Evaluation of KIR3DL1/KIR3DS1 polymorphism in Behçet's disease.

The Behçet's disease (BD)-associated human leukocyte antigen (HLA) allele, HLA-B*51 (B*51), encodes a ligand for a pair of allelic killer immunoglobulin-like receptors (KIR) present on cytotoxic cells-KIR3DL1, which inhibits their cytotoxicity, and KIR3DS1, which activates their cytotoxic activity. We tested whether KIR-regulated mechanisms contribute to BD by testing for association of KIR3DL1/KIR3DS1 genotypes with disease in 1799 BD patients and 1710 healthy controls from Turkey, as well as in different subsets of individuals with HLA-type-defined ligands for the KIR3D receptors. HLA types were imputed from single nucleotide polymorphism genotypes determined with the Immunochip. The presence of inhibitory KIR3DL1 or activating KIR3DS1 alleles did not differ significantly between cases and controls (KIR3DL1: 92.9% vs 93.4%, Pdominant=0.55; KIR3DS1: 42.7% vs 41.0%, Pdominant=0.29). The KIR3DL1/KIR3DS1 alleles were also present at similar frequencies among cases and controls bearing HLA-B with a Bw4 motif; HLA-B with a Bw4 motif with isoleucine at position 80; and HLA-B*51. Our results suggest that pathogenic mechanisms associated with HLA-B*51 do not primarily involve differential interactions with KIR3DL1 and KIR3DS1 receptors. However, due to the complexity of this locus (that is, sequence variation and copy number variation), we cannot exclude a role for other types of KIR variation in the pathogenesis of BD.

Relation of protein oxidation parameters and disease activity in patients with Behçet's disease.

BACKGROUND: Behçet's disease (BD) is a chronic inflammatory vasculitis characterized by endothelial dysfunction, elevated reactive oxygen species (ROS), and neutrophil hyperfunction production including acute attacks and remission periods. Ischemia modified albumin (IMA), advanced oxidation protein products (AOPP), prooxidants-antioxidants balance (PAB), and ferric reducing antioxidant power (FRAP) were evaluated in regard to their role in the pathogenesis of BD as well as their relation to clinical presentation, uveitis attacks and remission periods, and healthy volunteers. METHODS: The study included 28 BD cases and 27 healthy volunteers as the control group. Blood samples were taken twice from each patient; first during an attack and second about three months after an attack, during remission period. RESULTS: AOPP, IMA and PAB levels were significantly increased in active periods of patients with BD compared with healthy control and remission periods of patients with BD (p < 0.0001, p < 0.0001, p < 0.0001, respectively). FRABP levels were found to be lower in active periods of patients with than healthy controls and remission periods of patients with BD (p < 0.001, p < 0.05, respectively). The AOPP levels were negatively correlated with the levels of FRAB in patients (r = -0.468, p = 0.012; r = -0.394, p = 0.038, respectively). The PAB levels were positively correlated with the levels of CRP in patients (r = -0.606, p = 0.001). CONCLUSIONS: Our results show that these parameters play a major role in the inflammatory reactions observed in BD. Increased levels of IMA and PAB are likely to be a result of inflammation-induced oxidative stress and hence its potential significance as a new marker of oxidative stress in BD.

Frequency of pathergy phenomenon and other features of Behçet's syndrome among patients with inflammatory bowel disease.

OBJECTIVE: Crohn's disease (CD) and ulcerative colitis (UC) share common clinical features with Behçet's syndrome (BS). We surveyed UC and CD patients for pathergy phenomenon and features of BS with the aim of determining how much overlap is present between these 2 entities in a setting where BS is relatively common, the frequency of pathergy positivity in inflammatory bowel disease (IBD) patients and evaluating how International Study Group (ISG) criteria perform in differentiating IBD from BS. METHODS: This study was conducted among patients with CD and UC attending the gastroenterology outpatient clinic of a university hospital which is also a referral center for BS. Consecutive CD and UC patients were screened for BS using ISG criteria. Pathergy test was performed and evaluated by 2 independent observers in a masked manner. RESULTS: Ninety-three patients with CD and 130 with UC were surveyed. None of the CD patients fulfilled ISG criteria for BS while 2 of 130 UC patients did. Twenty CD patients had oral ulcers while 4 reported having genital ulcers but no scars could be observed. Twenty-two CD patients had papulopustular lesions, 2 had nodular lesions, 3 had arthritis and none had uveitis. Thirty-two UC patients had oral ulcers, none had genital ulcers, 23 had papulopustular lesions, 3 had nodular lesions, 2 had arthritis and 2 had uveitis. Pathergy test was positive according to at least one of the observers in 10/93 CD and 8/130 UC patients and according to both observers in 4/130 UC patients. CONCLUSION: Despite similarities between the clinical features of CD and UC with BS, coexistence is uncommon. ISG criteria perform well in differentiating these diseases. About 8% of IBD patients show the pathergy phenomenon.

