Adamantiades-Behçet's Disease Research Articles

Adamantiades-Behçet disease: from clinical heterogeneity to diagnosis during the COVID-19 pandemic.

Adamantiades-Behçet disease (ABD) is a systemic disease with vasculitis, characterized by recurrent oral aphthosis and ocular, cutaneous, articular, vascular, cardiopulmonary manifestations and it is mainly found in the territories of the antique "silk road". ABD pathogenesis remains unknown although genetic, infectious and environmental factors seem to be implicated in the development of the disease, which is considered an auto-inflammatory condition. COVID-19 infection can present some symptoms, in particular at the level of oral and pulmonary mucosa, which require a differential diagnosis with ABD. Furthermore, the immunological alterations of this disease, and the drugs used for its treatment could influence the infection by COVID-19, and its clinical evolution. Nevertheless, vaccination anti-COVID-19 is recommended in ABD patients. The most commonly used diagnostic criteria for ABD are those established in 2014 by the International Team for the Revision of the International Criteria for BD (ITR-ICBD). Furthermore, criteria for disease severity according to the Overall Damage Index of Behçet's Syndrome (BODI) have recently been proposed in order to quantify the severity of the disease as well as the evolution during follow-up. In ABD patients it is mandatory to investigate on the presence of active/latent tuberculosis, because of the common organ involvement, such as eyes and bowel. ABD has a high morbidity and low mortality, sometimes linked to the rupture of an arterial aneurysm and/or neurological complications. This article is based on a general review on ABD ranging from the history of ABD to possible causes and clinical manifestations. A specific section has been dedicated to the COVID-19 pandemic.

Adamantiades-Behçet's disease therapy: current treatment options and recommendations with regard to the COVID-19 pandemic.

Adamantiades-Behçet's disease (ABD) is a chronic, idiopathic, relapsing immune-mediate disease that may involve multiple organs. It is characterized by recurrent oral and genital ulcers, skin lesions, ocular, gastrointestinal, vascular, neurological and joint involvement. It can lead to significant morbidity and mortality. Due to its heterogeneity in clinical findings and physiopathology, its treatment can be various as ABD manifestations in different organs may differently respond to the same drug. The cornerstone of therapy for inducing remission is systemic corticosteroid, whereas immunomodulatory and immunosuppressive agents such as colchicine, azathioprine, cyclosporine-A, interferon-alpha, and cyclophosphamide are used as steroid-sparing agents and to prevent relapses. For aggressive, refractory or frequently relapsing cases, tumor necrosis factor (TNF) alpha inhibitors (infliximab, adalimumab, etanercept) have been reported beneficial. Herein, we describe our experience of 7 patients treated with TNF-alpha inhibitors with recommendations regarding treatment choice during the COVID-19 era.

The frequency of arthritis in Adamantiades-Behçet's disease in Greek patients.

Musculoskeletal manifestations are frequent in Adamantiades-Behçet's disease (ABD)but only represent non-specific clinical findings. They have not been included in the two commonly used sets of classification criteria. The occurrence of musculoskeletal manifestations at ABD onset may even delayor obscure the diagnosis; therefore, detailed knowledge of the different musculoskeletal manifestations is essential. Our objective was to describe musculoskeletal signs and their clinical course in Greek ABD patients. We conducted a retrospective cohort study, which included all patients with ABD, who had been examined in our Rheumatology Outpatient Division from 1995 to 2010. The study included 224 ABD patients (140 male, 84 female) that fulfilled the International Criteria for the diagnosis of BD. For statistical analysis, we have used chi-square and Fisher's exact tests. Arthritis as a presenting sign was seen in 10.2% of our patients. During the follow-up period, the frequency of arthritis was 58.4%. Monoarthritis was found in 32.8% and 22.6% of male and female patients, respectively (ns). During the follow-up period, polyarthritis was only occasionally observed in male patients (2.14%). Oligoarthritis was assessed in 20.0% and 41.6% of male and female patients, respectively (P<0.001), and was the only significantly different manifestation between sexes. Musculoskeletal manifestations are common in ABD both at presentation and during the disease course. The most frequent sign is mooarthritis. Oligoarthritis was the only significantly different articular manifestation between sexes (more common in women) in our study group.

