Rheumatoid Arthritis: Szántó S

Szekanecz Z, Kerekes G, Dér H, Sándor Z, Szabó Z, Végvári A, Simkovics E, Soós L, Szentpétery A, Besenyei T, Szücs G, Szántó S, Tamási L, Szegedi G, Shoenfeld Y, Soltész P. · Division of Rheumatology, Third Department of Medicine, University of Debrecen Medical and Health Science Center, Debrecen, Hungary. · Ann N Y Acad Sci. · Pubmed #17893998 No free full text.

Abstract: Cardiovascular disease is a leading cause of mortality in rheumatoid arthritis (RA). Endothelial dysfunction often precedes manifest atherosclerosis. Both traditional, Framingham risk factors and inflammation-associated factors are involved in RA-associated atherosclerosis. Among imaging techniques, the early determination of common carotid intima-media thickness (ccIMT), flow-mediated vasodilation (FMD), and nitroglycerine-mediated vasodilation (NMD) may be useful to determine atherosclerosis and endothelial dysfunction. We and others found increased ccIMT and impaired FMD in RA patients. Among immunological and metabolic laboratory markers, anticyclic citrullinated peptide (anti-CCP) antibodies, IgM rheumatoid factor, circulating immune complexes, pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), Th0/Th1 T cells, homocysteine, dyslipidemia, decreased folate and vitamin B12 production, and impaired paraoxonase activity may all be involved in the development of vascular disease in RA. The early diagnosis of endothelial dysfunction and atherosclerosis, active immunosuppressive treatment, the use of drugs that control atherosclerosis, changes in sedentary lifestyle, and the close follow-up of RA patients may help to minimize cardiovascular risk in these individuals.

Szekanecz Z, Szücs G, Szántó S, Koch AE. · Division of Rheumatology, Third Department of Medicine, University of Debrecen Medical and Health Sciences Center, Debrecen, H-4004, Hungary. · Curr Drug Targets. · Pubmed #16454702 No free full text.

Abstract: Chemotactic cytokines, termed chemokines, mediate the ingress of leukocytes into the inflamed synovium. In this review, authors discuss the role of the most relevant chemokines and chemokine receptors involved in chronic inflammatory rheumatic diseases. Rheumatoid arthritis was chosen as a prototype to discuss these issues, as the majority of studies on the role of chemokines in inflammatory diseases were carried out in arthritis. However, other rheumatic diseases including systemic lupus erythematosus, systemic sclerosis, Sjögren's syndrome, mixed connective tissue disease, polymyositis/dermatomyositis, antiphospholipid syndrome and systemic vasculitides are also discussed in this context. Apart from discussing the pathogenic role of chemokines and their receptors, authors also review the regulation of chemokine production by other inflammatory mediators, as well as the important relevance of chemokines for antirheumatic therapies.

Glant TT, Szántó S, Vegvari A, Szabo Z, Kis-Toth K, Mikecz K, Adarichev VA. · Department of Orthopedic Surgery, Section of Molecular Medicine, Rush University Medical Center, Chicago, IL 60612, USA. · J Immunol. · Pubmed #18606685 links to  free full text

Abstract: Using genetic linkage analysis of proteoglycan-induced arthritis (PGIA), a murine model for rheumatoid arthritis, we identified two loci, Pgia8 and Pgia9, on chromosome 15 (chr15) that appear to be implicated in disease susceptibility. Immunization of congenic strains carrying the entire chr15 and separately each of the two loci of DBA/2 arthritis-resistant origin in susceptible BALB/c background confirmed locations of two loci on chr15: the major Pgia9 and lesser Pgia8 locus. Distal part of chr15 (Pgia9) showed a major suppressive effect on PGIA susceptibility in females (40%, p < 0.001), whereas the effect of this locus in congenic males was still significant but weaker. Proximal part of chr15 (Pgia8) demonstrated mild and transient effect upon arthritis; this effect was PGIA-promoting in males and suppressive in females. Pgia8 and Pgia9 loci demonstrated an additive mode of inheritance, since when they were both incorporated in consomic chr15 strain, the total effect was a sum of the two loci. Using F(2) population of the intercross of wild-type and chr15 consomic strain, we confirmed and refined quantitative trait locus positions and identified a strong correlation between disease susceptibility and lymphocyte-producing cytokines of TNF-alpha and IL-6. Both Pgia8 and Pgia9 loci on chr15 appear to control IL-6 production in spleen cultures of arthritic mice, providing an important link to the mechanism of autoimmune inflammation.

