Kenan Aksu

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)).

Identification of multiple independent susceptibility loci in the HLA region in Behçet's disease

Behçets disease is an inflammatory disease characterized by recurrent oral and genital ulcers and significant organ involvement. Localizing the genetic association between HLA-B*51 and Behçets disease and exploring additional susceptibility loci in the human leukocyte antigen (HLA) region are complicated by the strong linkage disequilibrium in this region. We genotyped 8,572 variants in the extended HLA locus and carried out imputation and meta-analysis of 24,834 variants in 2 independent Behçets disease cohorts from 2 ancestry groups. Genotyped SNPs were used to infer classical HLA alleles in the HLA-A, HLA-B, HLA-C, HLA-DQA1, HLA-DQB1 and HLA-DRB1 loci. Our data suggest that the robust HLA-B*51 association in Behçets disease is explained by a variant located between the HLA-B and MICA genes (rs116799036: odds ratio (OR) = 3.88, P = 9.42 × 10−50). Three additional independent genetic associations within PSORS1C1 (rs12525170: OR = 3.01, P = 3.01 × 10−26), upstream of HLA-F-AS1 (rs114854070: OR = 1.95, P = 7.84 × 10−14) and with HLA-Cw*1602 (OR = 5.38, P = 6.07 × 10−18) were also identified and replicated.

Coexistence of vasculitides with Familial Mediterranean Fever

Familial Mediterranean fever (FMF) is the most common autoinflammatory disease characterized by recurrent self-limited attacks of fever accompanied with peritonitis, pleuritis, or arthritis. FMF may coexist with various systemic inflammatory diseases including vasculitides, spondyloarthritis, multiple sclerosis, and inflammatory bowel disease. Among these coexistences, this review concentrates on vasculitic disorders, with the aim of increasing the awareness of FMF-vasculitis association. This association does not merely show a coincidentally increased frequency of vasculitic disorders in FMF; rather, it seems that FMF patients might be at increased risk of developing vasculitis. Indeed, as also suggested by some authors, vasculitis might be an essential feature of FMF. Among the vasculitic disorders reported to be associated with FMF, Henoch–Schönlein purpura, and classical polyarteritis nodosa come the first, possibly followed up by protracted febrile myalgia. There is also an ongoing debate whether Behçet’s disease (BD) more frequently seen in FMF than expected by chance alone. In this review, the associations of various vasculitic disorders with FMF and the possible pathogenic mechanisms underlying these associations, as well as the frequencies and clinical significances of FMF-related MEFV mutations in various vasculitides including BD, are discussed in the context of the available data.

Gingival Crevicular Fluid MMP-8 and -13 and TIMP-1 Levels in Patients With Rheumatoid Arthritis and Inflammatory Periodontal Disease

BACKGROUND The purpose of this study was to compare gingival crevicular fluid (GCF) levels of matrix metalloproteinase (MMP)-8 and -13 and tissue inhibitor of MMP (TIMP)-1 in patients with rheumatoid arthritis (RA) and systemically healthy counterparts with inflammatory periodontal disease. METHODS Subjects (N = 74) were divided into five groups: 12 patients with RA and gingivitis; 13 patients with RA and periodontitis; 12 systemically healthy patients with gingivitis; 13 systemically healthy patients with periodontitis; and 24 periodontally and systemically healthy volunteers. Full-mouth clinical periodontal measurements were performed at six sites/tooth. GCF samples obtained from two sites in single-rooted teeth were analyzed by immunofluorometric assay and enzyme-linked immunosorbent assay. Data were assessed statistically by parametric tests. RESULTS The total amounts of MMP-8 were lower in the healthy control group than in RA-gingivitis, RA-periodontitis, and healthy-periodontitis groups (P <0.05). MMP-13 levels were similar in all five study groups (P >0.05). Patients with RA and gingivitis or periodontitis exhibited levels of MMP-8 and -13 and TIMP-1 that were similar to systemically healthy counterparts (P >0.05). CONCLUSIONS The coexistence of RA and periodontitis did not significantly affect the investigated parameters. GCF MMP-8 levels increased with periodontal inflammation. Despite the long-term usage of corticosteroids and non-steroidal anti-inflammatory drugs, similar GCF MMP-8 and -13 levels in patients with RA and systemically healthy counterparts suggest that RA may create a tendency to overproduce these enzymes.

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.

Detection of Microembolic Signals in Patients with Neuropsychiatric Lupus erythematosus

The pathogenesis of central nervous system involvement in systemic lupus erythematosus (SLE) is not completely understood. In this study, we investigated the association of microembolic signals (MES) with a variety of neuropsychiatric SLE manifestations and compared our results with those from SLE patients without neuropsychiatric lupus and normal controls. Fifty-three patients with SLE (45 females and 8 males), all fulfilling the revised classification criteria for SLE, and 50 control subjects (44 females and 6 males) were enrolled in this study. All SLE patients were assessed by neuropsychological examination, including various neuropsychiatric tests. Twenty-five patients with SLE were found to have at least one of the neuropsychiatric syndromes defined by The American College of Rheumatology. The mean MES count in patients with neuropsychiatric lupus was significantly higher than those without (5.4 ± 1.1 vs. 0.3 ± 0.8/h; p < 0.005). We found a positive correlation between higher mean MES counts and the presence of neuropsychiatric syndromes in SLE. The mean MES count in the whole group of SLE patients was also significantly higher than that in healthy controls. The mean MES count of SLE patients with antiphospholipid (aPL) antibody positivity was significantly higher than those without aPL antibodies (3.6 ± 1.6 vs. 0.8 ± 0.1/h; p < 0.005). In conclusion, the association of MES with neuropsychiatric lupus may support the possible contribution of MES to the complex pathophysiology of this syndrome. More importantly, detection of MES on transcranial Doppler monitoring might suggest a high risk of involvement of the central nervous system in SLE, and could be used as a diagnostic tool.

