Yilmaz Ozyazgan

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 All six patients withdrawn from the study because of severe eye disease were receiving placebo (P less than 0.001).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.

Genome-wide association analysis identifies new susceptibility loci for Behcet's disease and epistasis between HLA-B*51 and ERAP1.

Individuals with Behçets disease suffer from episodic inflammation often affecting the orogenital mucosa, skin and eyes. To discover new susceptibility loci for Behçets disease, we performed a genome-wide association study (GWAS) of 779,465 SNPs with imputed genotypes in 1,209 Turkish individuals with Behçets disease and 1,278 controls. We identified new associations at CCR1, STAT4 and KLRC4. Additionally, two SNPs in ERAP1, encoding ERAP1 p.Asp575Asn and p.Arg725Gln alterations, recessively conferred disease risk. These findings were replicated in 1,468 independent Turkish and/or 1,352 Japanese samples (combined meta-analysis P < 2 × 10−9). We also found evidence for interaction between HLA-B*51 and ERAP1 (P = 9 × 10−4). The CCR1 and STAT4 variants were associated with gene expression differences. Three risk loci shared with ankylosing spondylitis and psoriasis (the MHC class I region, ERAP1 and IL23R and the MHC class I–ERAP1 interaction), as well as two loci shared with inflammatory bowel disease (IL23R and IL10) implicate shared pathogenic pathways in the spondyloarthritides and Behçets 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.

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.

Targeted resequencing implicates the familial Mediterranean fever gene MEFV and the toll-like receptor 4 gene TLR4 in Behçet disease

Genome-wide association studies (GWAS) are a powerful means of identifying genes with disease-associated common variants, but they are not well-suited to detecting genes with disease-associated rare and low-frequency variants. In the current study of Behçet disease (BD), nonsynonymous variants (NSVs) identified by deep exonic resequencing of 10 genes found by GWAS (IL10, IL23R, CCR1, STAT4, KLRK1, KLRC1, KLRC2, KLRC3, KLRC4, and ERAP1) and 11 genes selected for their role in innate immunity (IL1B, IL1R1, IL1RN, NLRP3, MEFV, TNFRSF1A, PSTPIP1, CASP1, PYCARD, NOD2, and TLR4) were evaluated for BD association. A differential distribution of the rare and low-frequency NSVs of a gene in 2,461 BD cases compared with 2,458 controls indicated their collective association with disease. By stringent criteria requiring at least a single burden test with study-wide significance and a corroborating test with at least nominal significance, rare and low-frequency NSVs in one GWAS-identified gene, IL23R (P = 6.9 × 10−5), and one gene involved in innate immunity, TLR4 (P = 8.0 × 10−4), were associated with BD. In addition, damaging or rare damaging NOD2 variants were nominally significant across all three burden tests applied (P = 0.0063–0.045). Furthermore, carriage of the familial Mediterranean fever gene (MEFV) mutation Met694Val, which is known to cause recessively inherited familial Mediterranean fever, conferred BD risk in the Turkish population (OR, 2.65; P = 1.8 × 10−12). The disease-associated NSVs in MEFV and TLR4 implicate innate immune and bacterial sensing mechanisms in BD pathogenesis.

Safety and Efficacy of Gevokizumab in Patients with Behçet’s Disease Uveitis: Results of an Exploratory Phase 2 Study

ABSTRACT Purpose: To evaluate the safety and efficacy of gevokizumab for the treatment of Behçet’s disease uveitis in a prospective, open-label, randomized phase 2 trial. Methods: Behçet’s disease patients with new acute ocular exacerbation or at risk of exacerbation received 30 or 60 mg gevokizumab every 4 weeks intravenously or subcutaneously, on top of a stable regimen of immunosuppressives and corticosteroids (≤20 mg/day equivalent prednisolone). Patients withdrew in cases of ocular exacerbation. Results: A total of 21 patients were included (17 acute and 4 at-risk; mean duration of uveitis 45.6 ± 37.4 months). There were no serious adverse events related to gevokizumab. Recorded adverse events were mostly associated with exacerbation of uveitis or its complications. Response was evaluated for 14 acute patients and all showed rapid control of acute ocular exacerbation, mostly within 1 week, without any increase in corticosteroid dosage. Conclusions: Gevokizumab was well tolerated and rapidly controlled acute ocular exacerbations of Behçet’s disease uveitis without the need for high-dose corticosteroid.

Prognosis of Behçet's syndrome among men with mucocutaneous involvement at disease onset: long-term outcome of patients enrolled in a controlled trial

OBJECTIVE To assess the influence of being free of major organ involvement during the early years of the disease on the prognosis of men with Behçets syndrome (BS). METHODS Ninety-six men with BS, who had only active mucocutaneous manifestations when entering a controlled trial of thalidomide mean (s.d.) 11.7 (0.8) years ago, were re-evaluated for the use of immunosuppressives as an indication of major organ involvement during the post-trial period. RESULTS Outcome information was obtained in 91 (95%) patients. Thirty-nine (43%) patients had to use immunosuppressives during the post-trial period. Immunosuppressive use was significantly more frequent among patients developing BS at younger age (76%; <or=24 years) than older age (30%; >or=25 years). Developing BS at young age (OR = 6.3; 95% CI 2.09, 19.04) and not using colchicine during the post-trial period (OR = 3.860; 95% CI 1.484, 10.034) were risk factors for immunosuppressive use. However, 82% of the patients using colchicine had onset during old age. Colchicine showed a significant effect in decreasing the use of immunosuppressives only among patients of old age at onset (Fishers exact test = 5.026; P = 0.031) in the subgroup analysis. Eye disease (18 patients) and vascular involvement (14 patients) were the most frequent indications for immunosuppressive use. CONCLUSIONS Being free of major organ involvement during the early years of BS does not indicate a mild prognosis for men developing BS at young age. Whether colchicine will reduce the need for immunosuppressive use among men developing BS at old age awaits formal studies.

Ocular Involvement of Behçet’s Syndrome: a Comprehensive Review

Behçet’s syndrome (BS) is a vasculitis involving several organ systems including the eyes. Ocular involvement is one of the most disabling complications of BS, causing loss of vision that may progress to blindness if left untreated. The typical form of ocular involvement is a relapsing and remitting panuveitis and retinal vasculitis. Initial attacks may spontaneously improve and subsequently disappear in a few weeks but tend to recur if left untreated. Destructive and recurrent attacks, especially with posterior segment and retina involvement, may cause irreversible ocular structural changes and permanent damage in sensory retina, resulting in loss of vision. The risk of irreversible damage to ocular tissue which may result in loss of vision warrants early and intensive treatment especially in patients at high risk such as young men who tend to follow an aggressive disease course. The management strategy involves rapid suppression of inflammation during the attacks and prevention of recurrent attacks. Local and systemic measures including immunosuppressives, corticosteroids, and biologic agents are used for this purpose. Surgery may be required in selected cases. The prognosis of eye involvement has greatly improved over the last decades with the effective use of immunosuppressives.