[show abstract][hide abstract] ABSTRACT: 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)).
The American Journal of Human Genetics 07/2013; · 11.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: A similar disease severity among men and women in Brasil, a high frequency of gastrointestinal involvement in China, Japan and USA, a low frequency of pathergy positivity in Japan and USA underline the ethnic variations reported in recent studies. Polymorphisms pertaining both to innate and adaptive immunity in genome wide association studies, clusters in phenotype, and new mechanisms for emerging therapeutic implications have been reported. A Th17 dominance seems to be likely with the exception of gastrointestinal involvement. Infliximab, interferon-alpha and cyclosporine-A may be showing their beneficial effects also by affecting the Th17 cells. The clinical course and outcome of isolated pulmonary artery thrombosis is similar to pulmonary artery aneurysms. Parenchymal lesions (nodules, consolidations, cavities and ground glass lesions) are common in patients with pulmonary involvement. Pericarditis is a frequent cardiac manifestation in France. Treatment of BS became more intensive than before. Immunosuppressives and corticosteroids seem to prevent relapses of venous thrombosis. Studies are needed to understand the role of anticoagulants. Interferon alpha-2a appears to be effective at lower dosage, which brings the advantage of decreased cost and increased tolerability. Switching between anti-TNF agents, when needed, is possible. Interleukin-1 and interleukin-6 are new promising targets.
Clinical and experimental rheumatology 09/2012; · 2.66 Impact Factor
[show abstract][hide abstract] ABSTRACT: Immunosuppressives are frequently stopped in patients with granulomatosis with polyangiitis (GPA) (Wegener's granulomatosis) who develop end-stage renal disease. This is done because of the high frequency of infections reported among dialysis patients under immunosuppressives and the former impression that GPA patients no longer experience relapses after the development of end-stage renal disease. We present here a 22-year-old male patient with GPA who had gastrointestinal, genitourinary and respiratory system involvement. The patient died because of a gastrointestinal disease activation that occurred after immunosuppressives were stopped at the initiation of dialysis. The decision to stop immunosuppressives while starting dialysis should be made on an individual basis in patients with GPA, and the risks and benefits should be carefully evaluated.
[show abstract][hide abstract] ABSTRACT: HLA-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 Behçet's disease and HLA-B*52 in Takayasu's 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.
TAK 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.
We 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).
In 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.
Arthritis research & therapy 02/2012; 14(1):R27. · 4.27 Impact Factor
[show abstract][hide abstract] ABSTRACT: Takayasu's arteritis (TA) is a chronic arterial inflammation of unknown etiology involving mainly the aorta and its major branches. Based on the associations of programmed death-1 (PD-1) protein encoding gene (PDCD1) with connective tissue diseases and vasculitides, PDCD1 polymorphisms are studied for susceptibility to TA in this study.
The study group is made up of TA patients (n=229) fulfilling the 1990 ACR classification criteria and compared to 193 healthy controls (HC). PD-1.3, PD-1.5 and PD-1.6 single nucleotide polymorphisms of PDCD1 gene are genotyped by polymerase chain reaction and restriction analysis (PCR-RFLP).
The distribution of PD-1.5 polymorphism in TA patients and HC revealed a similar presence of TT genotype in patients and controls (13.3% vs. 11.4%). PD-1.3 and PD-1.6 were less polymorphic and did not differ between the groups. Rare AA genotype of PD-1.3 (1.4% vs. 1.0%) and AG genotype of PD-1.6 was again similarly (22.4% vs. 19.2%) present in TA and HC.
PD-1.3, 1.5 and 1.6 polymorphisms of PDCD1 gene, which were shown to be associated with various autoimmune disorders and vasculitides, are not associated with a susceptibility to TA in Turkish population.
