Rheumatoid Arthritis: Szekanecz Z

Szekanecz Z, Koch AE. · University of Debrecen Medical Center, Institute of Medicine, Department of Rheumatology, 22 Móricz street, Debrecen, H-4032, Hungary. · Arthritis Res Ther. · Pubmed #18947376 links to  free full text

Abstract: The vasculature plays a crucial role in inflammation, angiogenesis, and atherosclerosis associated with the pathogenesis of inflammatory rheumatic diseases, hence the term 'vascular rheumatology'. The endothelium lining the blood vessels becomes activated during the inflammatory process, resulting in the production of several mediators, the expression of endothelial adhesion molecules, and increased vascular permeability (leakage). All of this enables the extravasation of inflammatory cells into the interstitial matrix. The endothelial adhesion and transendothelial migration of leukocytes is a well-regulated sequence of events that involves many adhesion molecules and chemokines. Primarily selectins, integrins, and members of the immunoglobulin family of adhesion receptors are involved in leukocyte 'tethering', 'rolling', activation, and transmigration. There is a perpetuation of angiogenesis, the formation of new capillaries from pre-existing vessels, as well as that of vasculogenesis, the generation of new blood vessels in arthritis and connective tissue diseases. Several soluble and cell-bound angiogenic mediators produced mainly by monocytes/macrophages and endothelial cells stimulate neovascularization. On the other hand, endogenous angiogenesis inhibitors and exogenously administered angiostatic compounds may downregulate the process of capillary formation. Rheumatoid arthritis as well as systemic lupus erythematosus, scleroderma, the antiphospholipid syndrome, and systemic vasculitides have been associated with accelerated atherosclerosis and high cardiovascular risk leading to increased mortality. Apart from traditional risk factors such as smoking, obesity, hypertension, dyslipidemia, and diabetes, inflammatory risk factors, including C-reactive protein, homocysteine, folate deficiency, lipoprotein (a), anti-phospholipid antibodies, antibodies to oxidized low-density lipoprotein, and heat shock proteins, are all involved in atherosclerosis underlying inflammatory rheumatic diseases. Targeting of adhesion molecules, chemokines, and angiogenesis by administering nonspecific immunosuppressive drugs as well as monoclonal antibodies or small molecular compounds inhibiting the action of a single mediator may control inflammation and prevent tissue destruction. Vasoprotective agents may help to prevent premature atherosclerosis and cardiovascular disease.

Szekanecz Z, Koch AE. · Third Department of Medicine, Rheumatology Division, University of Debrecen Medical Center, 22 Móricz Zs Street, Debrecen, H-4012, Hungary. · Nat Clin Pract Rheumatol. · Pubmed #17968334 No free full text.

Abstract: Angiogenesis, the development of new vessels, is an important process in health and disease. The perpetuation of neovascularization in inflammatory diseases, such as rheumatoid arthritis, spondyloarthropathies and some systemic autoimmune diseases, might facilitate the ingress of inflammatory cells into the synovium and, therefore, stimulate pannus formation. Disorders associated with perpetuated neovascularization are considered to be angiogenic inflammatory diseases. Several angiogenic mediators, including growth factors, cytokines, matrix metalloproteinases, matrix macromolecules, cell adhesion receptors, chemokines and chemokine receptors, have been implicated in the process of capillary formation. There is a regulatory network in inflamed tissues that is involved in the upregulation or downregulation of angiogenesis. Endogenous angiostatic factors downregulate neovascularization and might act as angiostatic agents. Furthermore, angiogenesis might be targeted by several specific approaches that could be therapeutically used to control inflammatory diseases.

Brodszky V, Czirják L, Géher P, Hodinka L, Kárpáti K, Péntek M, Poór G, Szekanecz Z, Gulácsi L. · Budapesti Corvinus Egyetem, Közszolgálati Tanszék, Egészségügyi Gazdaságtani és Technológiaelemzési Kutatóközpont, Budapest. · Orv Hetil. · Pubmed #17905683 No free full text.

