Burak Erer

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.

Metabolic syndrome: major impact on coronary risk in a population with low cholesterol levels—a prospective and cross-sectional evaluation

UNLABELLED The prevalence and the excess coronary heart disease (CHD) risk of the metabolic syndrome (MS) and its components were investigated in the Turkish Adult Risk Factor Study in both a prospective and a cross-sectional manner. In a population sample, representative of Turkish adults who have low levels of high- and low-density lipoprotein-cholesterol (HDL-C and LDL-C), MS was identified in conformity with the definition used in the recent NCEP guidelines. Prospective analysis was based on 2398 men and women (mean age at baseline 49.1+/-13 years) who had a baseline examination in 1997/98 and were followed-up for a mean of 3 years. CHD was diagnosed based on clinical findings and Minnesota coding of resting electrocardiograms. Fatal and nonfatal CHD developed in 126 subjects. 27% of men and 38.6% of women were found to have MS at baseline examination. When adjusted for age, MS was an independent predictor of subsequent overall fatal and nonfatal CHD in both genders, displaying an RR of 1.71. At the final cross-sectional evaluation, coronary risk associated with MS in men was primarily accounted for by standard MS components (largely inherent in glucose intolerance, hypertension and in a surrogate of small, dense LDL particles), in addition to a minor independent contribution by C-reactive protein (CRP). In women with MS, a substantial residual coronary risk remained after controlling for five components, which was partly accounted for by levels of LDL-C and CRP. It was estimated that MS was the culprit in just over half the cases of CHD in Turkey. CONCLUSION MS was the major determinant of CHD risk in a population having generally low levels of HDL-C and LDL-C in middle-aged and elderly adults, extending to three out of every eight adults, and imposing an overall excess CHD risk of approximately 70%. In contrast to men, a substantial residual coronary risk is retained in Turkish women after controlling for five MS components.

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.

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.

EULAR recommendations for the management of familial Mediterranean fever

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease, but many rheumatologists are not well acquainted with its management. The objective of this report is to produce evidence-based recommendations to guide rheumatologists and other health professionals in the treatment and follow-up of patients with FMF. A multidisciplinary panel, including rheumatologists, internists, paediatricians, a nurse, a methodologist and a patient representative, was assembled. Panellists came from the Eastern Mediterranean area, Europe and North America. A preliminary systematic literature search on the pharmacological treatment of FMF was performed following which the expert group convened to define aims, scope and users of the guidelines and established the need for additional reviews on controversial topics. In a second meeting, recommendations were discussed and refined in light of available evidence. Finally, agreement with the recommendations was obtained from a larger group of experts through a Delphi survey. The level of evidence (LoE) and grade of recommendation (GR) were then incorporated. The final document comprises 18 recommendations, each presented with its degree of agreement (0–10), LoE, GR and rationale. The degree of agreement was greater than 7/10 in all instances. The more controversial statements were those related to follow-up and dose change, for which supporting evidence is limited. A set of widely accepted recommendations for the treatment and monitoring of FMF is presented, supported by the best available evidence and expert opinion. It is believed that these recommendations will be useful in guiding physicians in the care of patients with FMF.

Efficacy and safety of canakinumab in adolescents and adults with colchicine-resistant familial Mediterranean fever