A double-blind trial of depot corticosteroids in Behçet's syndrome.

OBJECTIVES: Corticosteroids are widely used in Behçet's syndrome despite the absence of controlled studies. We assessed the effect of depot corticosteroids primarily for genital ulcers and secondarily for the other mucocutaneous manifestations of Behçet's syndrome. METHODS: We randomized 86 patients who had active disease with genital ulcers to receive either intramuscular corticosteroid injections (40 mg methylprednisolone acetate) or placebo every 3 weeks for 27 weeks. RESULTS: Seventy-six patients (88%) completed the treatment. There were no significant differences in the mean number of genital and oral ulcers, or folliculitis between groups. The mean number of erythema nodosum lesions was less in the corticosteroid group as a whole (P = 0.0046); subgroup analyses revealed that this was significant for females (P = 0.0148) but not for males (P = 0.1). CONCLUSION: Low-dose depot corticosteroids did not have any beneficial effect on genital ulcers. However, it was useful in controlling erythema nodosum lesions, especially among the females.

A double-blind trial of colchicine in Behçet's syndrome.

OBJECTIVE: Colchicine is a widely used treatment for Behçet's syndrome, even though in a previous 6-month controlled study, it was shown to be effective only in controlling erythema nodosum and arthralgias. We reassessed the effect of colchicine in Behçet's syndrome in a study conducted among a larger group of patients for 2 years. METHODS: We randomized 116 patients with Behçet's syndrome (60 male/56 female), who had active mucocutaneous disease without eye or major organ involvement, to receive either placebo or colchicine (1-2 mg/day, adjusted to body weight) in a double-blind trial for 2 years. The primary outcome measure was the sustained absence of any lesions during treatment (complete response). The secondary outcome measure was the difference in the number of mucocutaneous lesions or arthritic joints between the active drug and placebo arms. Women and men were analyzed separately. RESULTS: Eighty-four patients (72%; 45 male, 39 female) completed the 24-month study. Kaplan-Meier analyses showed significantly more complete responses in the colchicine treatment group in terms of reduced occurrence of genital ulcers (P = 0.004), erythema nodosum (P = 0.004), and arthritis (P = 0.033) among the women, and reduced occurrence of arthritis (P = 0.012) among the men. The mean numbers of genital ulcers (P = 0.001), erythema nodosum lesions (P = 0.002), and arthritic joints (P = 0.014) among the women were less in the colchicine group, and the mean number of arthritic joints (P = 0.026) among the men was less in the colchicine group. Adverse effects were similar in both groups. CONCLUSION: Colchicine may be useful for treating some of the manifestations of Behçet's syndrome, especially among women. This might be a reflection of less severe disease among the women.

A reassessment of the International Study Group criteria for the diagnosis (classification) of Behçet's syndrome.

OBJECTIVE: Patients with ulcerative colitis (UC) and Crohn's disease (CD) were not represented in the diseased controls group that had been utilised in the development of the International Study Group (ISG) criteria for the diagnosis of Behçet's syndrome (BS). Having similar features, both of these conditions can pose problems in the differential diagnosis of BS. Moreover, there has been a recent awareness of coexistence of BS and familial Mediterranean fever (FMF). The aim of this study was to reassess the performance of ISG criteria among patients with BS and other rheumatological conditions, specifically including those with CD, UC, and FMF. METHODS: 302 consecutive patients with BS and 438 patients with other rheumatological conditions were surveyed for the presence or absence of the features of BS by means of a standard form which had been prepared according to ISG criteria. All control patients with a history of oral ulcer had a pathergy test and an eye examination by an experienced ophthalmologist with a slit lamp. The sensitivity and specificity of the ISG criteria were calculated. RESULTS: Seven of 302 patients with BS (2%) did not fulfill the ISG criteria while 5 of 438 controls (1%) fulfilled the ISG criteria. CONCLUSION: In this study ISG criteria performed well in correctly classifying BS. Further specificity studies might be considered in CD.