Abstract: INTRODUCTION: Biologic treatments are newly used in rheumatoid arthritis. Three tumornecrosis factor alfa (TNF-alpha) inhibitors--adalimumab, etanercept and infliximab--have been licensed for rheumatoid arthritis in Hungary. B-cell targeted treatment with rituximab is the next biologic treatment. Rituximab was used earlier for the treatment of non-Hodgkin's lymphoma. Rituximab was registered to be used in patients with rheumatoid arthritis who have had an inadequate response or an intolerance to one or more TNF-alpha blocking agents. AIM: Systematic review in the literature of efficacy of rituximab in rheumatoid arthritis. To assess the efficacy and safety of rituximab treatment in patients with rheumatoid arthritis. METHODS: MEDLINE and Cochrane database were searched for randomized controlled trials with rituximab in rheumatoid arthritis. A meta-analysis of trial data was conducted. RESULTS: Three randomized controlled trials were identified including 1145 patients. 54% of patients with inadequate response to TNF-alfa inhibitors and severe disease-activity have reached American College of Rheumatology 20 criteria. This ratio is larger with 33% (95% CI, 25-41%) than without treatment, and patients have almost five times (relative risk = 4.77 95% CI, 3.12-7.31) chance to improve. Functional status represented by Health Assessment Questionnaire score improves significantly (p < 0.001) in rituximab arms (-0.4 scores) compared with placebo arms (-0.1 scores). EULAR moderate and good responses in the rituximab group were significant (p < 0.00001) compared with the placebo group, rate difference is 38% (95% CI, 32-44%). Rituximab improves also radiological symptoms of rheumatoid arthritis. CONCLUSIONS: New therapeutic options, rituximab is efficacious in patients with rheumatoid arthritis. Rituximab can improve symptoms of patients with inadequate response to or intolerance of TNF-alpha inhibitors.

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.

Tamási L, Szekanecz Z. · Szent Ferenc Kórház Reumatológiai Osztály, Miskolc. · Orv Hetil. · Pubmed #17430797 No free full text.

Abstract: The concept of biological therapy arises from the specific targeting of a factor, e.g. a cytokine, involved in the inflammatory cascade. Thus, biologicals disrupt the complex network of autoimmune-inflammatory events. Today, rheumatoid arthritis is a prototype disease in this context as most compounds have been tried in this disease. Recently, biological therapy has been introduced to the treatment of other diseases including various forms of arthritis, such as ankylosing spondylitis and psoriatic arthritis, as well as systemic autoimmune disorders, such as systemic lupus erythematosus, scleroderma, inflammatory myopathies and Sjogren's syndrome. Anti-tumor necrosis factor-alpha (TNF-alpha) agents play a central role in biological therapy as these agents have been successfully tried in most of these diseases. When seeking for specific targets for biologicals, pathogenic factors of the disease, such as Th1 or Th2 type responses, should be evaluated. Some mostly T-cell mediated diseases, such as rheumatoid arthritis, ankylosing spondylitis, psoriasis, polymyositis, polyarticular juvenile arthritis respond well to anti-TNF agents and T cell targeting, while others, such as lupus, Sjogren's syndrome, dermatomyositis may rather respond to anti-B cell biologicals. In this review, authors discuss the most recent advances in the biological therapy of arthritis and systemic autoimmune diseases including issues of efficacy and safety.

Szekanecz Z, Koch AE. · Division of Rheumatology, Third Department of Medicine, University of Debrecen Medical and Health Sciences Center, Debrecen, Hungary. · Curr Opin Rheumatol. · Pubmed #17414958 No free full text.

