Yasar Karaaslan

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)).

A multicenter study of patients with adult-onset Still’s disease compared with systemic juvenile idiopathic arthritis

Adult-onset Still’s disease (AOSD) has often been regarded as the adult spectrum of systemic juvenile idiopathic arthritis (sJIA). The present study aims to compare the clinical and laboratory features, the disease course and the response to treatment in patients having AOSD with those having sJIA. Retrospective review of all available data that were filled out by adult and paediatric rheumatologists from six centers using a standard data extraction form was performed. A total of 95 patients with AOSD and 25 patients with sJIA were recruited for the study. The frequency of fever, rash, myalgia, weight loss and sore throat was higher in patients with AOSD. The pattern of joint involvement differed slightly. Laboratory findings were similar in both groups, except that liver dysfunction and neutrophilia were more common among adults. A multiphasic pattern dominated the childhood cases, whereas the most frequent course was a chronic one in adults. Corticosteroids and methotrexate were the most commonly employed therapy; however, chloroquine was another popular therapy in the adult group. We showed a difference in the rate of clinical and laboratory features between patients with AOSD and those with sJIA. AOSD and sJIA may still be the same disease, and children may simply be reacting differently as the result of the first encounter of the putative antigens with the immune system.

Selectin adhesion molecules in Behçet's disease

OBJECTIVES The pathogenesis of Behçets disease (BD) is closely related to endothelial cells, leucocyte functions and autoimmunity. The aim of this study was to investigate circulating selectin adhesion molecules, which are known to play a significant part in the immune response especially by regulating interactions of the leucocytes with endothelium, in BD. METHODS Plasma E-, L-, and P-selectin concentrations were evaluated in 11 patients with widespread BD (group I), 10 cases with merely mucocutaneous involvement (group II) and 15 age and sex matched healthy control subjects. The patients were newly or previously diagnosed cases not taking any drug for BD. RESULTS Plasma concentrations of all selectins were significantly higher in group I compared with group II. E-selectin and P-selectin were significantly increased in each subgroup of patients compared with the healthy controls. L-selectin concentrations were higher than the controls only in group I. CONCLUSIONS Increases in the selectins in BD may be a direct consequence of the leucocyte, endothelium and platelet activations observed during the disease process. However, abnormal/increased selectin expression to various triggers should also be considered. More prominent increases in patients with extensive disease suggest that circulating selectin concentrations are related to disease severity.

Effects of interferon-α2a treatment on serum levels of tumor necrosis factor-α, tumor necrosis factor-α2 receptor, interleukin-2, interleukin-2 receptor, and E-selectin in Behçet's disease

Abstract This study was performed to investigate serum levels of various cytokines and E-selectin in patients with Behçets disease (BD) before and after treatment with interferon-α2a (IFN-α). The study population consisted of 22 patients with active BD; 15 age- and sex-matched healthy adults served as the control group. IFN-α (3 million units subcutaneously) was given to all patients twice a week for 3 months. Twenty of twenty-two patients experienced clinical improvement with this therapy. Pre- and post-treatment serum levels of tumor necrosis factor-α (TNF-α), TNF-α2-receptor (TNFα2R), interleukin-2 (IL-2), IL-2 receptor (IL-2R), and E-selectin were measured by sandwich-type enzyme immunoassay. Baseline E-selectin, TNF-α, and TNF-α2R levels of the patients were increased in comparison with the control group and post-treatment values. However, IL-2 and IL-2R levels did not change either with treatment or compared with the control group levels. In conclusion, these results confirm the previously described efficacy of IFN-α in the treatment of BD. Serum levels of TNF-α, TNF-α2R, and E-selectin are prominently increased during active stage of the disease, indicating presence of immune system activation and endothelial injury/activation. Improvement of the pathological cytokinemia and endothelial disturbance accompany interferon-α-induced disease remission.

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.

Alterations in left ventricular function in patients with Behçet's disease using radionuclide ventriculography and Doppler echocardiography.

Behçets syndrome is a multisystem disease; however, cardiac involvement in this disorder has been relatively less recognized. Noninvasive imaging methods may reveal a cardiac disorder which has not manifested itself clinically. In this study, radionuclide ventriculography and Doppler echocardiography were performed in 24 patients with Behçets disease to assess the left ventricular systolic and diastolic function. Patients had neither known heart disease nor cardiac symptoms. Radionuclide ventriculography was performed using 99mTc-labeled red blood cells. Ejection fraction (EF), EF fraction in the first 100 ms (EFV), peak ejection rate, time to peak ejection, 1/3 EF, time to end systole, peak filling rate (PFR), time to peak filling and 1/3 filling fraction (1/3 FF) values were computed using Fourier analysis of the time activity curve of the left ventricle with 3 harmonics. Doppler echocardiography (DE) has described impairment of diastolic compliance using analysis of mitral flow. The mean EF (54.7 +/- 9%), EFV (11.6 +/- 3.6%), PFR (2.49 +/- 0.58 EDC/s) and 1/3 FF (33.64 +/- 14%) values were significantly lower in patients than those of the control group. Nine (37.5%) patients demonstrated an impairment of diastolic function and 3 (12.5%) had abnormal systolic function observed by the radionuclide method. DE showed abnormal ventricular compliance in 13.6% of patients. As a conclusion, noninvasive imaging methods such as radionuclide ventriculography and DE may be valuable to detect diastolic impairment as an early sign of cardiac involvement in Behçets disease.