IntroductionThis open-label pilot study aimed to investigate the efficacy of canakinumab in colchicine-resistant familial Mediterranean fever (FMF) patients.MethodPatients with one or more attacks in a month in the preceding 3 months despite colchicine were eligible to enter a 30-day run-in period. Patients who had an attack during the first run-in period advanced to a second 30-day period. At the first attack, patients started to receive three canakinumab 150 mg subcutaneous injections at 4-week intervals, and were then followed for an additional 2 months. Primary efficacy outcome measure was the proportion of patients with 50 % or more reduction in attack frequency. Secondary outcome measures included time to next attack following last canakinumab dose and changes in quality of life assessed by SF-36.ResultsThirteen patients were enrolled in the run-in period and 9 advanced to the treatment period. All 9 patients achieved a 50 % or more reduction in attack frequency, and only one patient had an attack during the treatment period. C-reactive protein and serum amyloid A protein levels remained low throughout the treatment period. Significant improvement was observed in both physical and mental component scores of the Short Form-36 at Day 8. Five patients had an attack during the 2-month follow-up, occurring median 71 (range, 31 to 78) days after the last dose. Adverse events were similar to those observed in the previous canakinumab trials.ConclusionCanakinumab was effective at controlling the attack recurrence in patients with FMF resistant to colchicine. Further investigations are warranted to explore canakinumab’s potential in the treatment of patients with colchicine resistant FMF.Trial registrationClinicalTrials.gov NCT01088880. Registered 16 March 2010.

Determinants of Early Radiographic Progression in Ankylosing Spondylitis

Objective. To investigate the demographic and clinical characteristics associated with early, extensive radiographic changes in ankylosing spondylitis (AS). Methods. Radiographic severity was assessed cross-sectionally in 235 patients with AS using the Bath AS Radiological Index spine score (BASRI-s). Patients with extensive radiographic changes on the lumbar portion of BASRI-s were defined as the early axial ankylosis (EAA) Group. ANCOVA and logistic regression analyses were used to identify factors affecting EAA. Results. Most study patients were men (139/235, 59.0%). Mean disease duration was 12.4 ± 9.3 years. Fifteen percent of women and 34.8% of men with AS were in the EAA group. HLA-B27-positive men with AS had significantly higher BASRI-lumbar scores, while HLA-B27 had no effect on radiographic progression of axial disease in women with AS. Peripheral joint involvement was associated with slow radiographic progression. Hip involvement had no effect on axial progression but uveitis was more frequent in the male EAA group. The odds for an HLA-B27-positive male patient with AS who did not have peripheral arthritis of having a BASRI-lumbar score of 3 or higher were 3.4 (77% chance to have axially progressive disease). Presence of uveitis increased these odds to 93%. Only 15% of female patients with AS had EAA, and the absence of peripheral arthritis was the only clinical measure associated with EAA in this group. Conclusion. EAA was more frequent in men with AS than in women. Absence of peripheral arthritis, HLA-B27 positivity, and uveitis were associated with multiple syndesmophytes or fusion of multiple vertebrae of the lumbar vertebrae.

EULAR / PReS standards and recommendations for the transitional care of young people with juvenile-onset rheumatic diseases

To develop standards and recommendations for transitional care for young people (YP) with juvenile-onset rheumatic and musculoskeletal diseases (jRMD). The consensus process involved the following: (1) establishing an international expert panel to include patients and representatives from multidisciplinary teams in adult and paediatric rheumatology; (2) a systematic review of published models of transitional care in jRMDs, potential standards and recommendations, strategies for implementation and tools to evaluate services and outcomes; (3) setting the framework, developing the process map and generating a first draft of standards and recommendations; (4) further iteration of recommendations; (5) establishing consensus recommendations with Delphi methodology and (6) establishing standards and quality indicators. The final consensus derived 12 specific recommendations for YP with jRMD focused on transitional care. These included: high-quality, multidisciplinary care starting in early adolescence; the integral role of a transition co-ordinator; transition policies and protocols; efficient communications; transfer documentation; an open electronic-based platform to access resources; appropriate training for paediatric and adult healthcare teams; secure funding to continue treatments and services into adult rheumatology and the need for increased evidence to inform best practice. These consensus-based recommendations inform strategies to reach optimal outcomes in transitional care for YP with jRMD based on available evidence and expert opinion. They need to be implemented in the context of individual countries, healthcare systems and regulatory frameworks.

