Rheumatoid Arthritis: Berkun Y

Nagar M, Vernitsky H, Cohen Y, Dominissini D, Berkun Y, Rechavi G, Amariglio N, Goldstein I. · Sheba Cancer Research Center, The Chaim Sheba Medical Center, Tel Hashomer and Tel Aviv University-Sackler Faculty of Medicine, Israel. · Int Immunol. · Pubmed #18567616 No free full text.

Abstract: The transcription factor forkhead box P3 (FOXP3 in humans; Foxp3 in mice) controls the development and function of regulatory T cells (Treg). In mice, CD4(+)CD25(-) T cells do not express Foxp3 following TCR activation. Whether FOXP3 is a common activation-induced molecule in human T cells--hence not Treg restricted--is currently a controversial issue. As FOXP3 can significantly modulate the function of T cells, understanding the mode (and regulation) of FOXP3 expression in human T cells is vital. Here we show that in conventional CD4(+)CD25(-) T cells, the induction of FOXP3 expression following TCR activation is both restricted to a fraction of the progeny and transient. Moreover, FOXP3 expression in vivo is particularly infrequent in activated effector CD4(+) T cells that accumulate within inflamed joints. We next demonstrate that the repression of FOXP3 transcription in resting conventional human CD25(-) T cells is linked to complete methylation of an evolutionarily conserved intronic CpG island. The dense methylation pattern is furthermore inherited after activation by progeny. This intronic CpG island, on the other hand, is frequently unmethylated in CD4(+)CD25(+) T cells. Importantly, blocking maintenance DNA methylation, by pharmacological inhibition of DNA methyltransferase-1, induced significant and stable activation-dependent FOXP3 expression in cycling conventional T cells, which was further amplified by co-treatment with transforming growth factor beta. In contrast to natural Treg, such induced CD4(+)FOXP3(+) T cells could produce pro-inflammatory cytokines upon activation. These results indicate that DNA methylation normally restricts FOXP3 transcription in conventional human T cells.

Berkun Y, Abou Atta I, Rubinow A, Orbach H, Levartovsky D, Aamar S, Arbel O, Dresner-Pollak R, Friedman G, Ben-Yehuda A. · Department of Pediatrics, Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel. · J Rheumatol. · Pubmed #17611986 No free full text.

Abstract: OBJECTIVE: To investigate the distribution of the A2756G polymorphism of the methionine synthase reductase (MTR) gene in patients with rheumatoid arthritis (RA) treated with methotrexate (MTX) compared with a healthy control group; and to examine the relationships among the A2756G polymorphism, plasma total homocysteine (tHcy), serum folate and vitamin B12 levels, disease activity, and MTX toxicity in patients with RA. METHODS: A cross-sectional study was performed on 86 MTX-treated RA patients, consisting of a clinical interview and physical examination to determine disease activity and MTX-related adverse reactions. Genotype analysis of the MTR gene was performed. Fasting plasma tHcy, serum folate, and vitamin B12 levels were measured. Allele and genotype distributions were compared to a healthy control group. RESULTS: The frequency of the 2756GG genotype (16.3%) in the RA study group was higher than that expected in the general population (3.6%; p < 0.000001). This genotype was associated with MTX-induced accelerated rheumatoid nodulosis (MIARN). No association of disease activity variables or plasma homocysteine with MTR A2756G polymorphisms was observed. The MTR 2756GG genotype, low plasma vitamin B12 levels, and the presence of rheumatoid nodules predicted MIARN. No association of nodulosis with any other indicator of disease activity or medical treatment was found. CONCLUSION: In our population of MTX-treated RA patients the 2756GG genotype of the MTR gene was more common than expected and was associated with MIARN.

Breuer GS, Orbach H, Elkayam O, Berkun Y, Paran D, Mates M, Nesher G. · Rheumatology Service, Department of Internal Medicine, Shaare Zedek Medical Center, Jerusalem, Israel. · Isr Med Assoc J. · Pubmed #16599054 links to  free full text

