Ilknur Tugal-Tutkun

Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet's disease

Behçets disease is a genetically complex disease of unknown etiology characterized by recurrent inflammatory attacks affecting the orogenital mucosa, eyes and skin. We performed a genome-wide association study with 311,459 SNPs in 1,215 individuals with Behçets disease (cases) and 1,278 healthy controls from Turkey. We confirmed the known association of Behçets disease with HLA-B*51 and identified a second, independent association within the MHC Class I region. We also identified an association at IL10 (rs1518111, P = 1.88 × 10−8). Using a meta-analysis with an additional five cohorts from Turkey, the Middle East, Europe and Asia, comprising a total of 2,430 cases and 2,660 controls, we identified associations at IL10 (rs1518111, P = 3.54 × 10−18, odds ratio = 1.45, 95% CI 1.34–1.58) and the IL23R-IL12RB2 locus (rs924080, P = 6.69 × 10−9, OR = 1.28, 95% CI 1.18–1.39). The disease-associated IL10 variant (the rs1518111 A allele) was associated with diminished mRNA expression and low protein production.

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.

Changing patterns in uveitis of childhood.

BACKGROUND Although uveitis is relatively uncommon in children, its diagnosis and management present a distinct clinical challenge for the physician. An improved knowledge of disease patterns and associated morbidity will help in the care of children with uveitis. METHODS The authors reviewed the records of 130 patients with onset of uveitis at 16 years of age or younger. The etiology of uveitis, complications encountered, treatment administered, and visual results were analyzed. RESULTS Uveitis associated with juvenile rheumatoid arthritis (JRA) was the largest group (41.5%) followed by idiopathic uveitis (21.5%) and pars planitis (15.3%). Twenty-six percent of the eyes had less than 20/200 visual acuity at the time of first referral. Patients with JRA had the highest rate of complications: cataract (71%), glaucoma (30%), band keratopathy (66%), and hypotony (19%). The most frequent complication of pars planitis was maculopathy (55%). Final visual acuity was less than 20/200 in 26% of eyes with JRA, 10.5% with pars planitis, and 14% with idiopathic uveitis. CONCLUSION Uveitis beginning in childhood is a serious disease associated with sight-threatening complications. Juvenile rheumatoid arthritis-associated uveitis remains a leading cause of ocular morbidity in patients with childhood uveitis. Increased awareness by pediatricians, rheumatologists, and ophthalmologists of the seriousness of ocular complications of uveitis in childhood may lead to earlier diagnosis and more effective treatment regimens in the future.

Interleukin-1β-regulating antibody XOMA 052 (gevokizumab) in the treatment of acute exacerbations of resistant uveitis of Behcet's disease: an open-label pilot study.

Objective Uveitis and retinal vasculitis are sight-threatening manifestations of Behçets disease with limited treatment options. This pilot study aimed to evaluate the safety, pharmacokinetics and clinical activity of XOMA 052 (gevokizumab), a recombinant humanised anti-interleukin 1β antibody, in Behçets disease patients with uveitis. Methods Patients with acute posterior or panuveitis, and/or retinal vasculitis, resistant to azathioprine and/or ciclosporin, and receiving 10 mg/day or less of prednisolone, were enrolled into the 98-day study. Immunosuppressive agents were discontinued at baseline. Patients received a single infusion of XOMA 052 (0.3 mg/kg). The safety and uveitis status and pharmacokinetics of XOMA 052 were evaluated. Results Seven patients enrolled and completed the study. No treatment-related adverse event was observed. XOMA 052 treatment was associated with rapid and durable clinical response in all patients. Complete resolution of intraocular inflammation was achieved in 4–21 days (median 14 days), with a median duration of response of 49 days (range 21–97 days); one patient remained exacerbation free throughout the study. Conclusions Well tolerated, XOMA 052 resulted in a rapid onset and sustained reduction in intraocular inflammation in patients with resistant uveitis and retinal vasculitis. Moreover, the effect was observed despite discontinuation of immunosuppressive agents and without the need to increase corticosteroid dosages.