Local (topical and intraocular) therapy for ocular Adamantiades−Behçetʼs disease

The purpose of this review is to outline agents currently in use for the local anti-inflammatory therapy of ocular Adamantiades-Behçet's disease (ABD), as well as those in translation from the laboratory to clinical use. Novel formulations and innovative intraocular delivery strategies have been recently applied to treat intraocular inflammation in ABD. ABD is a chronic multisystemic vasculitic disease with the highest prevalence in the Mediterranean basin and in the Eastern region of Asia. Bilateral autoimmune uveitis, oral and genital aphthous and skin lesions are the historically described triad. ABD uveitis is chronic relapsing and often sight-threatening and, according to the actual guidelines, to limit posterior segment involvement and prevent visual impairment high-dose and long-term systemic anti-inflammatory treatment is indicated. Corticosteroids, both topically and systemically, are the most effective treatment in the acute phase. To overcome the well known side-effects of corticosteroids over the long period, steroid-sparing drugs have been systemically administered showing positive results but having limited safety profile. To potentiate the intraocular pharmacological efficacy of these molecules in refractory ABD uveitis and to circumvent the risks of systemic administration, novel topical and intravitreal formulations and innovative delivering systems have been recently developed.

Analysis of diagnostic criteria in adamantiades-behçet disease: A retrospective study

Adamantiades-Behçet's disease (ABD) is a chronic-relapsing, inflammatory and multi-systemic disease. Any organ or system may be involved: ABD presents a great variety of cutaneous and mucosal lesions, ocular manifestations, central and peripheral nervous system abnormalities, joint as well as gastrointestinal involvement. Since clear pathognomonic clinical features and laboratory tests are lacking, the diagnosis of ABD mainly relies on the characteristic clinical features. Several sets of diagnostic criteria have been used. The International Study Group for Behçet Disease (ISGBD) in 1990 formulated a set of criteria to warrant uniformity of both diagnosis and classification. Therefore, in 2006, a new set was proposed by the International Team for the Revision of the International Criteria for Behçet's Disease (ITR-ICBD) not only to uniform the previous criteria but also to establish best accuracy, along with an optimum sensivity and specificity. The aims of this study are both to analyze the clinical features of ABD patients and to validate the ISGBD and ITR-ICDB criteria for the diagnosis of ABD in our cohort.

Behçet's Disease (Adamantiades-Behçet's Disease)

Adamantiades-Behçet's disease (ABD) is characterized by starting with oral aphthous ulceration and developing of the systemic involvements. The pathogenesis of ABD is closely correlated with the genetic factors and the triggering factors which acquire delayed-type hypersensitivity reaction against oral streptococci mediated by IL-12 cytokine family. HLA-B51 is associated in more than 60% of the patients and its restricted CD8+ T cell response is clearly correlated with the target tissues. Bes-1 gene encoded partial S. sanguinis genome which is highly homologous with retinal protein, and 65 kD heat shock protein (Hsp-65) released from streptococci is playing an important role with human Hsp-60 in the pathogenesis of ABD. Although Hsp-65/60 has homologies with the respective T cell epitope, it stimulates peripheral blood mononuclear cells (PBMCs) from ABD patients. On the other hand, some peptides of Hsp-65 were found to reduce IL-8 and IL-12 production from PBMCs of ABD patients in active stage.

The spectrum of mucocutaneous manifestations in Adamantiades‐Behçet’s disease in Greece

