Sebahattin Yurdakul

EULAR recommendations for the management of Behçet disease

Objectives: To develop evidence-based European League Against Rheumatism (EULAR) recommendations for the management of Behçet disease (BD) supplemented where necessary by expert opinion. Methods: The multidisciplinary expert committee, a task force of the EULAR Standing Committee for Clinical Affairs (ESCCA), consisted of nine rheumatologists (one who was also a clinical epidemiologist and one also a Rehabilitation Medicine doctor), three ophthalmologists, one internist, one dermatologist and one neurologist, representing six European countries plus Tunisia and Korea. A patient representative was also present. Problem areas and related keywords for systematic literature research were identified. Systematic literature research was performed using Medline and the Cochrane Library databases from 1966 through to December 2006. A total of 40 initial statements were generated based on the systematic literature research. These yielded the final recommendations developed from two blind Delphi rounds of voting. Results: Nine recommendations were developed for the management of different aspects of BD. The strength of each recommendation was determined by the level of evidence and the experts’ opinions. The level of agreement for each recommendation was determined using a visual analogue scale for the whole committee and for each individual aspect by the subgroups, who consider themselves experts in that field of BD. There was excellent concordance between the level of agreement of the whole group and the “experts in the field”. Conclusion: Recommendations related to the eye, skin–mucosa disease and arthritis are mainly evidence based, but recommendations on vascular disease, neurological and gastrointestinal involvement are based largely on expert opinion and uncontrolled evidence from open trials and observational studies. The need for further properly designed controlled clinical trials is apparent.

A Controlled Trial of Azathioprine in Behçet's Syndrome

Cytotoxic agents have long been used in Behcets syndrome, especially for eye involvement, but their effectiveness has been uncertain. We conducted a two-year randomized, placebo-controlled, double-blind trial of azathioprine (2.5 mg per kilogram of body weight per day) in Turkish men with Behcets syndrome without eye disease (group 1; n = 25) or with eye disease (group 2; n = 48). Corticosteroid treatment remained available to all the patients. All six patients withdrawn from the study because of severe eye disease were receiving placebo (P less than 0.001). Azathioprine was superior to placebo in the prevention of new eye disease in group 1 (1 vs. 8 patients; P less than 0.01) and in group 2 among the 14 patients who at entry had disease in only one eye (P less than 0.001). There were fewer episodes of hypopyon uveitis (1 vs. 15; P less than 0.001) among the group 2 patients who took azathioprine. The patients taking azathioprine also had less frequent oral ulcers, genital ulcers, and arthritis. There were no serious side effects attributable to azathioprine. We conclude that azathioprine is effective in controlling the progression of Behcets syndrome, especially its most serious manifestation, eye disease.

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.

Influence of age of onset and patient's sex on the prevalence and severity of manifestations of Behçet's syndrome.

Eye disease, arthritis, folliculitis, and thrombophlebitis were more common among males, and erythema nodosum among females, in 297 patients with Behćet syndrome (BS) at their first visit despite an identical disease duration. Younger males and females (age of onset 24 years or less) had a higher prevalence of eye disease and total clinical activity than did the older patients (age of onset 25 years or more). Among the 51 patients followed up for 52 months (SD 7 months) the total clinical activity became significantly less (p less than 0.05) in the whole group at the end of this period. This was particularly true for older females. While male sex and a younger age of onset are associated with more severe disease in BS, overall, the syndrome ran an improving or stable course over 4 1/2 years.

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

OBJECTIVE Colchicine is a widely used treatment for Behçets 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 Behçets syndrome in a study conducted among a larger group of patients for 2 years. METHODS We randomized 116 patients with Behçets 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 Behçets syndrome, especially among women. This might be a reflection of less severe disease among the women.

Clinical features of Behçet's disease in children: An international collaborative study of 86 cases

OBJECTIVES The objective of this study was to characterize the clinical picture of Behçets disease (BD) in children. STUDY DESIGN A questionnaire was completed by five BD specialists from Turkey, France, Iran, or Saudi Arabia. We first reviewed 86 cases retrospectively with a specially designed computerized database and then selected 65 who met the criteria of the International Study Group for BD, which include buccal aphthosis plus at least two among recurrent genital aphthosis, eye lesions, skin lesions, and positive pathergy test. The remaining 21 patients, who had features suggestive of BD but did not fulfill the international criteria, were analyzed separately and then compared with the other 65 patients. RESULTS BD affected boys and girls equally. The clinical picture frequently included mucocutaneous lesions. Uveitis was less frequent than in adults but carried a poor prognosis, especially in male patients (p < 0.001). The mortality rate (3%) was related to large vessel involvement. Familial cases were particularly frequent (15%). Erythema nodosum and skin hypersensitivity were common in Turkish patients, whereas neuro-BD was more frequent in French and Saudi Arabian patients. Patients who did not fulfill the international criteria had significantly less genital aphthosis (p < 0.01), less skin lesions or hypersensitivity (p < 0.01), and less uveitis (p < 0.01). CONCLUSION BD in children is similar to BD in adults. The high frequency of familial cases calls for further investigation of the immunogenetic factors that may favor early expression of the disease.