Secukinumab in the Treatment of Noninfectious Uveitis: Results of Three Randomized, Controlled Clinical Trials

PURPOSE To determine the efficacy and safety of different doses of secukinumab, a fully human monoclonal antibody for targeted interleukin-17A blockade, in patients with noninfectious uveitis. DESIGN Three multicenter, randomized, double-masked, placebo-controlled, dose-ranging phase III studies: SHIELD, INSURE, and ENDURE. PARTICIPANTS A total of 118 patients with Behçets uveitis (SHIELD study); 31 patients with active, noninfectious, non-Behçets uveitis (INSURE study); and 125 patients with quiescent, noninfectious, non-Behçets uveitis (ENDURE study) were enrolled. METHODS After an initial subcutaneous (s.c.) loading phase in each treatment arm, patients received s.c. maintenance therapy with secukinumab 300 mg every 2 weeks (q2w), secukinumab 300 mg monthly (q4w), or placebo in the SHIELD study; secukinumab 300 mg q2w, secukinumab 300 mg q4w, secukinumab 150 mg q4w, or placebo in the INSURE study; or secukinumab 300 mg q2w, secukinumab 300 mg q4w, secukinumab 150 mg q4w, or placebo in the ENDURE study. MAIN OUTCOME MEASURES Reduction of uveitis recurrence or vitreous haze score during withdrawal of concomitant immunosuppressive medication (ISM). Other end points included best-corrected visual acuity, ISM use (expressed as a standardized ISM score), and safety outcomes. RESULTS After completion or early termination of each trial, there were no statistically significant differences in uveitis recurrence between the secukinumab treatment groups and placebo groups in any study. Secukinumab was associated with a significant reduction in mean total post-baseline ISM score (P = 0.019; 300 mg q4w vs. placebo) in the SHIELD study. Likewise, secukinumab was associated with a greater median reduction in ISM score versus placebo in the INSURE study, although no statistical analysis of the difference was conducted because of the small sample size. Overall, there was no loss in visual acuity reported in any treatment group during follow-up in all 3 studies. According to descriptive safety statistics, the frequencies of ocular and nonocular adverse events seemed to be slightly higher among secukinumab groups versus placebo across the 3 studies. CONCLUSIONS The primary efficacy end points of the 3 studies were not met. The secondary efficacy data from these studies suggest a beneficial effect of secukinumab in reducing the use of concomitant ISM.

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.

Long-term follow-up of patients with atopic keratoconjunctivitis.

OBJECTIVE This study aimed to review the presenting features, treatment administered to, histopathologic findings, and complications encountered in a cohort of patients with atopic keratoconjunctivitis. DESIGN The study design was a retrospective cohort series. PARTICIPANTS The medical records of 20 patients with atopic keratoconjunctivitis and a minimum follow-up of 3 years were reviewed. MAIN OUTCOME MEASURES Conjunctival and corneal complications, visual acuity before and after surgery, and histopathologic features on conjunctival biopsy were measured. RESULTS Significant keratopathy developed in 70% of patients, corneal neovascularization in 60%, fornix foreshortening in 25%, and symblepharon in 20% during the course of their disease. Eleven patients (12 eyes) required penetrating keratoplasty (3 for tectonic purposes and 8 for visual rehabilitation). Vision improved by four or more lines of Snellen acuity in four eyes, improved by two lines in two eyes, remained the same in five eyes, and worsened by two lines in one eye after keratoplasty. Cataract surgery was performed in seven patients (nine eyes) with vision improving by four or more lines in six patients (eight eyes). CONCLUSION Atopic keratoconjunctivitis is a potentially blinding disease that may result in a poor visual outcome as a result of corneal complications. Elective surgical intervention may be of benefit and can be considered in those patients whose inflammation is well controlled.

Childhood-onset uveitis in Behçet disease:a descriptive study of 36 cases.

PURPOSE To describe the demographic and clinical features, complications, treatment, and visual results in patients with childhood-onset Behçet uveitis. DESIGN Observational case series. METHODS A retrospective study was made of 36 consecutive patients with Behçet disease seen at the Uveitis Service, Department of Ophthalmology, Istanbul Faculty of Medicine, Istanbul University, between January 1975 and January 2002. Inclusion criteria were fulfillment of the classification criteria of the International Study Group for Behçet Disease and onset of uveitis at 16 years of age or younger. The medical records of 36 patients with childhood-onset Behçet uveitis were reviewed. The main outcome measures were sex, age at onset of uveitis, the initial symptom of Behçet disease, clinical ocular features, ocular complications, systemic treatment, complications of treatment, and final visual acuity. RESULTS Twenty-five patients were male, 11 were female. Mean age at onset of uveitis was 13.6 years. The initial symptom was oral ulcer in 63.8% of the patients. The majority of patients (83.3%) had bilateral involvement. Panuveitis was the most common form (86.2%). Retinal vasculitis and retinitis were the most common ocular findings seen in 83.3% and 68.2% of the involved eyes, respectively. Cataract, maculopathy, and optic atrophy were the most common complications seen in 46.9%, 45.4%, and 39.4% of the involved eyes, respectively. Immunosuppressive therapy was administered to 75% of the patients. Response to treatment was variable. The most common complications of systemic treatment were associated with corticosteroid therapy. Final visual acuity was worse than 0.1 in 22.7% of the involved eyes. CONCLUSIONS Childhood-onset Behçet uveitis was more common among males. Bilateral panuveitis with retinal vasculitis and retinitis was the most common form of ocular involvement, similar to the adult patient. The treatment is challenging, as the use oral corticosteroids is associated with significant complications and the response to conventional immunosuppressive therapy is variable.