Abstract: PURPOSE OF REVIEW: Macrophages differentiate from peripheral-blood monocytes. Both monocytes and synovial macrophages are key players in rheumatoid arthritis. These cells are involved in the initiation and perpetuation of inflammation, leukocyte adhesion and migration, matrix degradation and angiogenesis. Macrophages express adhesion molecules, chemokine receptors and other surface antigens. They also secrete a number of chemokines, cytokines, growth factors, proteases and other mediators. RECENT FINDINGS: Macrophage migration-inhibitory factor has drawn significant attention recently. This cytokine is involved in macrophage activation and cytokine production. Migration-inhibitory factor also regulates glucocorticoid sensitivity and may be a pathogenic link between rheumatoid arthritis and atherosclerosis. Novel macrophage-derived chemokines and chemokine receptors have been identified. Interleukin-10 may have several proinflammatory effects that may influence its action in rheumatoid arthritis. Several proteinases including cathepsin G are produced by macrophages during rheumatoid arthritis-associated inflammatory and angiogenic events. Antirheumatic drugs, imatinib, chemokine receptor inhibitors and other specific strategies may become included in the therapy of rheumatoid arthritis. SUMMARY: Macrophages and their products are key players in the pathogenesis of rheumatoid arthritis and may be good therapeutic targets.

Szekanecz E, András C, Sándor Z, Antal-Szalmás P, Szántó J, Tamási L, Kiss E, Szekanecz Z. · Department of Oncology, University of Debrecen, Medical and Health Science Center, Móricz, Hungary. · Autoimmun Rev. · Pubmed #17110316 No free full text.

Abstract: Paraneoplastic symptoms, caused by a malignancy, but not directly related to invasion by the tumor or its metastases are the result of a wide variety of tumor-derived biologic mediators like hormones, peptides, antibodies, cytotoxic lymphocytes, autocrine and paracrine mediators. Recognition of paraneoplastic syndromes is important, as it may lead to an early diagnosis of cancer. There is some evidence that systemic inflammatory diseases, such as rheumatoid arthritis (RA), lupus, scleroderma or dermatomyositis may increase the risk for the development of malignancies, predominantly lymphoproliferative disorders. However, reports are somewhat controversial. Immunosuppressive and cytotoxic drugs used in antirheumatic therapy, such as methotrexate, cyclophosphamide, azathioprine or anti-TNF biologicals may also lead to the development of such tumors. Tumor-associated antigens may be produced by inflammatory cells and their production may be increased in RA and other autoimmune diseases.

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.

Szekanecz Z, Gáspár L, Koch AE. · Division of Rheumatology, Third Department of Medicine, University of Debrecen Medical and Health Sciences Center, Debrecen, H-4004, Hungary. <> · Front Biosci. · Pubmed #15769663 No free full text.

Abstract: Endothelial cells lining the lumina of blood vessels are involved in leukocyte extravasation underlying inflammatory states, such as rheumatoid arthritis (RA). New vessel formation, termed angiogenesis, is also crucial for leukocyte extravasation during inflammatory synovitis. The outcome of neovascularization in the RA synovium is highly dependent on the balance or imbalance between angiogenic mediators and inhibitors. There have been several attempts to therapeutically interfere with the cellular and molecular mechanisms underlying RA-associated neovascularization. Most studies have been performed using animal models of arthritis. In addition, a limited number of human clinical trials gave promising results. In this review, authors summarize some relevant information on those angiogenic and angiostatic agents, which have also been studied in context with RA. In addition, further perspectives of anti-angiogenic therapy in arthritis are also discussed. Specific targeting of angiogenesis may be useful in the future management of various inflammatory, as well as malignant, diseases.

Szekanecz Z, Koch AE. · University of Debrecen, Hungary. · Methods Mol Biol. · Pubmed #12769496 No free full text.

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Szekanecz Z, Kim J, Koch AE. · Rheumatology Division, Third Department of Medicine, University of Debrecen Medical and Health Sciences Center, Debrecen H-4004, Hungary. · Semin Immunol. · Pubmed #12495637 No free full text.