Predictors of Damage and Survival in Patients with Wegener’s Granulomatosis: Analysis of 50 Patients

Objective. To evaluate damage features and impact on survival by Vasculitis Damage Index (VDI) in a cohort of Turkish patients with Wegener’s granulomatosis (WG). Methods. We enrolled 50 (25 female) patients with WG according to ACR criteria. Birmingham Vasculitis Activity Score (BVAS) and VDI were used to analyze disease activity and damage. Results. Patients had kidney (82%), upper airway (72%), lung (70%), and nervous system (15%) involvement. Median age at diagnosis was 45 years, time to diagnosis was 3.5 months, and total followup time was 35.5 months. All but one patient was positive for antineutrophil cytoplasmic antibodies (ANCA). Mean final dose and duration of corticosteroid and cyclophosphamide was 15 ± 14 g, 39 ± 33 months and 36 ± 34 g, 21 ± 2 months, respectively. Mean early (e) BVAS were 20.2 ± 7.1 (4–38) (median 21). Mean e-BVAS and e-VDI scores at presentation and final (f)-VDI scores at last visit were 20.2 ± 7.1 (4–38), 3.1 ± 1.7 (median 3) (0–7) and 4.4 ± 2.6 (0–12), consecutively. Disease related damage was prominent in kidneys (50%) and upper airways (27%). Amenorrhea (90%), cataract (28%), and diabetes (24%) were the most frequent treatment related damages. Rapidly progressive glomerulonephritis at presentation (42%) progressed to endstage renal failure in 20%. Relapses occurred in 25% with mean BVAS of 6.5 ± 2.3 (4–11). Survival rate was 77% at 37 months. Deaths occurred early (90% in the first year). f-VDI was high in patients who relapsed (6 ± 3 vs 3.8 ± 2.1, p = 0.03). Logistic regression analysis demonstrated that age at time of diagnosis and e-VDI were lower in survivors with OR = 0.9 (p = 0.06, 95% CI: 0.78–1) and OR = 0.5 (p = 0.04, 95%CI: 0.25–0.98), respectively. In this cohort, e-VDI score of 5 or more was related to death with 98% sensitivity and 56% specificity (p = 0.004) (CI: 0.66–0.95). Conclusion. Disease related damage outweighed treatment related damage in our cohort of predominantly generalized disease activity. Early damage and older age were found to be predictors of final damage and death.

Metabolic syndrome is not only a risk factor for cardiovascular diseases in systemic lupus erythematosus but is also associated with cumulative organ damage: a cross-sectional analysis of 311 patients.

Background/Purpose Patients with systemic lupus erythematosus (SLE) have increased rates of cardiovascular disease (CVD) that are one of the major causes of mortality. The aim of this study was to determine the frequencies of metabolic syndrome (MetS) and CVD in SLE patients and investigate the link between these and clinical features of SLE. Methods A total of 311 SLE patients were consecutively assessed for cumulative organ damage (SDI/SLICC scores), history of CVD and MetS as defined by the National Cholesterol Educational Program Adult Treatment Panel III (NCEP ATP III). Clinical data of SLE patients were collected from the records. Results The mean age of the patients was 40.2 ± 13.4 years and 89% were female. The frequencies of CVD and MetS were 15.2% and 19%, respectively. In this SLE cohort increased age, cumulative damage, disease duration and CVD were associated with MetS. CVD was associated with disease duration, cumulative damage, pericarditis, hematologic involvement, lymphopenia, thrombocytopenia, neurological involvement and antiphospholipid antibody (aPL) positivity. Hydroxychloroquine (HCQ) use was found as a protective factor for CVD. Conclusion In SLE patients, MetS was associated with CVD and both increased with disease duration. Patients who developed MetS and/or CVD had increased cumulative organ damage. Certain clinical features of SLE and the presence of aPL were also associated with CVD. There was a significant protective effect of HCQ from CVD. The prevention of MetS and long-term use of HCQ may be beneficial in improving the prognosis of SLE.