 and -6 release by HMEC-1 maintained in both patients' and controls' sera, but only IL-6 release by keratinocytes maintained in patients' sera. VEGF release by both cells was markedly increased after nicotine treatment in either serum. CES significantly decreased IL-8 release and increased production of VEGF in keratinocytes maintained in patients' serum. The phytoestrogen biochanin A alone and in combination with nicotine further decreased the secretion of IL-8, -6, and VEGF in all experimental settings. Our data support a specific anti-inflammatory effect of nicotine on keratinocytes and endothelial cells maintained in the serum of patients with Beh?et's disease. Moreover, biochanin A is likely to exhibit similar and even more profound results than nicotine.     

HLA typing in patients of German origin with recurrent benign aphthosis and Beh?et's disease

HLA-pattern was analysed in 60 patients with recurrent benign aphthosis (RBA), in another 14 suffering from Beh?et's disease (BD) and in 200 healthy individuals, all of German origin. High prevalence rates of HLA-A2, HLA-B5 and HLA-Cw3 haplotypes were found in patients with RBA, yet significant only for HLA-Cw3 (p = 0.01). HLA-B5 was shown in none but two German patients with BD. These results are discussed with particular regard to reports on racial differences of HLA-patterns in the populations of several continents including patients with aphthous disorders.     

Recurrent aphthous stomatitis: treatment with colchicine. An open trial of 54 cases

INTRODUCTION: Colchicine is a treatment used for aphthous stomatitis but its efficacy has never been proved. We report the results of an open trial of 54 patients treated with colchicine for aphthous stomatitis. The aim of our study was to assess the long and short term efficacy and tolerance of this molecule in this disease. PATIENTS AND METHODS: The case reports of 64 patients presenting with severe, recurrent aphthous stomatitis treated with colchicine between 1986 and 2000 were analyzed retrospectively. Only immunocompetent patients exhibiting idiopathic aphthous stomatitis or Beh?et's disease were included. Ten patients were excluded: 4 cases of Beh?et's disease treated with colchicine and systemic corticosteroids, 4 cases of aphthous stomatitis secondary to a hematological cause and 2 patients who were lost to follow-up after 3 month's treatment. Colchicine was prescribed at a dose of 1 to 1.5 mg/d for at least 3 months. All the patients were assessed after 3 month's treatment and all were contacted by phone in May 2000. Our end-point criteria were: the frequency and duration of the episodes, intensity of pain and impact on the quality of life of the patients. RESULTS: Fifty-four patients were included: 39 women (mean age=44 +/- 16.8) and 15 men (mean age=49 +/- 13.5). The disease had progressed for a mean of 11.6 +/- 13.5 years. After 3 month's treatment, 12 patients (22 p. 100) no longer had aphta and were in complete remission, 22 patients (41 p. 100) were significantly improved, since the frequency and duration of the lesions had decreased by at least 50 p. 100 and the latter were no longer painful. Treatment failed or tolerance was poor in 20 patients (37 p. 100). Patients were monitored and assessed for a mean of 4.7 years (range: 6 months to 13 years). Six patients were lost to follow-up. Three patients (6 p. 100) were considered as cured, since they were still in complete remission after suspension of colchicine respectively 6, 24 and 72 months later. Fifteen patients (31 p. 100) had still improved. Among the latter, 10 continued colchicine for a mean of 27 months, and 5 patients stopped treatment, which they considered tedious, after a mean of 16 months. These 15 patients noted a significant reduction in the frequency and duration of the lesions. Moreover, the subjective end-point criteria had improved significantly for them not to wish to change treatment. Thirty patients (63 p. 100) were not improved by the treatment. Some benign adverse events were noted in 10 patients (18.5 p. 100) and led to suspension of treatment in 4 cases. DISCUSSION: This study, which is the first in size (n=54) and duration of follow-up (4.7 years), showed that colchicine is an efficient preventive treatment of severe aphthous stomatitis for 63 p. 100 of patients after 3 month's treatment and that this improvement was lasting in 37 p. 100 of them. Colchicine should therefore be proposed in first intention in severe recurrent aphthous stomatitis, since it is effective, well tolerated and easy to use.     