Amyloidosis and its related factors in Turkish patients with familial Mediterranean fever: a multicentre study

OBJECTIVE The primary aim of this study was to investigate the prevalence of amyloidosis and its related factors in a large number of FMF patients. METHODS Fifteen centres from the different geographical regions of Turkey were included in the study. Detailed demographic and medical data based on a structured questionnaire and medical records were collected. The diagnosis of amyloidosis was based on histological proof of congophilic fibrillar deposits in tissue biopsy specimens. RESULTS There were 2246 FMF patients. The male/female ratio was 0.87 (1049/1197). The mean age of the patients was 34.5 years (S.D. 11.9). Peritonitis was the most frequent clinical finding and it was present in 94.6% of patients. Genetic testing was available in 1719 patients (76.5%). The most frequently observed genotype was homozygous M694V mutation, which was present in 413 (24%) patients. Amyloidosis was present in 193 patients (8.6%). Male sex, arthritis, delay in diagnosis, M694V genotype, patients with end-stage renal disease (ESRD) and family history of amyloidosis and ESRD were significantly more prevalent in patients with amyloidosis compared with the amyloidosis-negative subjects. Patients with homozygous M694V mutations had a 6-fold higher risk of amyloidosis compared with the other genotypes (95% CI 4.29, 8.7, P < 0.001). CONCLUSION In this nationwide study we found that 8.6% of our FMF patients had amyloidosis and homozygosity for M694V was the most common mutation in these patients. The latter finding confirms the association of homozygous M694V mutation with amyloidosis in Turkish FMF patients.

Renal Behçet's Disease: An Update

OBJECTIVE The aims of this study are (1) to report 33 patients with Behçets disease (BD) having various renal manifestations, and (2) to update current data using our patients and published papers about BD and renal manifestations. METHODS The PubMed database was searched using the terms BD or Behçets syndrome. We found reports of 94 patients (including ours) with BD and specific renal diseases (amyloidosis, 39; glomerulonephritis [GN], 37; renal vascular disease, 19; interstitial nephritis, 1). RESULTS The presentation of renal disease was edema/nephrotic syndrome in 12 patients (36%). Renal disease was incidentally diagnosed by routine urine analysis and measurement of serum creatinine level in 20 patients (61%). Renal failure was present in 23 patients (70%) and 5 of them have had cyclosporine treatment. The frequency of renal disease among BD patients has been reported to vary from less than 1 to 29%. CONCLUSIONS The clinical spectrum of renal BD shows a wide variation. Amyloidosis (AA type), GN, and macroscopic/microscopic vascular disease are the main causes of renal BD. Patients with vascular involvement have a high risk of amyloidosis and amyloidosis is the most common cause of renal failure in BD. Several types of glomerular lesions are seen in BD. Current treatment options for renal BD are not evidence based. Radiological vascular intervention combined with immunosuppressive drugs can be useful in selected cases. Routine urine analysis and measurement of serum creatinine level are needed for early diagnosis of renal BD.

Quality of life in patients with Takayasu's arteritis is impaired and comparable with rheumatoid arthritis and ankylosing spondylitis patients

The aims of the study were to assess the health-related quality of life (QOL) in patients with Takayasus arteritis (TA) by two different generic QOL instruments and to compare the results with those patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), and healthy controls (HC). A cross-sectional study was performed in 51 patients with TA (41 women; mean age 38.4 ± 13.5), 43 RA (36 women; 55.2 ± 9.6), 31 AS (12 women; 41.2 ± 13.1), and 75 HC (53 women; 38.8 ± 10.9). Quality of life was assessed by using Short-Form 36 (SF-36) and Nottingham Health Profile (NHP). Separate dimensions of SF-36 and NHP and physical and mental summary scores of SF-36 as well were compared between patients and control groups. Physical and mental health summary scores and all SF-36 subscales, except for social functioning, were significantly lower in patients with TA than healthy controls. No significant differences between TA, RA, and AS patients were found in all SF-36 subscales and summary scores. NHP scores for energy level, pain, emotional reactions, and physical mobility were significantly higher in TA patients than controls. All NHP subscales, except for pain, were comparable in patients with TA, RA, and AS. Pain score was worse in RA patients. The NHP scores for sleep and social isolation were not different between patients and controls. Many aspects of QOL in patients with TA are significantly impaired in comparison with local healthy controls and similar to those in patients with RA and AS.

Hodgkin’s lymphoma following treatment with etanercept in ankylosing spondylitis

It has been well known that anti-TNF drugs might increase lymphoma risk in rheumatoid arthritis (RA), where the rate of lymphoma has already been increased. However, unlike RA, an increased rate of lymphoma has not been reported in ankylosing spondylitis (AS). Hereby, we present a case with AS developing Hodgkin’s lymphoma (HL) following 6 months of etanercept treatment. Pathological analysis revealed mixed cellular type of HL. Although we report a single case, it should be kept in mind that anti-TNF drugs might cause lymphoma development not only in RA, but also in AS.