Szekanecz Z, Soós L, Szabó Z, Fekete A, Kapitány A, Végvári A, Sipka S, Szücs G, Szántó S, Lakos G. · Division of Rheumatology, 3rd Department of Medicine, Medical and Health Science Center, University of Debrecen, 22 Moricz Street, Debrecen, H-4004, Hungary, · Clin Rev Allergy Immunol. · Pubmed #18270854 No free full text.

Abstract: Anti-citrullinated protein antibodies (ACPAs) have recently emerged as sensitive and specific serological markers of rheumatoid arthritis (RA), providing superior alternative of the rheumatoid factor (RF) test in the laboratory diagnostics of RA. The first members of this autoantibody family were anti-perinuclear factor (APF) and anti-keratin antibodies (AKA). It became evident that both APF and AKA recognize citrullinated epitopes of filaggrin. Citrullination is a post-translational modification of arginine by deimination, physiologically occurring during apoptosis, inflammation or keratinization. The presence of several citrullinated proteins has been demonstrated in the RA synovium. The identification of citrullinated epitopes as targets for anti-filaggrin antibodies led to the development of the first and later second generation anti-cyclic citrullinated peptide (anti-CCP) antibody assays. The widely used anti-CCP2 assays have high diagnostic sensitivity and specificity, and they also show important predictive and prognostic value in RA. The anti-Sa antibody has been identified a decade ago; however, recent studies confirmed that anti-Sa is directed against citrullinated vimentin, hence it is a new member of the family of ACPAs. The newly developed anti-mutated citrullinated vimentin (anti-MCV) assay has similar diagnostic performance than the anti-CCP2 ELISA; however, the diagnostic spectrum of the anti-MCV test is somewhat different from that of anti-CCP2. It's especially useful in the diagnosis of RA in RF and anti-CCP2 seronegative patients. The combined application of anti-CCP2 and anti-MCV assays can improve the laboratory diagnostics of RA. The family of ACPAs is expected to expand; there is an increasing need for developing new diagnostic strategies after careful evaluation of the characteristics of the available assays.

Szántó S, Koreny T, Mikecz K, Glant TT, Szekanecz Z, Varga J. · Section of Molecular Medicine, Department of Orthopedic Surgery, Rush University Medical Center, Cohn Research Building, Room 708, 1735 W, Harrison, Chicago, IL 60612, USA. · Arthritis Res Ther. · Pubmed #17511858 links to  free full text

Abstract: Indoleamine 2,3-dioxygenase (IDO) is one of the initial and rate-limiting enzymes involved in the catabolism of the essential amino acid tryptophan. In cultured cells, the induction of IDO leads to depletion of tryptophan and tryptophan starvation. Recent studies suggest that modulation of tryptophan concentration via IDO plays a fundamental role in innate immune responses. Induction of IDO by interferon-gamma in macrophages and dendritic cells results in tryptophan depletion and suppresses the immune-mediated activation of fibroblasts and T, B, and natural killer cells. To assess the role of IDO in collagen-induced arthritis (CIA), a model of rheumatoid arthritis characterized by a primarily Th1-like immune response, activity of IDO was inhibited by 1-methyl-tryptophan (1-MT) in vivo. The results showed significantly increased incidence and severity of CIA in mice treated with 1-MT. Activity of IDO, as determined by measuring the levels of kynurenine/tryptophan ratio in the sera, was increased in the acute phase of arthritis and was higher in collagen-immunized mice that did not develop arthritis. Treatment with 1-MT resulted in an enhanced cellular and humoral immune response and a more dominant polarization to Th1 in mice with arthritis compared with vehicle-treated arthritic mice. The results demonstrated that development of CIA was associated with increased IDO activity and enhanced tryptophan catabolism in mice. Blocking IDO with 1-MT aggravated the severity of arthritis and enhanced the immune responses. These findings suggest that IDO may play an important and novel role in the negative feedback of CIA and possibly in the pathogenesis of rheumatoid arthritis.

