Izzet Fresko

The long-term mortality and morbidity of Behçet syndrome: a 2-decade outcome survey of 387 patients followed at a dedicated center.

We surveyed the 20-year outcome of a cohort of patients with Behçet syndrome with emphasis on both mortality and morbidity. During 1999 and 2000, we collected outcome information on 387/428 (90.4%) of a cohort of patients (262 male, 125 female) who had registered in a dedicated outpatient clinic between July 1977 and December 1983. In 245/345 (71.0%) patients, outcome information was based on a formal hospital reevaluation, and in the remaining patients, on detailed telephone interviews.Forty-two patients (9.8%) (39 male, 3 female) had died, mainly due to major vessel disease and neurologic involvement. Mortality, as measured by standardized mortality ratios (SMR), was specifically increased among young males, among whom morbidity was also the highest. However, the SMR tended to decrease significantly with the passage of time. The same was also true for all mucocutaneous and articular manifestations. Both the onset of eye disease and its greatest damage were also usually within the first few years of disease onset. These suggest that the “disease burden” of Behçet syndrome is usually confined to the early years of its course, and in many patients the syndrome “burns out.” However, central nervous system involvement and major vessel disease are exceptions. They can have their onset late (5–10 yr) during the disease course. As reflected in the mortality figures, the disease was less severe among the females for almost each disease manifestation. There were no female patients with arterial aneurysms.Severely impaired vision did not always mean an eventual loss of useful vision, and those patients with a late onset of eye disease had a better visual prognosis.

Identification of multiple genetic susceptibility loci in Takayasu arteritis

Takayasu arteritis is a rare inflammatory disease of large arteries. The etiology of Takayasu arteritis remains poorly understood, but genetic contribution to the disease pathogenesis is supported by the genetic association with HLA-B*52. We genotyped ~200,000 genetic variants in two ethnically divergent Takayasu arteritis cohorts from Turkey and North America by using a custom-designed genotyping platform (Immunochip). Additional genetic variants and the classical HLA alleles were imputed and analyzed. We identified and confirmed two independent susceptibility loci within the HLA region (r(2) < 0.2): HLA-B/MICA (rs12524487, OR = 3.29, p = 5.57 × 10(-16)) and HLA-DQB1/HLA-DRB1 (rs113452171, OR = 2.34, p = 3.74 × 10(-9); and rs189754752, OR = 2.47, p = 4.22 × 10(-9)). In addition, we identified and confirmed a genetic association between Takayasu arteritis and the FCGR2A/FCGR3A locus on chromosome 1 (rs10919543, OR = 1.81, p = 5.89 × 10(-12)). The risk allele in this locus results in increased mRNA expression of FCGR2A. We also established the genetic association between IL12B and Takayasu arteritis (rs56167332, OR = 1.54, p = 2.18 × 10(-8)).

Genetic anticipation in Behçet’s syndrome

OBJECTIVE To examine the presence of genetic anticipation in families with Behçet’s syndrome (BS). METHODS A total of 18 families with 40 affected members in two successive generations were evaluated by interviewing them for their ages at the onset of the first symptom of BS and for their ages at the time they fulfilled the diagnostic criteria. RESULTS It was noted that the age of onset of the first symptom was lower in the second generation in 14 families (p=0.01) with a mean (SD) age of 20.57 (7.47) years in the children compared with 33.29 (9.92) years in the parents (t=7.79, p<0.0001), whereas the diagnostic criteria were fulfilled at an earlier age in the children in 15 families (p=0.01) with a mean age of 21.2 (6.74) years in the children compared with 36.4 (9.55) years in the parents (t=7.41, p<0.0001). CONCLUSION Genetic anticipation was present in 15 of 18 (84%) of the families with BS in the form of earlier disease onset in the children compared with their parents.

Increased enthesopathy among Behçet's syndrome patients with acne and arthritis: An ultrasonography study