[show abstract][hide abstract] ABSTRACT: Determination of oxidant stress in plasma of rheumatoid arthritis (RA) and primary osteoarthritis (POA) patients is important in understanding the pathogenesis of these diseases. In this study, we examined the relationship between oxidant stress and inflammation by measuring protein carbonyl content, thiol levels and plasma protein fractions as the oxidation markers and erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) tests as inflammation markers. Protein carbonyls content was higher in RA and POA patients, as compared to controls (p<0.0001), while the plasma thiol levels in both groups of patients were significantly lower than controls (p<0.0001). Increased levels of proteins under 40 kDa molecular mass were detected in the RA and POA patients compared to that of controls (p<0.0001) both in HPLC and SDS-PAGE analysis. Total protein concentration in plasma of RA patients was higher than the controls (p<0.001), while in POA patients was lower than that of controls (p<0.001). ESR and CRP levels were higher in both the patient groups than the normal group (p<0.001). These results suggested that alterations in the oxidant stress markers could be the cause of inflammation in these diseases. Thus, while working for RA/POA treatment strategies, consideration of the relationship between oxidant stress and inflammation would be worth evaluating.
Indian journal of biochemistry & biophysics 12/2010; 47(6):353-8. · 1.03 Impact Factor
[show abstract][hide abstract] ABSTRACT: Behçet's disease (BD) is a multisytemic vasculitis characterized by oral and genital ulceration, other skin lesions, uveitis and manifestations affecting the blood vessels, CNS and gastrointestinal system. It is rare in the Western world but is frequent in the Middle and Far East.
The aim of this review is to discuss treatment strategies in BD. These might vary between simple reassurance and a combination of immunosuppressives.
A systematic literature search was done using the Cochrane and Medline databases in June 2008. The EULAR recommendations for the management of BD were also taken into account.
The last two decades have witnessed considerable improvement in eye disease and musculoskeletal involvement. However, the treatment of thrombophlebitis, CNS, and gastrointestinal manifestations remains problematic.
Expert Opinion on Pharmacotherapy 01/2009; 9(18):3211-9. · 2.86 Impact Factor
[show abstract][hide abstract] ABSTRACT: We had the impression and preliminary evidence that atherosclerosis was not much increased in Behçet's syndrome (BS). Thus, we evaluated the presence of subclinical atherosclerosis in a sizeable group of patients with BS both with major organ involvement and mucocutaneous disease along with diseased and healthy controls.
We studied 239 (162 M/ 77 F; mean age: 40.7+/-7.0) patients with BS. Seventy-two (32 M/ 40 F) had only mucocutaneous and/or joint disease and 167 (130 M/ 37 F) had major organ involvement. Also 100 (24 M/ 76 F; mean age: 44.7+/-7.1) patients with rheumatoid arthritis (RA), 74 (58 M/ 16 F; mean age: 39.4+/-7.0) patients with ankylosing spondylitis (AS) and 156 (83 M/ 73 F; mean age: 39.2+/-6.6) healthy controls (HC) were studied as the control groups. We used B-mode USG to assess the frequency of plaques and intima-media thickness (IMT) in the carotid and femoral arteries. Traditional atherosclerotic risk factors were also evaluated. Men and women were analyzed separately.
The frequency of plaques and the mean IMT in the carotid and femoral arteries were similar between patients with BS, AS and HC and also between the 2 subgroups of BS, among both men and women. Only men with RA were found to have significantly increased frequency of carotid artery plaques after adjustment for atherosclerotic risk factors.
Increased atherosclerosis is not a prominent feature of BS, even among those patients with major organ involvement.
Seminars in Arthritis and Rheumatism 09/2008; 38(1):1-12. · 3.81 Impact Factor
[show abstract][hide abstract] ABSTRACT: Takayasu's arteritis (TA) is a chronic, rare granulomatous panarteritis of unknown aetiology involving mainly the aorta and its major branches. In this study, genetic susceptibility to TA has been investigated by screening the functional single nucleotide polymorphism (SNP) of PTPN22 gene encoding the lymphoid-specific protein tyrosine phosphatase.