Szücs G, Szekanecz Z, Zilahi E, Kapitány A, Baráth S, Szamosi S, Végvári A, Szabó Z, Szántó S, Czirják L, György Kiss C. · Third Department of Medicine, Rheumatology Division, University of Debrecen Medical and Health Science Center, 22 Móricz Zs str, Debrecen H-4004, Hungary. · Rheumatology (Oxford). · Pubmed #17384178 links to  free full text

Abstract: OBJECTIVE: To determine the genetic, clinical and serological characteristics of systemic sclerosis (SSc)-rheumatoid arthritis (RA) overlap syndrome. METHODS: Clinical manifestations and immunolaboratory features of 22 SSc-RA patients were assessed. The HLA-DR genotype of the 22 SSc-RA patients determined by SSP-PCR was compared with that of 38 SSc patients, 100 RA patients and 50 healthy controls. RESULTS: All overlap patients fulfilled the American College of Rheumatology (ACR) criteria for SSc and RA. Five of the 22 patients (23%) had diffuse cutaneous SSc (dcSSc) and 17 patients (77%) had limited cutaneous SSc (lcSSc). Antinuclear antibody, anti-Scl70, IgM rheumatoid factor and anti-CCP antibody positivity were detected in 22 (100%), 5 (23%), 16 (73%) and 18 patients (82%), respectively. Seventeen patients (77%) had pulmonary fibrosis, 12 (55%) had oesophageal dismotility, 11 (50%) had cardiac and five (23%) had renal involvement. Hand joint destruction was observed in 18 patients (82%). Significantly increased frequencies of HLA-DR3 (36% vs 5%), HLA-DR7 (9% vs 4%), HLA-DR11 (36% vs 7%) and HLA-DRw53 (23% vs 5%) were observed in SSc-RA compared with RA patients (P < 0.05). Allele frequencies of the 'shared epitope' (HLA-DR1 and -DR4) were significantly increased in SSc-RA (32% and 27%, respectively) and RA patients (46% and 31%, respectively) in comparison with SSc patients (10.5% and 16%, respectively) or healthy controls (16% and 14%, respectively) (P < 0.05). CONCLUSIONS: To date this is the largest SSc-RA overlap cohort. Genetics, clinical and immunolaboratory features suggest a mixed phenotype. Our data suggest that SSc-RA overlap syndrome may be a distinct genetic, immunological and clinical entity.

Gál I, Bajnok E, Szántó S, Sarraj B, Glant TT, Mikecz K. · Rush University Medical Center, Chicago, Illinois 60612, USA. · Arthritis Rheum. · Pubmed #16206283 links to  free full text

Abstract: OBJECTIVE: To describe the kinetics of leukocyte migration into a distal joint during the development of chronic inflammation in a murine model of rheumatoid arthritis (RA), to identify leukocyte subpopulations recruited in the synovial vessels, and to test in real time the effects of an antiinflammatory compound on leukocyte-endothelial cell interactions in the arthritic joint. METHODS: We used intravital video microscopy (IVM), which was adapted to the microcirculation of the mouse ankle, to monitor the kinetics of leukocyte-endothelium interactions (rolling and firm adhesion) during the onset and progression of proteoglycan-induced arthritis (PGIA), a chronic autoimmune model of RA. Subpopulations of rolling and adherent leukocytes were identified by in vivo immunostaining. Leukocyte extravasation into the ankle joint was verified histologically. RESULTS: Between the onset of arthritis and the beginning of the destructive phase of PGIA, we found a steady increase in the number of leukocytes that exhibited firm adherence to the endothelium of synovial vessels, which clearly underscores the chronic, self-perpetuating character of joint inflammation in this autoimmune model. We showed, however, that granulocytes, and not T cells, constituted the major cell population that was continuously recruited to the inflamed ankle. Using IVM, we could detect instant changes in leukocyte adhesion behavior in the synovial vessels of the arthritic joint upon administration of a compound that antagonizes leukocyte rolling. CONCLUSION: IVM of the microcirculation of the mouse ankle could become an essential tool for investigating the mechanisms that regulate leukocyte migration to the joint in systemic models of RA as well as for preclinical testing of antiinflammatory therapies.

Kapitány A, Zilahi E, Szántó S, Szücs G, Szabó Z, Végvári A, Rass P, Sipka S, Szegedi G, Szekanecz Z. · Laboratory of Immunology, Third Department of Medicine, University of Debrecen Medical Center, 22 Moricz Zs Street, Debrecen H-4004, Hungary. · Ann N Y Acad Sci. · Pubmed #16126967 No free full text.