Abstract: Chemokines are chemotactic cytokines involved in a number of pathological processes, including inflammatory conditions. Chemokines play a role in the pathogenesis of various inflammatory diseases. Based on a burgeoning body of literature, RA was chosen as a prototype to discuss this issue. In this review, the authors give a detailed introduction to the classification and function of chemokines and their receptors. This is followed by a discussion of the role of chemokines and chemokine receptors in RA. Chemokines interact with other inflammatory mediators, such as cytokines. Thus, the regulation of chemokine production and the place of chemokines in the network of inflammatory mediators present in the rheumatoid synovium are also reviewed. Finally, potential strategies using anti-chemokine or anti-chemokine receptor biologicals in anti-rheumatic therapy are discussed.

Bodolay E, Koch AE, Kim J, Szegedi G, Szekanecz Z. · Division of Rheumatology, Third Department of Medicine, University of Debrecen Medical and Health Sciences Center, Debrecen, H-4004, Hungary. · J Cell Mol Med. · Pubmed #12417052 No free full text.

Abstract: Angiogenesis, the formation of new vessels, is important in the pathogenesis of rheumatoid arthritis (RA) and other inflammatory diseases. Chemotactic cytokines termed chemokines mediate the ingress of leukocytes, including neutrophils and monocytes into the inflamed synovium. In this review, authors discuss the role of the most important angiogenic factors and angiogenesis inhibitors, as well as relevant chemokines and chemokine receptors involved in chronic inflammatory rheumatic diseases. RA was chosen as a prototype to discuss these issues, as the majority of studies on the role of angiogenesis and chemokines in inflammatory diseases were carried out in arthritis. However, other systemic inflammatory (autoimmune) diseases including systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjögren's syndrome (SS), mixed connective tissue disease (MCTD), polymyositis/dermatomyositis (PM/DM) and systemic vasculites are also discussed in this context. As a number of chemokines may also play a role in neovascularization, this issue is also described here. Apart from discussing the pathogenic role of angiogenesis and chemokines, authors also review the regulation of angiogenesis and chemokine production by other inflammatory mediators, as well as the important relevance of neovascularization and chemokines for antirheumatic intervention.

Szekanecz Z, Koch AE. · Third Department of Medicine, University of Debrecen Medical and Health Sciences Center, Debrecen, Hungary. · Curr Opin Rheumatol. · Pubmed #11333349 No free full text.

Abstract: Chemokines mediate the ingress of leukocytes, including neutrophils and monocytes, into the inflamed synovium. Among the four known chemokine families, C-X-C and C-C chemokines seem to be of outstanding importance in this process. Angiogenesis, the formation of new vessels, is also important in the pathogenesis of rheumatoid arthritis. In this review, the authors discuss the role of the most important chemokines in the pathogenesis of rheumatoid synovitis. The most relevant angiogenic factors and angiogenesis inhibitors involved in rheumatoid arthritis are also discussed. Because certain chemokines may also play a role in neovascularization, chemokines and the process of angiogenesis are described in this context as well. Apart from discussing the pathogenic role of these factors, the authors also review the important relevance of chemokines and angiogenesis for therapeutic intervention.

Szekanecz Z, Koch AE. · Department of Medicine, Division of Arthritis and Connective Tissue Diseases, Northwestern University Medical School, Ward Building 3-315, 303 East Chicago Avenue, Chicago, IL 60611, USA. · Curr Rheumatol Rep. · Pubmed #11177771 No free full text.

Abstract: Rheumatoid arthritis (RA) is an inflammatory disorder associated with chronic synovitis, eventually leading to cartilage and bone destruction in the joints. Synovitis is associated with the activation of various cells in the synovium including synovial lining cells, interstitial macrophages, endothelial cells, lymphocytes, and fibroblasts. The key mechanisms underlying synovitis include inflammatory cell adhesion and activation, the production of mediators (such as cytokines, chemokines, and growth factors), angiogenesis, joint destruction, fibrosis, and bone resorption. These important events, as well as the role of inflammatory cells, cell surface molecules, and soluble mediators are updated and discussed in this review. Some aspects and strategies of current or future immunotherapy are also discussed because these animal and human trials provide information on the pathogenesis of inflammatory synovitis.