OBJECTIVE Behçets syndrome is characterized by clusters of disease expression, one of which is the coexistence of acne and arthritis. The aim of this study was to test the hypothesis that enthesopathy is increased in this cluster, having features reminiscent of acne-associated arthritis. METHODS The study group comprised 35 patients with Behçets syndrome who had acne and arthritis (BS-AA), 38 patients with Behçets syndrome who did not have arthritis (BS-WA), 37 patients with ankylosing spondylitis (AS), 25 patients with rheumatoid arthritis (RA), and 25 healthy control subjects. Five entheseal sites (the superior and inferior poles of the patella, the tibial tuberosity, and the superior and inferior poles of the calcaneus) on both lower extremities were examined by 2 independent observers, using ultrasonography. A previously validated composite score was calculated for each patient. The numbers of entheseal sites giving a positive power Doppler signal in each group were also compared. RESULTS Patients with AS had the highest enthesopathy score (mean +/- SD 4.1 +/- 2.4; F [4df] = 8.43, P < 0.001) followed by BS-AA patients (3.0 +/- 1.9; F [3df] = 3.63, P = 0.015). The mean +/- SD enthesopathy scores among the remaining 3 groups were similar (for BS-WA, 1.8 +/- 1.4; for RA, 2.2 +/- 1.6; for healthy controls, 2.0 +/- 1.5 [F (2df) = 0.65, P = 0.53]). Power Doppler scores were highest for the BS-AA group (mean +/- SD 3.0 +/- 1.5; F [4df] = 15.54, P < 0.001) followed by the AS group (2.7 +/- 1.8; F [3df] = 14.38, P < 0.001), the RA group (2.6 +/- 1.8; F [2df] = 13.88, P < 0.001), the BS-WA group (1.2 +/- 1.3; F [1df] = 4.48, P = 0.038), and the control group (0.5 +/- 1.1). There was 87% agreement between the 2 observers (kappa = 0.55, intraclass correlation coefficient 0.71). CONCLUSION The increased presence of enthesopathy among BS-AA patients compared with that among BS-WA patients further supports the hypothesis that patients with Behçets syndrome who also have arthritis and acne form a distinct cluster.

Atherosclerosis in Behçet's Syndrome

OBJECTIVES We had the impression and preliminary evidence that atherosclerosis was not much increased in Behçets syndrome (BS). Thus, we evaluated the presence of subclinical atherosclerosis in a sizeable group of patients with BS both with major organ involvement and mucocutaneous disease along with diseased and healthy controls. METHODS We studied 239 (162 M/ 77 F; mean age: 40.7+/-7.0) patients with BS. Seventy-two (32 M/ 40 F) had only mucocutaneous and/or joint disease and 167 (130 M/ 37 F) had major organ involvement. Also 100 (24 M/ 76 F; mean age: 44.7+/-7.1) patients with rheumatoid arthritis (RA), 74 (58 M/ 16 F; mean age: 39.4+/-7.0) patients with ankylosing spondylitis (AS) and 156 (83 M/ 73 F; mean age: 39.2+/-6.6) healthy controls (HC) were studied as the control groups. We used B-mode USG to assess the frequency of plaques and intima-media thickness (IMT) in the carotid and femoral arteries. Traditional atherosclerotic risk factors were also evaluated. Men and women were analyzed separately. RESULTS The frequency of plaques and the mean IMT in the carotid and femoral arteries were similar between patients with BS, AS and HC and also between the 2 subgroups of BS, among both men and women. Only men with RA were found to have significantly increased frequency of carotid artery plaques after adjustment for atherosclerotic risk factors. CONCLUSION Increased atherosclerosis is not a prominent feature of BS, even among those patients with major organ involvement.

Effect of surgical cleaning of the skin on the pathergy phenomenon in Behçet's syndrome.

OBJECTIVES--To assess the effect of surgical cleaning of the skin on the pathergy phenomenon in Behçets syndrome. METHODS--The pathergy phenomenon was assessed in 183 patients with Behçets syndrome in a single blind study at 48 hours after a needle prick of the forearm skin, cleaned in the conventional way with alcohol, with 10% povidine iodine, with 100% chlorhexidine, and with a 4% aqueous solution of chlorhexidine. RESULTS--The surgical cleaning of the forearm with povidone iodine before the application of the needle prick reduced the prevalence of the pathergy reaction to 27% from 48% in the conventionally (by alcohol swab) cleaned forearm. Cleaning the forearm with 100% chlorhexidine reduced the prevalence of the pathergy to 36% from 59% in the conventionally cleaned forearm. No significant changes were observed with a 4% aqueous solution of chlorhexidine. CONCLUSIONS--Surgical cleaning of the skin with disinfectants of various concentrations reduces the prevalence of a positive pathergy test in Behçets syndrome. This implies that more than the disruption of the structural integrity of the dermis and epidermis is involved in the production of the pathergy phenomenon in Behçets syndrome.