Anti-MHC autoimmunity in Behçet's disease: T cell responses to an HLA-B-derived peptide cross-reactive with retinal-S antigen in patients with uveitis.

Immune response to retinal autoantigens plays a central role in the pathogenesis of uveitis. A synthetic peptide (B27PD) from a common sequence of various HLA-B molecules associated with uveitis, such as HLA-B27 and 51, which shares amino acid homologies with a retinal-S antigen (S-Ag)-derived peptide (PDSAg), was shown to be immunogenic in human and experimental uveitis in the rat. In this study we investigated T cell responses to B27PD and PDSAg in patients with Behçet's disease and posterior uveitis (BD-posterior uveitis; n = 33) in comparison with non-Behçet anterior uveitis (AU, n = 14), Behçet's patients without uveitis (BD, n = 15) and healthy controls (HC, n = 32) in a 6-day proliferation assay. Patients with BD and posterior uveitis had significantly higher responses (stimulation index (SI) 2.8 +/- 1.3) than those with AU (SI 1.5 +/- 0.4), BD without uveitis (SI 1.1 +/- 0.4) and HC (SI 1.1 +/- 0.6) for B27PD (P < 0.0001). Responses to PDSAg were also higher in BD with posterior uveitis patients (SI 3.3 +/- 1.6) than AU (SI 1.5 +/- 0.4), BD without uveitis (SI 1.2 +/- 0.3) and HC (SI 1.1 +/- 0.6) (P < 0. 0001). A significant correlation between the responses to PDSAg and B27PD (r = 0.56, P < 0.001) was observed. Elevated levels of IL-2 and tumour necrosis factor-alpha were also observed in culture supernatants obtained from peripheral blood mononuclear cells after stimulation with the peptides, but no correlation was found between the proliferative responses and cytokine levels. These results suggest that cellular immunity to cross-reactive HLA-B and S-Ag-derived peptides might play a role in the pathogenesis of posterior uveitis in BD.

Behçet's syndrome. The Cerrahpasa experience. Members of the Behçet's Syndrome Research Centre.

Behçet's syndrome (BS) is a systemic vasculitis of unknown etiology. There are several reasons for doubting a primary autoimmune pathogenesis of this condition. Recent information suggests evidence for genetic anticipation. Although there is heightened inflammatory activity, as exemplified by the pathergy reaction, wound healing in BS is normal. BS also runs a more stormy course in adults and in the young. However, the amount of androgen receptors in scrotal skin have not found to be increased. Another unsolved problem is the nature of acne-like lesions and how they differ from acne vulgaris (AV). Only lesions in "non-acne" areas were compared between the two conditions, and no differences were detected. Mortality is increased in BS, especially among males. Azathioprine proved to be effective in disease control after 8 years of follow-up. We have also recently finished a 24 week controlled trial of two doses of thalidomide, 100 mg and 300 mg per day. Both doses were superior to placebo, with no real differences in efficacy, in controlling the oral and genital ulcers.

The management of Behçet's syndrome.

Behçet's syndrome (BS), originally described as a triad of oral aphthae, genital ulcerations and uveitis, is a systemic vasculitis that is prevalent in the Middle east, Far East and in the Mediterranean basin. It is characterized by a heightened state of inflammation although the main drive that initiates and sustains this is not yet elucidated. Suppression of this inflammatory state constitutes the major goal of treatment and therapy is tailored according to the specific manifestations observed. We now have considerable more insight on drug management of BS compared to 20 years ago. Particularly, within the recent past we have learned to use more rationally the agents that were already available to us. This is especially true for azathioprine, cyclosporin A, thalidomide and colchicine. Promising data are also being collected with alpha-interferon. With these agents, significant progress has been achieved in the management of uveitis and mucocutaneous symptoms but treatment issues related to thrombotic problems, major vessel involvement and neurological disease have not yet been resolved.