Autoimmune liver disease in patients with systemic lupus erythematosus: A retrospective analysis of 147 cases

Abstract Objective. We aimed to investigate the characteristics of autoimmune liver disease (AILD) developed in patients with systemic lupus erythematosus (SLE), including autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and the AIH/PBC overlap syndrome. We also evaluated the accuracy of diagnostic criteria and scoring systems for AILD in SLE. Methods. A retrospective analysis of patients attending the rheumatology and gastroenterology clinics in Ankara, Turkey, between 1999 and 2010. SLE patients with elevated liver enzymes were investigated for liver diseases. Results. A total of 147 SLE patients were identified and 36 of them had liver enzyme abnormalities. AILD was diagnosed in 4.7% of all SLE patients, in 19.4% of those with elevated liver enzymes. Of patients with liver enzyme abnormalities, 72.3% fulfilled the criteria for AIH proposed by the International Autoimmune Hepatitis Group (IAIHG), whereas 66.7% had AIH by using the simplified criteria. Yet, only 13.8% of these patients had liver biopsy findings consistent with AIH. Patients with AILD were treated with conventional therapy including ursodeoxycholic acid, prednisolone, azathioprine or combinations of these. Treatment failure and subsequent advanced liver disease developed in one patient. Conclusions. AILD may occur during the course of SLE. Due to biochemical similarities between AIH and SLE, AIH could be considered very probable by using both IAIHG scoring system and simplified criteria. For definitive diagnosis of AIH, liver biopsy should be performed in all SLE patients with chronic enzyme abnormalities. The response to therapy is favorable in these patients, and early diagnosis is important for preventing advanced liver disease.

Identification of Susceptibility Loci in IL6, RPS9/LILRB3, and an Intergenic Locus on Chromosome 21q22 in Takayasu Arteritis in a Genome-Wide Association Study

Takayasu arteritis is a rare large vessel vasculitis with incompletely understood etiology. This study was undertaken to perform the first unbiased genome‐wide association analysis of Takayasu arteritis.

Hemostatic parameters in Behçet's disease: a reappraisal.

Abstract. Behçets disease (BD) is a relapsing vasculitis in which orogenital ulceration is a prominent feature. The disease presents a tendency to thrombosis. The prevalence of venous or arterial thrombosis in BD reaches 40% in some series. Molecular markers of imbalance have been extensively studied in BD. The aim of this paper is to review current data on essential hemostatic parameters. The precise pathogenetic mechanism(s) underlying the prothrombotic state of BD is unknown. Thrombophilic factors could contribute to thrombosis in BD. Vasculitic endothelial injury may trigger or enhance the pathological hemostatic process.

Osteomalacia Associated with Carbamazepine/Valproate

1. Borland CD, Farrar WE. Reversible neutropenia from vancomycin. JAMA 1979;242:2392-3. 2 . Kesarwala HH, Rahill WJ, Amaran N. Vancomycin induced neutropenia (letter). Lancet 1981;1(8235):1423. 3 . Morris A, Ward C. High incidence of vancomycin-associated leucopenia and neutropenia in a cardiothoracic surgical unit. J Infect 1991;22:21723. 4 . Vancomycin hydrochloride. In: Reynolds JEF, Parfitt K, eds. Martindale: the extra pharmacopoeia. 29th ed. London: The Pharmaceutical Press, 1989:332-3. 5 . Mandl DL, Garrison MW, Palpant SD. Agranulocytosis induced by vancomycin or ticarcillin/clavulanate. Ann Pharmacother 1997;31:1321-4. 6 . Farber BF, Mollering RC Jr. Retrospective study of the toxicity of preparations of vancomycin from 1974 to 1981. Antimicrob Agents Chemother 1983;23:138-41. 7 . Walker RW, Heaton A. Thrombocytopenia due to vancomycin (letter). Lancet 1985;1(8434):932. 8. Carmichael AJ, Al-Zahawi MF. Pancytopenia associated with vancomycin (letter). BMJ 1986;293:1103. 9 . Shinohara YT, Colbert J. Vancomycin-induced neutropenia during treatment of endocarditis in a pediatric patient. Ann Pharmacother 1994;28: 7 2 3 6 . 1 0 . Wallace MR, Mascola JR, Oldfield EC 3rd. Red Man syndrome: incidence, etiology, and prophylaxis. J Infect Dis 1991;164:1180-5. 1 1 . Newfield P, Roizen MF. Hazards of rapid administration of vancomycin (letter). Arch Intern Med 1979;91:581. 1 2 . Pau AK, Khakoo R. “Red-Neck syndrome” with slow infusion of vancomycin. N Engl J Med 1985;313:756-7. 13. Dipyrone. In: Partiff K, ed. Martindale: the complete drug reference. 32nd ed. Taunton, MA: Pharmaceutical Press, 1999:35. 1 4 . Bactrim (trimethoprim/sulfamethoxazole). In: Physician’s desk reference. 50th ed. Montvale, NJ: Medical Economics Co., Inc., 1996:2082-7. 1 5 . Fortaz (ceftazidime for injection, Glaxo). In: Physician’s desk reference. 53rd ed. Montvale, NJ: Medical Economics Co., Inc., 1999:1130-2. 1 6 . Rains CP, Bryson HM, Peters DH. Ceftazidime. Drugs 1995;49:5776 1 7 . 1 7 . Clayman MD, Capaldo RA. Vancomycin allergy presenting as fever of unknown origin. Arch Intern Med 1989;149:1425-6. 1 8 . Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.