Use of laser flare-cell photometry to quantify intraocular inflammation in patients with Behçet Uveitis

PurposeTo assess the usefulness of laser flare-cell photometry to quantify intraocular inflammation in patients with Behçet disease.MethodsThe study comprised 47 healthy individuals, 78 Behçet patients without ocular involvement, 54 Behçet patients with a uveitis attack and 53 Behçet patients with uveitis in clinical remission. A single observer assigned clinical scores to anterior chamber cells, vitreous haze, and fundus lesions in the attack group. Laser flare-cell photometry measurements were performed by another observer who was masked to the clinical findings. Fundus fluorescein angiography was performed only in the remission group, and fluorescein leakage was scored by a masked retina specialist. The risk of recurrent uveitis attack was analyzed in eyes with high versus low flare values in the remission group. Main outcome measures were anterior chamber flare in Behçet patients compared to the control group, and correlations of flare with clinical scores of intraocular inflammation and with fluorescein leakage. Mann-Whitney U-test, Spearman’s bivariate correlation test, linear regression method, and Kaplan-Meier method were used for statistical analyses.ResultsMean flare was not increased in Behçet patients without ocular involvement. It was significantly higher in patients with Behçet uveitis both during attacks and in remission (P < 0.001 for each). A significant correlation was found between anterior chamber flare and anterior chamber cell score (rho = 0.705), vitreous haze score (rho = 0.588), and fundus score (rho = 0.464) in the attack group. In the remission group, there was a significant correlation between flare and fluorescein angiography leakage score, and the risk of recurrent uveitis attack was significantly higher in eyes with flare values >6 photons/msec than in eyes with flare values ≤6 photons/msec (right eyes, P < 0.001; left eyes, P = 0.0184).ConclusionsLaser flare-cell photometry is a useful objective method in the quantitative assessment of intraocular inflammation in patients with Behçet uveitis. The use of this quantitative technique in clinical trials of Behçet uveitis may provide comparable data, as it gives an objective measure of intraocular inflammation. In clinical practice, it may reduce the need for fluorescein angiography because it seems to be especially useful in monitoring persistent retinal vascular leakage in patients who are clinically in remission.

Scoring of dual fluorescein and ICG inflammatory angiographic signs for the grading of posterior segment inflammation (dual fluorescein and ICG angiographic scoring system for uveitis)

Purpose To propose a semiquantitative dual fluorescein angiography (FA) and indocyanine green angiography (ICGA) scoring system for uveitis that would assist in the follow-up of disease progression and monitoring response to treatment. Methods The scoring system was based on the FA scoring systems, the standardized ICGA protocol, and schematic interpretation of ICGA findings in posterior uveitis that have been previously published. We assigned scores to the fluorescein and ICG angiographic signs that represent ongoing inflammatory process in the posterior segment. We rated each angiographic sign according to the impact it has on our appreciation of active intraocular inflammation. In order to permit direct comparison between FA and ICGA, we multiplied the total ICGA score by a coefficient of 2 to adjust to the total score of FA. Results A total maximum score of 40 was assigned to the FA signs, including optic disc hyperfluorescence, macular edema, retinal vascular staining and/or leakage, capillary leakage, retinal capillary nonperfusion, neovascularization of the optic disc, neovascularization elsewhere, pinpoint leaks, and retinal staining and/or subretinal pooling. A total maximum score of 20 was assigned to the ICGA signs, including early stromal vessel hyperfluorescence, choroidal vasculitis, dark dots or areas (excluding atrophy), and optic disc hyperfluorescence. Conclusion The combined fluorescein and ICG angiographic scoring system proposed herein may help estimate the magnitude of retinal versus choroidal inflammation, monitor disease progression and response to treatment, and provide comparable data for clinical studies. The applicability of the proposed system needs to be tested in clinical settings, and intra- and interobserver variations need to be determined.