Szekanecz Z, Koch AE. · Third Department of Medicine, University of Debrecen Medical and Health Sciences Center, Debrecen, Hungary. · Arthritis Res. · Pubmed #11094450 links to  free full text

Abstract: Leukocyte ingress into the synovium is a key process in the pathogenesis of rheumatoid arthritis and other inflammatory conditions. In this review, the role of endothelial cells in leukocyte extravasation will be discussed, including the role of the most relevant cellular adhesion molecules. These molecules play an important role in mediating leukocyte--endothelial interactions. It is likely that different adhesive pathways are involved in different steps of leukocyte adhesion to and migration through endothelia. Targeting of pathological endothelial function, including leukocyte--endothelial adhesion, may be useful for the future management of inflammatory arthritis.

Kerekes G, Soltész P, Dér H, Veres K, Szabó Z, Végvári A, Szegedi G, Shoenfeld Y, Szekanecz Z. · Cardiovascular Unit, Third Department of Medicine, University of Debrecen Medical and Health Science Center, Móricz Zs krt. 22., 4032, Debrecen, Hungary. · Clin Rheumatol. · Pubmed #19319624 No free full text.

Abstract: Increased cardiovascular mortality has been associated with rheumatoid arthritis (RA). There have been reports indicating that tumor necrosis factor blockers may exert favorable but transient effects on lipid profile, flow-mediated vasodilation (FMD) of the brachial artery, and common carotid intima-media thickness (ccIMT) in RA. In this study, we assessed the effects of rituximab on FMD, ccIMT, and lipid profile. Five female RA patients received two infusions of 1000 mg rituximab i.v. High-resolution B-mode ultrasound was used to assess brachial FMD and ccIMT. We also determined plasma total cholesterol (TC), HDL-C, LDL-C, and triglyceride (Tg) levels. Assessments were performed at baseline, as well as at weeks 2, 6, and 16 after the first infusion. Rituximab (RTX) treatment resulted in a rapid and sustained improvement in FMD. The mean improvement was 30%, 22%, and 81% at weeks 2, 6, and 16, respectively. RTX had little effect on atherosclerosis within this short period of time; however, we observed 10%, 9%, and 2% decreases in ccIMT at weeks 2, 6, and 16, respectively. RTX therapy resulted in 3-11% decrease in TC, as well as 14-35% increase in HDL-C levels. Two infusions of RTX exerted early and sustained favorable effects on endothelial dysfunction, as well as plasma TC and HDL-C levels. RTX may also decrease ccIMT; however, longer follow-up is needed to assess the prolonged effects of RTX on vascular function and lipid profile in RA patients.

Szekanecz Z. · Debreceni Egyetem, Orvos- és Egészségtudományi Centrum, Altalános Orvostudományi Kar Belgyógyászati Intézet, Reumatológiai Tanszék Debrecen Nagyerdei krt. 98. 4012. · Orv Hetil. · Pubmed #19581162 No free full text.

This publication has no abstract.

Szekanecz Z, Pakozdi A, Szentpetery A, Besenyei T, Koch AE. · Division of Rheumatology, Third Department of Medicine, University of Debrecen Medical and Health Sciences Center, Debrecen, H-4004, Hungary. · Front Biosci (Elite Ed). · Pubmed #19482623 No free full text.

Abstract: In rheumatoid arthritis, chemokines mediate the migration of inflammatory leukocytes into the synovium. Among the four known chemokine families, CXC, CC chemokines and fractalkine seem to be of outstanding importance in this process. Angiogenesis, the formation of new vessels, is also important during the perpetuation of inflammation underlying rheumatoid arthritis. In this review, authors discuss the role of the most important chemokines and chemokine repetors in arthritis-associated neovascularization. The process and regulation of angiogenesis are described in this context as well. Apart from discussing the pathogenic role of chemokines and chemokine receptors in arthritic vessel formation, authors also review the important relevance of chemokines and angiogenesis for therapeutic intervention.