Low dose cyclosporin A versus pulsed cyclophosphamide in Behcet'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 Behçets 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 Behçets syndrome are warranted.

Management of Behçet disease: a systematic literature review for the European League Against Rheumatism evidence-based recommendations for the management of Behçet disease

Objectives: To present and analyse the literature sources regarding the management of Behçet disease (BD) identified during the systematic literature research, which formed the basis for the European League Against Rheumatism (EULAR) evidence-based recommendations for the management of BD. Methods: Problem areas and related keywords regarding the management of BD were determined by the multidisciplinary expert committee commissioned by EULAR for developing the recommendations. A systematic literature research was performed using MedLine and Cochrane Library resources through to December 2006. Meta-analyses, systematic reviews, randomised controlled trials (RCTs), open studies, observational studies, case control studies and case series’ involving ⩾5 patients were included. For each intervention the effect size and number needed to treat were calculated for efficacy. Odds ratios and numbers needed to harm were calculated for safety issues of different treatment modalities where possible. Results: The literature research yielded 137 articles that met the inclusion criteria; 20 of these were RCTs. There was good evidence supporting the use of azathioprine and ciclosporin A in eye involvement and interferon (IFN)α in mucocutaneous involvement. There were no RCTs with IFNα or tumour necrosis factor (TNF)α antagonists in eye involvement. Similarly controlled data for the management of vascular, gastrointestinal and neurological involvement is lacking. Conclusion: Properly designed, controlled studies (new and confirmatory) are still needed to guide us in managing BD.

The arthritis of Behçet's disease: a prospective study.

A prospective study of arthritis was performed in 47 patients with Behçets disease followed up over a 47-month period (mean 19.25 months, SD 14.09). These patients had a total of 80 episodes of arthritis, which were analysed for joint distribution and symmetry, in 56 of which the duration could also be determined. Attacks were oligoarticular, affecting up to 4 joints per patient, 54 (68%) being monoarticular. Knees, ankles, and wrists were the most commonly involved joints. Involvement of spinal, shoulder, hip, and sacroiliac joints was rare. The arthritis was usually not deforming and subacute; 82% (46/56) of the attacks lasted for 2 months or less and 18% (10/56) for between 3 months and 4 years. The ESR was moderately elevated during the attacks. In 32 specimens the synovial fluid was inflammatory (cell count 14.7 +/- 10.1 x 10(9)/l), but in 19 (59%) a good mucin clot formed. Synovial biopsy in 12 patients revealed superficial ulceration, paucity of plasma cells, and in 5 instances lymphoid follicle formation.

Gastrointestinal involvement in Behçet's syndrome: a controlled study.

OBJECTIVE: To make a retrospective and prospective analysis of the frequency of symptomatic inflammatory bowel disease in patients with Behçets syndrome (BS). METHODS: The medical records of the first 1000 patients with BS were reviewed retrospectively for past or present history of diarrhoea. The past and present history of diarrhoea was also elicited prospectively among 147 consecutive patients with BS and 78 diseased controls (42 with rheumatoid arthritis, 17 with systemic lupus erythematosus, seven with seronegative spondylarthropathy, and 12 with miscellaneous rheumatic diseases). Inflammatory mucosal changes were sought in rectal biopsy specimens from 75 patients with BS, 47 diseased controls (29 with nephrotic syndrome, eight with rheumatoid arthritis, six with familial Mediterranean fever, and four with ankylosing spondylitis), and 14 patients with ulcerative colitis. RESULTS: In chart review there were only seven Behçets patients with diarrhoea; none of them had inflammatory bowel disease. In the prospective survey there were no significant differences between the BS and control groups in the past and present history of diarrhoea. There were no significant differences in the rectal mucosal histology between patients with BS and controls, while patients with ulcerative colitis showed pronounced differences. CONCLUSION: Symptomatic inflammatory bowel disease is not common in BS patients from Turkey.