This is the largest specific demographic and clinical study performed until now in Greece. To analyse the spectrum of mucocutaneous manifestations in 202 patients with Adamantiades-Behçet's disease (ABD) in Greece. Any mucocutaneous symptom at disease onset and during the follow-up was recorded in a particular questionnaire that included 58 items. All patients fulfilled the International Study Group Criteria for BD. Consecutive patients (130 men and 72 women) were included in this study. Their mean age was 42.03 +/- 12.41 and 44.96 +/- 11.99 years for male and female patients respectively. Pathergy test was positive in 38%, whereas HLA-B5 (51) positivity was evident in 76% of patients. Onset signs: oral aphthous ulcers were found in 64.36%, genital ulcers in 6.93%, skin lesions in 8.91%, erythema nodosum in 7.42% and pseudofolliculitis in 1.5%. One patient had leg ulcers. During the follow-up, oral aphthous ulcers were found in 100%, genital ulcers in 65.4% and in 51.4%, erythema nodosum in 42.9% and in 78.1%, whereas pseudofolliculitis in 57.1% and in 21.9% in men and women respectively. Significant differences pointing to a different course of mucocutaneous disease were found between men and women. The nature and frequency of mucocutaneous manifestations at presentation are important for the diagnosis of ABD, whereas significant differences were found between genders in this Greek patient cohort. Significant differences were also observed when our results were compared with those of four other series, probably explained by genetic and environmental factors.

Ocular involvement in Adamantiades-Behçet’s disease in Berlin, Germany

Epidemiological studies demonstrate a prevalence of Adamantiades-Behçet's disease (ABD) in the range of 0.12-420 per 100,000 inhabitants, with the highest rates in Istanbul, Turkey, and the lowest rates in the USA. Ophthalmological data on the prevalence of ocular involvement are limited for ABD in Germany, because most epidemiological studies are based on rheumatological or dermatological data. Berlin is the city with the highest number of non-native German inhabitants, and its multi-ethnic character renders it uniquely appropriate for epidemiological studies on ABD. We retrospectively analyzed all ABD patients seen in our department since 1982. All patients fulfilled the criteria of the International Study Group for Behçet's Disease. We found 140 patients (63 female, 77 male), with a mean follow-up of 6.4 years (0.5-22 years). The mean age was 23 at the first manifestation and 32 when the full-blown disease was noted. The mean age at onset of ocular involvement was 30. Most of the patients were of Turkish (n = 73) or German (n = 34) origin. Fifty-six percent developed ocular involvement, which was the first manifestation in 8.6% and the second manifestation in 19.3% of cases. More than half the patients developed ocular involvement. The calculated prevalence of ocular involvement in ABD is 1.77/100,000 inhabitants for the municipality of Berlin.

A case of Adamantiades‐Behçet disease with ischemic optic neuritis (posterior optic neuropathy)

Adamantiades-Behçet disease (ABD) may present with cutaneous and ophthalmologic findings. A 29-year old woman complained of fever and general fatigue, along with erythema nodosum and vesiculo-pustular lesions on the legs, acneiform lesions, genital ulcerations and painful oral ulcers. She also complained of reduced visual acuity, visual disturbance and blurred vision in the left eye. Her left visual acuity was 6/20. Light reflex in the left eye was reduced. The relative afferent pupillary defect (RAPD) was positive in the left eye where a central scotoma was present. The vitreous was clear; the optic disc, macula, retina and iris were all normal. Uveitis was not observed. The patient was diagnosed with ischemic optic neuritis (posterior optic neuropathy) with ABD. Histopathological findings taken from a blister on the leg showed subepidermal bulla, dense dermal neutrophil infiltration, and extravasation of erythrocytes, suggesting leukocytoclastic vasculitis. She was treated orally with high-dose corticosteroids (methylprednisolone 500 mg/d) for three days. Her general condition and ophthalmic symptoms resolved completely. Optic neuropathy with ABD is very rare; we know of two previous cases [1, 2] of ABD with ischemic posterior optic neuritis.

Concurrent relapsing central nervous system and ocular involvement in a case of life-threatening Adamantiades-Behçet Disease (ABD)

Adamantiades-Behçet disease (ABD) is characterised by oral and genital ulcerations, skin lesions and ocular manifestations and, rarely, by central nervous system (CNS) involvement. Neuro-Behçet disease (NBD) is categorised to parenchymal or non-parenchymal, while combined CNS disease is rarely reported in the literature. A case of NBD, with severe relapsing ocular and neurological disease of combined pattern is presented. Neurological complications included brainstem manifestations, as well as neurovascular involvement, while ocular involvement consisted of bilateral uveitis and branch retinal vein occlusion. Manifestations responded to corticosteroid plus cyclophosphamide pulse therapy. Maintenance therapy included cyclosporine A, azathioprine and corticosteroids. Case individualities are discussed, focusing on scepticism concerning treatment of NBD relapses in the long term.