Soltész P, Dér H, Kerekes G, Szodoray P, Szücs G, Dankó K, Shoenfeld Y, Szegedi G, Szekanecz Z. · Cardiovascular Unit, Institute of Medicine, Third Department of Medicine, University of Debrecen Medical and Health Science Center, Debrecen, 4032, Hungary. · Clin Rheumatol. · Pubmed #19224126 No free full text.

Abstract: Patients with autoimmune diseases may have increased vascular risk leading to higher mortality rates. Novel imaging techniques are necessary for the early assessment and management of these patients. In this study, we compared augmentation index (AIx) and pulse wave velocity (PWV), indicators of arterial stiffness, to brachial arterial flow-mediated vasodilation (FMD) and common carotid artery intima-media thickness (ccIMT), standard indicators of endothelial dysfunction and atherosclerosis, respectively. We wished to assess the vascular status of autoimmune patients by using a novel, cheap, and reproducible technique, the arteriograph. Altogether, 101 patients with systemic autoimmune diseases including primary antiphospholipid syndrome, systemic sclerosis, rheumatoid arthritis, and polymyositis, all having various types of vasculopathies, as well as 36 healthy individuals were investigated. Arterial stiffness was assessed by a TensioClinic arteriograph, a recently validated technique. Brachial arterial FMD and ccIMT were determined using high-resolution ultrasonography. Autoimmune patients exerted impaired FMD (3.7 +/- 3.8%), increased ccIMT (0.7 +/- 0.2 mm), AIx (1.2 +/- 32.2%), and PWV (9.7 +/- 2.4 m/s) in comparison to control subjects (FMD = 8.4 +/- 4.0%; ccIMT = 0.6 +/- 0.1 mm; Aix = -41.1 +/- 22.5%; PWV = 8.0 +/- 1.5 m/s; p < 0.05). We found a significant negative correlation of FMD with AIx (R = -0.64; p < 0.0001) and PWV (R = -0.37; p = 0.00014). There were significant positive correlations between ccIMT and AIx (R = 0.34; p = 0.0009), ccIMT and PWV (R = 0.44; p < 0.0001), as well as AIx and PWV (R = 0.47; p < 0.0001). AIx, PWV, and ccIMT positively correlated and FMD negatively correlated with the age of the autoimmune patients. Arterial stiffness indicated by increased AIx and PWV may be strongly associated with endothelial dysfunction and overt atherosclerosis in patients with autoimmune diseases. Assessment of arterial stiffness, FMD, and ccIMT are reproducible and reliable noninvasive techniques for the complex assessment of vascular abnormalities in patients at high risk.

Szekanecz Z, Koch AE. · Department of Rheumatology, Institute of Medicine, University of Debrecen Medical and Health Sciences Center, Debrecen, H-4012 Hungary. · Vascul Pharmacol. · Pubmed #19217946 No free full text.

Abstract: Angiogenesis, the development of new capillaries, is involved in leukocyte ingress into the synovium during the development and progression of rheumatoid arthritis. Several soluble and cell surface-bound mediators including growth factors, cytokines, chemokines, proteolytic matrix-degrading enzymes, cell adhesion molecules and others may promote synovial neovascularization. On the other hand, endogenous angiostatic factors, such as angiostatin, endostatin, interleukin-4 (IL-4), IL-13, interferons and some angiostatic chemokines are also produced within the rheumatoid synovium, however, their effects are insufficient to control synovial angiogenesis and inflammation. Several specific and non-specific strategies have been developed to block the action of angiogenic mediators. The first line of angiostatic agents include vascular endothelial growth factor (VEGF), angiopoietin, alpha(V)beta(3) integrin antagonist, as well as non-specific angiogenesis inhibitors including traditional disease-modifying agents (DMARDs), anti-tumor necrosis factor biologics, angiostatin, endostatin, fumagillin analogues or thalidomide. Potentially any angiostatic compound could be introduced to studies using animal models of arthritis or even to human rheumatoid arthritis trials.