Totally, 181 patients with TA and 177 healthy controls are genotyped by PCR-RFLP method for the SNP rs2476601 (A/G) of PTPN22 gene. Polymorphic region was amplified by PCR and digested with Xcm I enzyme.
Detected frequencies of heterozygous genotype (AG) were 5.1% (9/177) in control group and 3.8% (7/181) in TA group (P = 0.61, odds ratio: 0.75, 95% CI: 0.3, 2.0). No association with angiographic type, vascular involvement or prognosis of TA was observed either.
The distribution of PTPN22 polymorphism did not reveal any association with TA in Turkey.
[show abstract][hide abstract] ABSTRACT: Behçet's syndrome is characterized by clusters of disease expression, one of which is the coexistence of acne and arthritis. The aim of this study was to test the hypothesis that enthesopathy is increased in this cluster, having features reminiscent of acne-associated arthritis.
The study group comprised 35 patients with Behçet's syndrome who had acne and arthritis (BS-AA), 38 patients with Behçet's syndrome who did not have arthritis (BS-WA), 37 patients with ankylosing spondylitis (AS), 25 patients with rheumatoid arthritis (RA), and 25 healthy control subjects. Five entheseal sites (the superior and inferior poles of the patella, the tibial tuberosity, and the superior and inferior poles of the calcaneus) on both lower extremities were examined by 2 independent observers, using ultrasonography. A previously validated composite score was calculated for each patient. The numbers of entheseal sites giving a positive power Doppler signal in each group were also compared.
Patients with AS had the highest enthesopathy score (mean +/- SD 4.1 +/- 2.4; F [4df] = 8.43, P < 0.001) followed by BS-AA patients (3.0 +/- 1.9; F [3df] = 3.63, P = 0.015). The mean +/- SD enthesopathy scores among the remaining 3 groups were similar (for BS-WA, 1.8 +/- 1.4; for RA, 2.2 +/- 1.6; for healthy controls, 2.0 +/- 1.5 [F (2df) = 0.65, P = 0.53]). Power Doppler scores were highest for the BS-AA group (mean +/- SD 3.0 +/- 1.5; F [4df] = 15.54, P < 0.001) followed by the AS group (2.7 +/- 1.8; F [3df] = 14.38, P < 0.001), the RA group (2.6 +/- 1.8; F [2df] = 13.88, P < 0.001), the BS-WA group (1.2 +/- 1.3; F [1df] = 4.48, P = 0.038), and the control group (0.5 +/- 1.1). There was 87% agreement between the 2 observers (kappa = 0.55, intraclass correlation coefficient 0.71).
The increased presence of enthesopathy among BS-AA patients compared with that among BS-WA patients further supports the hypothesis that patients with Behçet's syndrome who also have arthritis and acne form a distinct cluster.
[show abstract][hide abstract] ABSTRACT: To investigate the role of shared epitope (SE) alleles in the short-term clinical response to leflunomide for the treatment of active RA.
In an open-label, multi-centre study of 16-weeks duration, 93 patients (82% female) fulfilling ARA 1987 RA criteria were treated with leflunomide (100 mg loading dose for 3 days, then 20 mg/day as the maintenance dose). The primary efficacy criterion was the response status according to the European League Against Rheumatism (EULAR) response criteria using Disease Activity Score-28 (DAS28) activity measure. SE determinations have been undertaken by polymerase chain reaction and sequence-specific oligonucleotide genotyping methods.