Arterial Wave Reflections Are Associated With Left Ventricular Diastolic Dysfunction in Adamantiades-Behçet's Disease

Background Adamantiades-Behçet's disease (ABD) is characterized by systemic vasculitis. We investigated whether aortic distensibility and arterial wave reflections are linked to left ventricular (LV) diastolic dysfunction in ABD. Methods and Results Eighty-two patients and 40 controls with similar atherosclerotic risk factors were examined by applanation tonometry of the radial artery (SphygmoCor) and echocardiography. Augmentation index (AI%) and arrival time (Δt, ms) of reflected arterial waves as well as aortic distensibility (AoD) assessed by echocardiography were estimated. Doppler diastolic abnormalities were defined as proposed by the European Study Group on Diastolic Heart Failure by measurement of E/A ratio, isovolumic relaxation time, deceleration time, and flow propagation velocity. Patients had impaired central augmentation index (CAI), Δt, and AoD compared with controls ( P > .05). After adjusting for age, atherosclerotic risk factors, left ventricular mass, and medication the odds-ratio of AoD and CAI for left ventricular diastolic dysfunction was 0.664 (95%CI 0.449–0.982), P = .04, and 1.073 (95% CI 1.014–1.140), P = .001, respectively. The addition of CAI to the multivariable model including AoD significantly increased the power of the model for prediction of left ventricular diastolic dysfunction (−2 Log likelihood change = 18.8, P for change > .01). Conclusion Augmentation index has a complementary value to aortic distensibility in the assessment of left ventricular diastolic dysfunction in ABD.

HLA-Independent Antibacterial Host Response toward Th1 Immunity Mediated by IL-12: a New Concept for the Pathogenesis of Adamantiades–Behçet's Disease

Yanagihori et al. found an HLA-independent higher frequency of IL-12B promoter polymorphism in Adamantiades-Behçet's disease (ABD) patients than in controls. Stimulation with streptococcal antigens specifically increased expression of patients' peripheral blood mononuclear cells IL-12 p40/p70. The authors provide evidence for an antibacterial host response toward T-helper type 1 immunity mediated by IL-12 in patients with ABD, which is HLA independent.

Adamantiades–Behçet's disease, deep venous thrombosis and anticardiolipin antibodies: report of two cases

Vascular thrombosis was found in different proportions of patients with Adamantiades-Behçet's disease (ABD), depending on the ethnicity of the population under study. Various thrombophilic factors, including the levels of anticardiolipin antibodies (ACA), were investigated for their role in the thrombotic process with conflicting results. The prevalence of ACA varies considerably in different studies, but their presence has not been associated with increased risk for vascular thrombosis. We present two cases with ABD, deep venous thrombosis (DVT) and elevated levels of ACA that fulfil the criteria for both ABD and antiphospholipid syndrome (APS).

Therapeutic effects of gemcitabine on cutaneous manifestations in an Adamantiades-Behçet's disease-like mouse model.

The aim of this work was to study the effects and side effects of gemcitabine (2',2'-difluorodeoxycytidine, dFdC), a pyrimidine synthesis inhibitor, on skin lesions of a herpes simplex virus (HSV)-induced Adamantiades-Behçet's disease (ABD)-like mouse model. For the dose-escalation study, ICR mice were treated intraperitoneally with dFdC over 5 days. For the efficacy study, ICR mice were inoculated with HSV and classified as having ABD according to a revised Japanese classification, and then 18 ABD mice were randomly assigned to placebo, 0.06 or 0.12 microg of dFdC/day over 5 days. Serum levels of interleukin-4 (IL-4), IL-6, IL-10, interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha) were determined using enzyme-linked immunosorbent assay. After application of 3 microg of dFdC over 5 days, alanine aminotransferase increased (P = 0.032), but all other kidney and liver parameters were unchanged. In ABD mice, 5 days of dFdC treatment with 0.06 or 0.12 microg of dFdC/day resulted in a dose-dependent improvement of cutaneous manifestations by more than 60% (P = 0.017). There was no significant change in cytokine levels, and none of the cytokine levels correlated with response to treatment. Moreover, dFdC shows promising effects to improve cutaneous lesions in the HSV-induced ABD-like mouse model. In this animal model, effects of dFdC on the cytokine profile remained inconclusive.