Takayasu's arteritis is associated with HLA-B*52, but not with HLA-B*51, in Turkey

IntroductionHLA-B*51 and HLA-B*52 are two close human leukocyte antigen (HLA) allele groups with minor amino acid differences. However, they are associated with two different vasculitides (HLA-B*51 in Behçets disease and HLA-B*52 in Takayasus arteritis (TAK)) and with major clinical and immunological differences. In this study, we aimed to screen a large cohort of TAK patients from Turkey for the presence of HLA-B*51 and HLA-B*52 as susceptibility and severity factors.MethodsTAK patients (n = 330) followed at a total of 15 centers were included in the study. The mean age of the patients was 37.8 years, and 86% were women. DNA samples from the patients and healthy controls (HC; n = 210) were isolated, and the presence of HLA-B*51 or HLA-B*52 was screened for by using PCR with sequence-specific primers.ResultsWe found a significant association of HLA-B*52 with TAK (20.9% vs HC = 6.7%, P = 0.000, OR = 3.7, 95% CI = 2.02 to 6.77). The distribution of HLA-B*51 did not differ between TAK patients and HCs (22.7% vs 24.8%, OR = 0.9, 95% CI = 0.60 to 1.34). The presence of HLA-B*52 decreased in late-onset patients (> 40 years of age; 12.0%, P = 0.024, OR = 0.43, 95% CI = 0.20 to 0.91). Patients with angiographic type I disease with limited aortic involvement also had a lower presence of HLA-B*52 compared to those with all other disease subtypes (13.1% vs 26%, P = 0.005, OR = 0.43, 95% CI = 0.23 to 0.78).ConclusionsIn this study, the previously reported association of TAK with HLA-B*52 in other populations was confirmed in patients from Turkey. The functional relevance of HLA-B*52 in TAK pathogenesis needs to be explored further.

Behçet's disease in the Middle East.

Behcet’s disease (BD), originally described as oral and genital ulcers and uveitis, is a vasculitis that can involve any organ system. It is a commonly encountered health problem in the Mediterranean countries and in the Far East. The disease has protean manifestations that vary in different geographical locations. The diagnosis of the disease is based on a combination of clinical findings and a positive pathergy test since the etiological agent has not been determined. Various genetic, environmental, and immunological factors play a role in the pathogenesis but the unknown still surpasses the known.

Increased CD4+CD16+ and CD4+CD56+ T cell subsets in Behçet's disease

Abstract Behçets disease is a systemic vasculitis of unknown etiology. Various immune abnormalities have previously been shown in Behçets disease. We investigated T lymphocyte subsets associated with cytotoxic activity and natural killer (NK) cells by flow cytometry in 37 patients with Behçets disease, 38 healthy controls, and 17 diseased control patients. Compared to the healthy controls, CD4+CD16+ and CD4+CD56+ subsets were found to be higher in the Behçets disease group as well as in the disease control group (CD4+CD16+: BD=5 ± 3, DC=14 ± 14, HC= 3 ± 2, P=0.001; CD4+CD56+: BD=11 ± 5, DC= 18 ± 17, HC=8 ± 6, P=0.01). CD8+CD16+ and CD8+CD56+ T cell subsets were at normal levels in Behçets disease but found to be elevated in disease controls. Similarly, NK cells (CD16+CD56+) were high only in the disease control group. Significant increases in CD4+CD16+ and CD4+CD56+ cell subsets in Behçets patients and disease controls suggest that T cell activation patterns of these subsets in Behçets disease are similar to those in other inflammatory disorders.

Intestinal permeability in Behçet's syndrome

OBJECTIVE To measure the intestinal permeability in patients with Behçets syndrome (BS) and to compare the results with those obtained from healthy and diseased controls. METHOD The study group comprised 34 patients with BS without known gastrointestinal disease. Ten patients with ankylosing spondylitis (AS), 6 with inflammatory bowel diseases (IBD), 17 with systemic lupus erythematosus (SLE), and 15 healthy subjects (HC) constituted the controls. All patients received 100 μCi (3.7 MBq) of chromium-51 EDTA (51Cr-EDTA) as a radioactive tracer after a 72 hour abstinence from all drugs. The percentage of the isotope excreted in a 24 hour urinary specimen was the measure of permeability. RESULTS The percentage (SD) rate of excretion of 51Cr-EDTA was 4.6 (2.6) in BS, 6 (2.4) in AS, 5.2 (1.9) in IBD, 5.56 (1.78) in SLE, and 2.3 (1) in healthy controls. (Analysis of variance: f=6.4, p=0.0002. BSv HC, AS vHC, SLE v HC significant.) CONCLUSION The intestinal permeability in BS was significantly more than that seen among the healthy controls. Similar results in all the diseased controls cast doubt on its specificity.