Abstract: BACKGROUND: Complementary and alternative medicine has recently attracted attention due to its widespread use. In a recent study in Israel, almost a half of CAM users in the general population used it for joint diseases or back pain. OBJECTIVE: To evaluate the prevalence of CAM use among patients with defined rheumatic diseases, and analyze the demographic features of CAM users, their reasons for using CAM and the use of specific CAM methods. METHODS: We conducted face-to-face structured interviews of 350 patients attending rheumatology clinics, regarding past or present use of CAM, specifying the various CAM types they used, and reasons for using CAM. Demographic data including age, gender, country of birth and origin, and level of education were also collected. RESULTS: Altogether, 148 patients reported using CAM (42%). In general, homeopathy and acupuncture were the most commonly used types (44% and 41% of the patients, respectively). The mean number of CAM methods per patient was 1.9 +/- 1.1. CAM was more commonly used by patients with advanced education (52% vs. 37% of patients with lower education, P= 0.007). Patients with rheumatoid arthritis used CAM significantly less than patients with other rheumatologic conditions (32% vs. 48%, P= 0.008). CONCLUSION: CAM use is influenced by level of education. The choice of the preferred CAM method among patients with rheumatic diseases seemed to follow the popular CAM methods in the general population, and was not specific to rheumatic diseases.

Breuer GS, Orbach H, Elkayam O, Berkun Y, Paran D, Mates M, Nesher G. · Rheumatology Service, Department of Internal Medicine, Shaare-Zedek Medical Center and the Hebrew University Medical School, Jerusalem, Israel. · Clin Exp Rheumatol. · Pubmed #16173249 No free full text.

Abstract: OBJECTIVE: The purpose of this cross-sectional survey was to obtain and analyze data on self-perceived efficacy of different types of complementary alternative medicine (CAM) by patients with various rheumatologic conditions. METHODS: Patients followed in rheumatology outpatient clinics were screened for the use of CAM. Patients reporting the use of CAM were asked to participate in face-to-face structured interviews, specifying the various CAM types they used, and grading their subjective impression of efficacy of each CAM type on a scale of 1-10. RESULTS: 350 consecutive patients were screened and 148 reported using CAM. In general, homeopathy and acupuncture were the most commonly used CAM types (44% and 41% of the CAM users, respectively). The mean number of different CAM methods used by a CAM user was 1.9 +/- 1.1. Patients with fibromyalgia used significantly more CAM methods (2.7 +/- 1.4, p = 0.005). On patients' self-perceived efficacy scale of 1-10, the mean score of the whole group was 5.3 +/- 3.2. Acupuncture and homeopathy achieved significantly higher self-perceived efficacy scores in CAM users with spondylo-arthropathies and osteoarthritis, respectively, when compared to some of the other disease groups. Satisfaction was lowest among CAM users with rheumatoid arthritis, vasculitis and connective tissue diseases. CONCLUSION: In general, CAM users were less than moderately satisfied with self-perceived-efficacy of CAM therapies. However efficacy of specific CAM methods differed significantly among patients in different disease groups.

Berkun Y, Levartovsky D, Rubinow A, Orbach H, Aamar S, Grenader T, Abou Atta I, Mevorach D, Friedman G, Ben-Yehuda A. · Department of Paediatrics, Bikur Cholim General Hospital, POB 492, Jerusalem 91004, Israel. · Ann Rheum Dis. · Pubmed #15361376 links to  free full text

Abstract: BACKGROUND: There is an association between C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene and methotrexate related toxicity. OBJECTIVE: To examine the relations between the recently described A1298C polymorphism of the MTHFR gene, plasma homocysteine, methotrexate toxicity, and disease activity in patients with rheumatoid arthritis. DESIGN: A cross sectional study on 93 methotrexate treated patients with rheumatoid arthritis, comprising a clinical interview and physical examination to determine disease activity and methotrexate related adverse reactions. Genotype analysis of the MTHFR gene was carried out and fasting plasma homocysteine and serum folate concentrations were measured. The data were analysed using univariate analysis. Allele and genotype distributions were compared with those of a healthy control group. RESULTS: The frequency of the 1298CC genotype (24.7%) in the rheumatoid study group was greater than expected in the general population (12.8%, p<0.001). This genotype was associated with a significantly low rate of methotrexate related side effects. The odds ratio for side effects in patients with wild type 1298AA genotype v 1298CC genotype was 5.24 (95% confidence interval, 1.38 to 20). No correlation of disease activity variables or plasma homocysteine with MTHFR A1298C and C677T polymorphisms was observed. CONCLUSIONS: 1298CC polymorphism was more common in methotrexate treated rheumatoid patients than expected in the population, and was associated with a reduction in methotrexate related adverse effects. The A1298C polymorphism of the MTHFR gene may indicate a need to adjust the dose of methotrexate given to patients with rheumatoid arthritis.