Farago B, Talian GC, Komlosi K, Nagy G, Berki T, Gyetvai A, Szekanecz Z, Nyarady Z, Kiss CG, Nemeth P, Czirjak L, Melegh B. · Department of Medical Genetics and Child Development, University of Pécs, Szigeti ut 12, 7624, Pecs, Hungary. · Rheumatol Int. · Pubmed #19034456 No free full text.

Abstract: The C1858T allele of the PTPN22 gene has been reported to confer risk for RA; but in some reports, the effect was restricted to RF- and/or anti-CCP-seropositive patients. Hungarian RA patients and matched controls were genotyped. The 1858T allele showed an increased prevalence in RA patients compared to controls. The 1858T allele represents a risk factor in the whole RA population (P = 0.001); an association was found both in RF-seropositive (P = 0.001) and anti-CCP-seropositive patients (P = 0.001), and in subjects with the combination of these factors (P = 0.002). In TT homozygotes, the estimated susceptibility to RA was more than double (OR = 5.04) of that seen in TC heterozygotes (OR = 1.89); the same gene dosage effect was observed in all seropositive RA subgroups. Our data show that the Hungarian RA patients belong to the populations in which the 1858T allele represents a susceptibility factor both in the RF- and/or anti-CCP-seropositive subjects, and the association exhibit a gene dosage dependency.

Szekanecz E, Szucs G, Szekanecz Z, Tarr T, Antal-Szalmás P, Szamosi S, Szántó J, Kiss E. · Department of Oncology, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary. · J Autoimmun. · Pubmed #18926664 No free full text.

Abstract: BACKGROUND: Some tumor-associated antigens (TAAs) are expressed on inflammatory cells. We previously detected increased production of CA15-3, CA19-9 and CA125 in rheumatoid arthritis (RA). The production of some TAAs may also be increased in patients with systemic sclerosis (SSc), systemic lupus erythematosus (SLE) and other connective tissue diseases. Some of these TAAs contain sialylated carbohydrate motifs and they are involved in tumor-associated cell adhesion and metastasis. OBJECTIVES: We assessed levels of TAAs in the sera of SSc, SLE patients, patients with infectious diseases and healthy subjects. Serum TAA levels were correlated with each other, as well as with disease activity markers and organ involvement. METHODS: TAAs including CEA, CA15-3, CA72-4, CA125 and CA19-9 were assessed by immunoassay in the sera of 92 patients with SSc, 40 patients with SLE, 50 age- and sex-matched healthy controls, as well as with 40 patients with current bacterial or viral infections. Normal upper limits for these TAAs were 3.4 mg/l, 25 kU/l, 6.9 kU/l, 35 kU/l and 34 kU/l, respectively. RESULTS: There were significantly more SSc patients showing abnormally high levels of CA19-9 (8.8% vs 2.0%), CA125 (11.0% vs 6.0%) and CA15-3 (28.4% vs 14.0%) in comparison to controls (p < 0.05). In SLE, significantly more patients had elevated levels of CEA (32.5% vs 20.0%), CA19-9 (7.5% vs 2.0%), CA125 (15.0% vs 6.0%) and CA72-4 (15.0% vs 8.0%) than did controls (p < 0.05). The mean absolute serum levels of CEA (6.6+/-1.7 vs 1.8+/-1.4 mg/l) and CA15-3 (22.9 +/- 1.8 vs 18.6 +/- 2.2 kU/l) were also significantly higher in SSc compared to controls (p < 0.05). We found numerous correlations between the serum levels of different TAAs within the SSc and SLE population. Among SSc patients, serum CEA (R = 0.290; p = 0.005), CA15-3 (R = 0.260; p = 0.020) and CA19-9 (R = 0.257; p = 0.013) correlated with renal involvement. Serum CA15-3 also correlated with joint involvement (R = 0.329; p = 0.003), ANA positivity (R = 0.288; p = 0.010) and CRP levels (R = 0.407; p < 0.001). Within the SLE population, serum CA72-4 correlated with central nervous involvement (R = 0.624; p = 0.004) and CA125 correlated with the SLEDAI composite activity index (R = 0.666; p = 0.002). Patients with infections exerted serum TAA patterns similar to healthy controls. CONCLUSION: The concentration of some TAAs may be elevated in the sera of patients with SSc or SLE in comparison to healthy subjects. Pathogenically, most of these TAAs contain carbohydrate motifs and thus they may be involved in inflammation-associated adhesive events. Furthermore, the production of some TAAs may correlate with organ involvement or disease activity in scleroderma or lupus.