Abstract: Susceptibility to and outcome for rheumatoid arthritis (RA) have been associated with particular HLA-DR alleles, but these alleles vary among ethnic groups and geographic areas. The frequency of HLA-DR1 (HLA-DRB1*0101, DRB1*0102) and HLA-DR4 (DRB1*0401, DRB1*0404) alleles is elevated among Caucasian patients with RA. We studied a northeastern Hungarian population of RA patients to determine the frequency of HLA-DR1 and HLA-DR4 phenotypes in this population and to compare it with healthy control subjects, as well as to investigate whether the presence of these alleles could be a marker for RA. We performed HLA-DRB1 genotyping (DRB1*01-DRB1*16) in 83 RA patients and 55 healthy controls using polymerase chain reaction with sequence-specific primers (PCR-SSP). In the case of HLA-DR1- or HLA-DR4-positive patients, the DR1 and DR4 subtypes were also determined. The frequency of HLA-DR4 alleles was significantly higher in RA patients than in controls (31.3 vs. 10.9%; P <.05). HLA-DR1, in particular, tended to be more frequent in patients than in controls (32.5 vs. 18.1%). Among the HLA-DR4 subtypes, DRB1*0401 and DRB1*0404 were the most common alleles found in both groups. However, no significant differences were seen in the frequency of HLA-DRB1*0401 and HLA-DRB1*0404 between RA patients and controls. In contrast, HLA-DRB1*0405 and HLA-DRB1*0408 were significantly more common in RA patients than in control subjects. Among HLA-DR1 subtypes, the DRB1*0101 allele was most commonly detected, but HLA-DRB1*0101 as well as DRB1*0102 and DRB1*0105 were similarly frequent in RA patients and controls. HLA-DR12 was more common among controls than in RA patients (18.1 vs. 0%; P <.05). Our results generally agree with the findings in other Caucasian populations. Nonetheless, we found differences in the frequency of HLA-DR1 and HLA-DR4 subtypes among Hungarian patients compared with reports from other geographic regions (e.g., Finland and Asia). Our data suggest that in northeastern Hungary, HLA-DR4 as well as its subtypes DRB1*0405 and DRB1*0408 may be involved in susceptibility to RA, but HLA-DR1 may not. In addition, the presence of HLA-DR12, at least in Hungary, may protect from this disease.

Szántó S, Bárdos T, Szabó Z, David CS, Buzás EI, Mikecz K, Glant TT. · Rush University Medical Center, Chicago, Illinois 60612, USA. · Arthritis Rheum. · Pubmed #15188376 links to  free full text

Abstract: OBJECTIVE: To determine whether the rheumatoid arthritis (RA)-predisposing class II molecules of the major histocompatibility complex (MHC) can present cartilage proteoglycan (PG) aggrecan, and if so, to determine the epitope repertoire of the human cartilage PG in HLA-transgenic mice and determine whether HLA-transgenic mice develop arthritis in response to immunization with human cartilage PG. METHODS: Mice transgenic for HLA-DR2.Ab(0), DR3.Ab(0), DR4.Ab(0), and DQ8.Ab(0), lacking their own (mouse) class II antigens (Ab(0)), on the original (arthritis-resistant) and the arthritis-susceptible BALB/c backgrounds, were immunized with human cartilage PG. The T cell epitope repertoire presented by these class II MHC alleles was determined using a synthetic peptide library (143 peptides of the core protein of human cartilage PG), and arthritis development was monitored and compared in wild-type and HLA-transgenic/congenic BALB/c mice. RESULTS: Mice of the 4 HLA-transgenic lines, either on the original mixed, arthritis-resistant background or DR4.Ab(0)- and DQ8.Ab(0)-transgenic/congenic mice on the arthritis-susceptible BALB/c genetic background, responded well to PG immunization (as assessed by T cell responses and antibody and cytokine production), and a number of T cell epitopes along the core protein of human cartilage PG were identified. DR4.Ab(0)- and DQ8.Ab(0)-transgenic mice immunized with human cartilage PG developed arthritis, but only when these class II MHC molecules were present on the arthritis-susceptible (BALB/c) genetic background. CONCLUSION: A number of human cartilage PG epitopes can be presented by HLA alleles that predispose to the development of RA, but the epitopes of the cartilage PG presented by HLA-DR4 or HLA-DQ8 can induce arthritis only in the presence of an appropriate genetic (non-MHC) background.