Wound healing in Behçet's syndrome.

BACKGROUND: Because there is an increased inflammatory response to trauma, particularly of the skin, in patients with Behçet's syndrome (BS), an alteration in wound healing in BS is expected. The aim of this study was to investigate the healing features of punch biopsy wounds in BS and acne vulgaris (AV) patients used as controls. METHOD: Full-thickness skin punch biopsies (4 mm) were taken from the hairless sites of the non-dominant forearms in 20 BS and 20 AV patients. Each patient was examined on days 1, 2, 3, 4, 5, 8, and 10, and the biopsy wound area and induration were marked on sterile glass slides. Other inflammatory changes, such as suppuration and pain, were also recorded. No antiseptic solutions or ointment, except saline, were used. RESULTS: The wound area healed similarly in both groups (p > 0.05). Thirteen (65%) BS patients had erythematous haloes around the wound on the first day. The number of patients presenting inflammatory changes reached 18 (90%) on the second day in the BS group. The area of erythema around the wound in BS patients was significantly greater than that in AV patients (5; 25%). It gradually decreased day by day. Purulent changes were observed in four BS patients on day 1, and induration around the biopsy wound in six patients on day 2. Only one patient with AV had suppuration, which appeared on the second day, while no AV patient displayed induration. CONCLUSION: Biopsy-induced trauma may cause increased inflammation in BS, but wound healing is not altered.

Thalidomide in the treatment of the mucocutaneous lesions of the Behçet syndrome. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Recurrent oral and genital ulcers are the most frequent problem in the management of the Behçet syndrome. Uncontrolled experience suggests that thalidomide may help prevent recurrences of these ulcers. OBJECTIVE: To determine the efficacy of two thalidomide dosages in the treatment of mucocutaneous lesions of the Behçet syndrome. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Specialist outpatient clinic for the Behçet syndrome in Turkey. PATIENTS: 96 male patients with the Behçet syndrome who primarily had mucocutaneous lesions without major organ involvement. INTERVENTION: Thalidomide, 100 mg/d or 300 mg/d, or placebo for 24 weeks. MEASUREMENTS: Sustained absence of any oral and genital ulceration during treatment (complete response) and changes in the number of mucocutaneous lesions. An additional evaluation was done 4 weeks after treatment ended. RESULTS: A complete response occurred in 2 of the 32 patients (6% [95% CI, 0.8% to 20.8%]) receiving thalidomide, 100 mg/d; in 5 of the 31 patients (16% [CI, 5.5% to 33.7%]) receiving thalidomide, 300 mg/d; and in none of the 32 patients (0% [CI, 0% to 10.9%]) receiving placebo (P = 0.031). The suppressive effect of thalidomide with either dosage was evident at 4 weeks for oral ulcers (P < 0.001) and at 8 weeks for genital ulcers (P < 0.001) and follicular lesions (P = 0.008). This effect persisted during treatment but diminished rapidly after treatment was discontinued. Both thalidomide dosages led to significant increases in the number of erythema nodosum lesions during the first 8 weeks of treatment (P = 0.03). Polyneuropathy developed in 4 patients (1 in the 100-mg/d group and 3 in the 300-mg/d group); in 3 of these patients, the condition was diagnosed after the trial had ended. CONCLUSIONS: Thalidomide is effective for treating the oral and genital ulcers and follicular lesions of the Behçet syndrome. A dosage of 100 mg/d is as effective as a dosage of 300 mg/day.

Azathioprine in Behcet's syndrome: effects on long-term prognosis.

OBJECTIVE: To assess the effect of azathioprine (AZA) treatment on long-term prognosis in Behçet's syndrome. METHODS: Patients (all male) who took part in a double-blind, placebo-controlled trial of AZA a mean +/- SD of 94 +/- 10 months previously were reevaluated. RESULTS: The emergence of blindness (log rank chi2 = 5.6, P = 0.02) and a 2-line drop in the visual acuity of the right eye (log rank chi2 = 5.9, P = 0.015) occurred significantly more frequently among the patients originally allocated to the placebo group compared with patients who originally received AZA, despite posttrial treatment for patients in both groups when needed. There was also a trend toward more frequent occurrence of extraocular complications in the placebo group. The beneficial effect of AZA was especially pronounced among patients who had eye involvement of short duration prior to their entry into the trial. CONCLUSION: Early treatment with AZA tends to favorably affect the long-term prognosis of Behçet's syndrome.