Review of the chronology of clinical manifestations in 60 patients with Behçet's disease

BACKGROUND: The natural course of Beh?et's disease is not fully known. OBJECTIVE: The aim of the present study was to determine the occurrence of the symptoms retrospectively in chronologic order in patients with Beh?et's disease, diagnosed according to the criteria of the International Study Group for Beh?et's Disease. METHODS: A total of 60 consecutive patients (29 male and 31 female; aged 35.87 +/- 9.84 years) were involved in the study. The symptoms of the disease were retrospectively recorded in the time order of the manifestations per patient. RESULTS: Oral ulcer was the most commonly observed onset manifestation (51 of 60 patients: 85%), followed by genital ulcer (13 of 60 patients: 21.7%) and articular symptoms (10 of 60 patients: 16.7%). The duration between the oral ulcer and the fulfillment of diagnostic criteria was calculated to be 3.77 +/- 4.43 years. The same duration was 2.50 +/- 4.74 and 2.11 +/- 3.44 years for genital ulcer and articular symptoms, respectively. The duration between the time point of fulfillment of diagnostic criteria and the diagnosis (2.83 +/- 2.3 years) was found to be longer in female patients (3.2 +/- 2.5 years). The duration was also longer in patients having only mucocutaneous lesions (3.18 +/- 2.5 years) than in patients having serious organ involvement such as eye disease (1.63 +/- 0.7 years; p < 0.05). CONCLUSION: Our study indicates that oral ulcer is the onset manifestation in the majority of the patients and the disease is often diagnosed with a delay of several years after the appearance of the onset sign.     

Diagnosis and management of vulvar ulcers

The diagnosis and management of the following non-infectious vulvar ulcers are reviewed: vulvar aphthae in adult and pediatric patients, aphthae associated with Beh?et's disease, vulvar ulcers resulting from Crohn's disease, and vulvar ulcers associated with human immunodeficiency virus infection. There are many resources providing excellent reviews of infectious ulcers; therefore this topic will not be covered here.     

Mycophenolate mofetil is ineffective in the treatment of mucocutaneous Adamantiades-Beh?et's disease.

BACKGROUND: Cyclosporine A and azathioprine are effective on mucocutaneous lesions in Adamantiades-Beh?et's disease. Mycophenolate mofetil (MMF) is a drug resembling their activity but with comparably negligible adverse reactions. OBJECTIVE: A prospective clinical proof-of-principle study was conducted to investigate the effectiveness and toxicity of MMF in mucocutaneous Adamantiades-Beh?et's disease. METHODS: Thirty patients were to be treated with MMF 2 g/day p.o. for 6 months, in combination with prednisolone 30 mg/day p.o. during the first month of treatment. Inefficacy was followed by an increase in MMF dose to 3 g/day. The primary efficacy variable was the decrease in the disease activity index (DAI) according to a modified variant of the Iran Beh?et's Disease Dynamic Activity Measure system. RESULTS: The study was interrupted due to inefficacy of the compound after the intermediate evaluation of the first 6 patients (aged 37.0 +/- 7.7 years with disease duration of 10.0 +/- 8.9 years) as required by the ethical committee. Although an improvement of the DAI from 5.2 +/- 3.5 to 1.3 +/- 0.5 was found after the first month of combination treatment, withdrawal of prednisolone led to quick relapses with a new index increase (3.0 +/- 3.5). The treatment was discontinued in 3 patients after 3 months, in 2 patients after 4 months and in another one after 5 months due to deterioration of the disease. Introduction of interferon alpha(2a) (3 x 9 million IU 3x/week s.c.) in 3 patients decreased the activity index from 4.0 +/- 1.0 to 0.0 +/- 0.0. No adverse effects were detected under MMF treatment. CONCLUSION: MMF (2-3 g/day) is unable to control the signs of mucocutaneous Adamantiades-Beh?et's disease.     

Comparative analysis of severe aphthosis and Beh?et's disease: 104 cases.

BACKGROUND: The nosologic field of aphthosis is not well defined. While criteria for Beh?et's disease (BD) are lacking in severe unipolar or bipolar aphthosis, these disorders however lead to an important impairment of quality of life. The aim of this study was to assess the relationship between severe aphthosis and BD. METHODS: Records of all patients hospitalized for aphthosis or BD during a 20-year period were reviewed. RESULTS: According to clinical data, cases (n = 104) were classified as unipolar aphthosis (group I, n = 53), bipolar aphthosis (group II, n = 30) or BD (group III, n = 21). The characteristics of aphthae (number, localization, recurrences, presence of scars) were similar in all groups. Specific cutaneous manifestations (erythema nodosum, pseudofolliculitis, papulonodules) were present in 15, 17 and 95% of patients of groups I, II and III. Cutaneous puncture hypersensitivity was present in 14 out of 18 patients of group III and no patient of the two other groups. At least one extramucous specific manifestation (cutaneous, ophthalmologic, neurologic, articular, vascular) was present in 43% of patients of group I and II, and 100% in group III. CONCLUSION: These data support the hypothesis of a continuous spectrum linking severe aphthosis to BD.