The mean (s.d.) Disease Activity Score-28 (DAS28) was 5.1 (1.3) before the treatment, which was significantly decreased after 16 weeks [3.0 (1.1), P < 0.001]. According to the EULAR response criteria, 55 patients (59.1%) were classified as good responders. SE was positive in 51 (54.8%) of the patients, with 13 (13.9%) having SE homozygosity or carrying any two SE alleles. Among SE-positive patients, 68.6% (35/51) were good responders, compared with 47.6% (20/42) in SE negatives (P = 0.04). No difference was present according to SE hetero- or homozygosity (68.4 vs 69.2%). RF was also present significantly more frequently in the SE-positive group compared with negatives (78.4 vs 57.1%, P = 0.03). However, no significant difference was observed in the prevalence of RF positivity in patients with a good clinical response (72.7 vs 63.2%, P = 0.32).
The results suggest that HLA-DRB1 SE presence may favourably affect the outcome of leflunomide monotherapy in an unselected group of RA patients with an active disease and naive to leflunomide.
[show abstract][hide abstract] ABSTRACT: Accumulation of oxidized proteins and impaired antioxidant system have been shown to be associated with arthritis. Serum sialic acid (SA) is known as a parameter of inflammation. In the present study, to explore the potential role of SA in arthritis, we measured serum SA levels, plasma protein oxidation, and antioxidant status in patients with primary osteoarthritis (POA) and inactive rheumatoid arthritis (RA). Inactive RA (iRA) was defined upon the American College of Rheumatology criteria for clinical remission of RA. A total of 40 patients (20 POA patients, including 4 male subjects, and 20 iRA female patients) and 20 healthy female subjects were included in this study. SA, antioxidants, and protein oxidation levels were determined spectrophotometrically in serum or plasma samples. Serum SA levels were significantly increased in POA (3.34 +/- 0.37 mM, p < 0.0001) and iRA (3.11 +/- 0.47 mM, p < 0.05), compared with healthy controls (2.41 +/- 0.16 mM). Plasma total antioxidant activity, plasma superoxide dismutase activity and serum reduced glutathione levels were significantly decreased in patients with POA and those with iRA, whereas plasma carbonyl content and serum total protein were increased in those patients. Moreover, plasma total thiol levels were significantly increased in iRA and decreased in POA. Thus, increased SA and protein oxidation levels are associated with the decreased antioxidant levels in POA and iRA patients. These results suggest that SA may be considered as a potent defense molecule against oxidative damage in arthritis. Antioxidant therapy may halt or ameliorate the progression of arthritis.
The Tohoku Journal of Experimental Medicine 11/2007; 213(3):241-8. · 1.37 Impact Factor
[show abstract][hide abstract] ABSTRACT: Tuberculin skin testing with purified protein derivative (PPD) is part of tuberculosis (TB) screening in patients receiving infliximab. We assessed whether infliximab, a strong inhibitor of inflammation, suppressed dermal induration, the outcome of this test. We also reassessed the booster phenomenon and the interobserver variability in tuberculin testing.
Forty-seven patients with various diagnoses, who had had a PPD test before infliximab use, were retested after infliximab treatment. The test was also assessed cross-sectionally among 31 patients with rheumatoid arthritis (RA) after 8.6 [+/- 4.1 standard deviation (SD)] months of infliximab use and in 82 patients with RA who had never used this agent. Booster phenomenon and the interobserver variability of reading the test were reassessed among 163 infliximab-naive patients with RA and Behcet's disease (BD) and 47 healthy controls.
Among the 47 patients who received infliximab, and for whom sequential data were available, the mean skin induration was 5.9 +/- 8.0 SD mm before and 6.1 +/- 7.5 mm after 4.8 +/- 3.7 months of treatment (p = 0.890). In the cross-sectional study the mean PPD induration was 7.8 +/- 8.4 mm among infliximab-naive patients with RA, while it was 6.6 +/- 2.1 mm in those receiving infliximab (p = 0.271). Booster phenomenon was observed in 14/49 (29%) of patients with RA, 7/31 (23%) of those with BD, and 1/10 of healthy controls. Interobserver variability of PPD reading was good (kappa = 0.92).
Infliximab use does not suppress the skin reaction to tuberculin. We confirm the booster phenomenon and that the PPD skin test has an acceptable interobserver reliability for an in vivo test.