The ten-year mortality in Behçet's syndrome.

We surveyed the 10-yr mortality among 152 Behçet's syndrome (BS) patients who had registered at a BS out-patient clinic and compared it to the expected mortality in the general population. Information on mortality was available in 79% of the study group, among whom six patients (all males) had died. The observed mortality of two patients in the 15-24 yr age bracket was significantly above that expected in the general population. BS is a cause of increased mortality in the young male patients

Systemic interferon alpha 2b treatment in Behçet's syndrome.

OBJECTIVE: To test the efficacy of systemic interferon alpha 2b (IFN alpha 2b) treatment in the mucocutaneous and joint symptoms of Behçet's syndrome. METHODS: The 48-week open, self-controlled trial was conducted in 3 phases. After the pretreatment phase of 16 weeks, 20 patients (8 men, 12 women; mean age 37 +/- 7 years SD) were treated with IFN-alpha 2b at a dose of 5 million units 3 times a week for 6 weeks followed by 5 million units once a week for 10 weeks. The subsequent 16 weeks not taking the medication was the posttreatment phase. RESULTS: Treatment with IFN-alpha 2b significantly reduced the mean number of arthritis attacks (F = 3.48; p < 0.05), their mean duration (F = 3.77; p < 0.05), and the mean erythrocyte sedimentation rate (F = 6.66; p < 0.001). The mean number of mucocutaneous lesions also showed a decrease, but this was not statistically significant. Except for the duration of arthritis, the mean number and frequency of all symptoms tended to return to pretreatment levels in the posttreatment phase. CONCLUSION: This pilot study shows that systemic IFN may be effective in the treatment of arthritis of Behçet's syndrome.

Pulmonary arterial aneurysms in Behçet's syndrome: a report of 24 cases.

Pulmonary arterial involvement is an important complication of Behçet's syndrome (BS). Among 2179 patients with BS, 24 (1.1%) were diagnosed as having pulmonary arterial aneurysms (PAAs). Haemoptysis was the presenting symptom in all but one. All were male. The mean age at the time of the diagnosis of PAA was 30 +/- 11 S.D. yr (range 17-59 yr). Their mean disease duration was 5 +/- 4 yr (range 3 months-16 yr). There was a high prevalence of thrombophlebitis (21/24, 88%). Histopathological examination showed pulmonary vasculitis involving all layers of pulmonary arteries and veins. Twelve patients (50%) died after a mean of 9.5 +/- 11 S.D. months (range 1-36 months) after the onset of haemoptysis. The mean duration of follow-up of the remaining 12 patients was 25.5 +/- 24 S.D. months (range 1-78 months). The treatment consisted mainly of pulsed or oral cyclophosphamide alone or with prednisolone. As is true with other severe manifestations of Behçet's syndrome, PAAs are more common among males. They are associated with a prevalence of thrombophlebitis and there is high mortality despite treatment.

Low dose cyclosporin A versus pulsed cyclophosphamide in Behçet's syndrome: a single masked trial.

A single masked trial of cyclosporin A 5 mg/kg/day versus monthly 1 g intravenous boluses of cyclophosphamide was conducted among 23 patients with Behçet's syndrome and active, potentially reversible uveitis. The trial was unmasked after a mean of 12 (SD 2) months for the cyclosporin A group (n = 12) and a mean of 10 (SD 3) months for the cyclophosphamide group (n = 11). During the initial 6 months the visual acuity significantly improved (p < 0.001) in the cyclosporin A group whereas this was not observed in the cyclophosphamide group. The subsequent follow-up of patients up to 24 months suggested that the initial improvement in visual acuity with cyclosporin A was not sustained. More extensive and especially long-term studies of cyclosporin A in the uveitis of Behçet's syndrome are warranted.