Inhibition of cytokine production by the traditional oriental medicine, ‘Gamcho-Sasim-Tang’ in mitogen-stimulated peripheral blood mononuclear cells from Adamantiades-Behçet's patients

Gamcho-Sasim-Tang (GS-Tang) is a traditional Chinese medication, which has been successfully used in Korea for the treatment of Adamantiades-Behçet's disease (ABD). We investigated the modulation effects of GS-Tang on cytokine production from phytohaemagglutinin-stimulated peripheral blood mononuclear cells of Behçet's patients. ABD is a systemic inflammatory disorder and might involve immune dysfunction. Cytokines involved in the regulation of inflammatory reactions and immune responses may play a role in the pathogenesis of ABD. GS-Tang (1 mg/ml) significantly inhibited the production of proinflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), compared to absence of GS-Tang (by 42.0±6.6% inhibition for TNF-α and 95.9±5.7% for IL-1β, P<0.05). GS-Tang also inhibited the production of IFN-γ, immunoregulatory T helper cell type 1 cytokine, by 80.2±5.3% ( P=0.001). The inhibitory effects of GS-Tang on cytokine production showed dose-dependent manner. Our results suggest that GS-Tang might have anti-inflammatory and immuno-regulatory effects through the cytokine modulation.

The demonstration of serum interleukin-8 and superoxide dismutase in Adamantiades-Behçet's disease.

Serum interleukin-8 (IL-8) production was measured in 43 Adamantiades-Behçet's disease (A-BD) patients and in 46 healthy volunteers using a sandwich enzyme-linked immunosorbent assay (ELISA). The mean serum IL-8 level of the patients (14.6 +/- 3 pg/ml) was significantly higher than that of controls (10.8 +/- 3 pg/ml, P < 0.05). Since IL-8 is known to have proinflammatory properties, it may play some role in the pathogenesis of A-BD. We also investigated the activity of serum superoxide dismutase (SOD) in the 43 patients with A-BD and in the 46 healthy volunteers. Serum SOD activity was markedly increased in the patients with A-BD (13.1 +/- 3%), especially in active A-BD, compared with that in the healthy volunteers (6.7 +/- 3%, P < 0.01). Our results suggest the involvement of IL-8 and SOD in the pathogenesis of A-BD as seen in other inflammatory diseases.

Enhanced Interaction of Patients' Lymphocytes With Human Dermal Microvascular Endothelial Cell Cultures in Active Adamantiades-Behçet Disease

To elucidate the role of lymphocyte/endothelial cell interactions in patients with Adamantiades-Behçet disease (ABD), we studied 16 patients of German and Turkish nationality (aged 18-57 years), all with active ABD, and 12 healthy volunteers (controls) of similar age and nationality. Peripheral blood lymphocytes (PBL) of patients were coincubated with human dermal microvascular endothelial cells (HDMEC) and human keratinocytes (HK) in vitro; interactions of PBL with HDMEC and HK were investigated using an established fluorometric assay. Interactions of patients' PBL with HDMEC, HK, or both were the main outcome measures. A significant increase of fluorescence with increasing PBL/HDMEC ratios was seen in patients and controls (P < .001); patients showed a significantly higher increase of fluorescence at higher PBL/HDMEC ratios (P < .05). The PBL/HK coincubation did not show significant alterations compared with the basal fluorescence signals of HK monolayers alone. Peripheral blood lymphocyte and HDMEC fluorescence values that were more than 2 SDs of controls (defined as positive result of assay) were found in a significantly higher number of patients with 2 or more active symptoms at the time of investigation (83%) compared with patients with only 1 active symptom (10%) (P = .008). Other clinical data did not correlate with the results of the PBL/HDMEC coincubation assay. Our results indicate enhanced in vitro interaction of PBL from patients with ABD with HDMEC, which was additionally shown to be a marker of the activity of the disease.