The Journal of Rheumatology 04/2007; 34(3):474-80. · 3.26 Impact Factor
[show abstract][hide abstract] ABSTRACT: The acne lesions characteristic of Behçet's syndrome are not sterile and are commonly observed in combination with arthritis. The two main nodular skin lesions--superficial thrombophlebitis and erythema nodosum--are equally frequent, and rather difficult to distinguish. Superficial thrombophlebitis is usually observed in combination with thrombosis in large veins, and thrombosis of the large veins usually clusters with dural sinus thrombi, which make up approximately 20% of all central nervous system (CNS) lesions of Behçet's syndrome. The remaining CNS lesions are parenchymal, mainly located in the brainstem, and associated with a graver prognosis than dural sinus thrombi. The presence of clinical clusters indicates that there are at least two pathogenetic pathways in Behçet's syndrome: a reactive arthritis pathway and a thrombophilia pathway. Research into the pathogenesis of Behçet's syndrome has shown that the most consistent genetic marker of Behçet's syndrome is HLA-B51; however, the genetic association of this true-to-form 'complex' disorder with HLA-B51 is only 20%, and a whole-genome study showed associations with 16 different loci. The severity of Behçet's syndrome and the mortality associated with it tend to decrease with time, and there is no associated increase in incidence of atherosclerosis. Although treatment of skin-mucosa manifestations, eye disease and pulmonary artery aneurysms has improved significantly in the past decades, the treatment of CNS lesions and thrombophilia are still problematic.
Nature Clinical Practice Rheumatology 04/2007; 3(3):148-55. · 5.85 Impact Factor
[show abstract][hide abstract] ABSTRACT: Takayasu's arteritis (TA) is a chronic arterial inflammation of unknown etiology involving mainly the aorta and its major branches. Genetic polymorphisms of cytokines are screened as susceptibility factors for TA in Turkey. A total of 94 patients with TA were investigated for the genetic polymorphisms of the interleukin genes IL12, IL2,and IL6 and were compared with 108 healthy control subjects using polymerase chain reaction-sequence-specific primer method. The frequencies of IL12B 1188 C allele (p = 0.03, OR = 1.7) and CC genotype (p = 0.007, OR = 3.7) were both higher in TA patients than in control subjects. TT genotype at IL2-330 (p = 0.006, OR = 2.4) and GG genotype at IL6-174 (p = 0.04, OR = 1.9) were more frequent in TA patients. Lower prevalence of GT genotype at IL2-330 (p = 0.005, OR = 0.4), CG genotype at IL6-174 (p = 0.001, OR = 0.4), and AG genotypes at IL6-598 (p = 0.01, OR = 0.4) were also detected. The polymorphism of IL-12 as well as IL-6 and IL-2 genes may contribute to susceptibility and pathogenesis of TA by altering cytokine production and inducing inflammation.
Human Immunology 10/2006; 67(9):735-40. · 2.30 Impact Factor
[show abstract][hide abstract] ABSTRACT: Corticosteroids are widely used in Behçet's syndrome despite the absence of controlled studies. We assessed the effect of depot corticosteroids primarily for genital ulcers and secondarily for the other mucocutaneous manifestations of Behçet's syndrome.
We randomized 86 patients who had active disease with genital ulcers to receive either intramuscular corticosteroid injections (40 mg methylprednisolone acetate) or placebo every 3 weeks for 27 weeks.
Seventy-six patients (88%) completed the treatment. There were no significant differences in the mean number of genital and oral ulcers, or folliculitis between groups. The mean number of erythema nodosum lesions was less in the corticosteroid group as a whole (P = 0.0046); subgroup analyses revealed that this was significant for females (P = 0.0148) but not for males (P = 0.1).
Low-dose depot corticosteroids did not have any beneficial effect on genital ulcers. However, it was useful in controlling erythema nodosum lesions, especially among the females.