Váróczy L, Illés A, Kiss E, Szekanecz Z, Soltész P, Sipka S, Kiss A, Udvardy M, Szegedi G, Zeher M. · Debreceni Egyetem, Orvos- és Egészségtudományi Centrum, Altalános Orvostudományi Kar, Belgyógyászati III. Belgyógyászati Klinika, Belgyógyászati Intézet Debrecen. · Orv Hetil. · Pubmed #18621599 No free full text.

Abstract: High dose chemotherapy followed by autologous stem cell support is a promising therapeutical approach in the treatment of severe refractory multisystem autoimmune diseases. The aim of this study was to perform the authors' first experiences in this field. Results: Between August 2006 and November 2007 autologous stem cell transplantation was performed for seven patients: two of them had systemic lupus erythematosus, four of them had rheumatoid arthritis and one of them had systemic sclerosis. Cyclophosphamide plus colony stimulating factor were administered to mobilize stem cells. The conditioning protocol included high dose cyclophosphamide (200 mg/kg) and anti-thymocyte globulin (9 mg/kg). The re-infused stem cells were successfully engrafted by all patients. One of the lupus patients died on the 46th day due to a lethal cytomegalovirus infection, but the rest of them had no severe complications. Complete remission of their diseases and significant improvement in their quality of life were observed during a mean follow-up period of 10 months. Conclusions: Autologous stem cell therapy can be effectively administered in special cases of severe autoimmune disorders.

Lakos G, Soós L, Fekete A, Szabó Z, Zeher M, Horváth IF, Dankó K, Kapitány A, Gyetvai A, Szegedi G, Szekanecz Z. · Laboratory of Immunology, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary. · Clin Exp Rheumatol. · Pubmed #18565246 No free full text.

Abstract: OBJECTIVE: Anti-cyclic citrullinated peptide (anti-CCP) antibodies of IgG isotype are specific diagnostic markers of rheumatoid arthritis (RA). Recent evidence also points to their direct involvement in the pathophysiology. Little information is available, however, regarding the isotype distribution of anti-CCP antibodies and the characteristics of IgA and IgM anti-CCP. METHODS: IgG, IgA and IgM anti-CCP2 and rheumatoid factor (RF) levels were measured in the sera of 119 RA patients and 118 controls, including patients with other rheumatic diseases and healthy subjects. We analyzed the diagnostic performance of IgA and IgM anti-CCP2 antibodies and their relationship with IgG anti-CCP2, RFs, disease duration and the presence of HLA-DRB1 shared epitope (SE) alleles. RESULTS: Patients with RA had significantly higher serum IgA and IgM anti-CCP2 antibody levels than healthy subjects and patients with other rheumatic diseases (p<0.0001). IgG, IgA and IgM anti-CCP2 antibodies were present in 74.8%, 52.9% and 44.5% of RA patients, and their diagnostic specificity was 95.8%, 95.8% and 91.6%, respectively. The presence of anti-CCP2 antibodies was significantly associated with SE alleles (p=0.03). The frequency of IgM anti-CCP2 positivity was lower in longstanding disease compared to early RA (p=0.03). CONCLUSION: IgA and IgM anti-CCP2 antibodies are present in RA patients, and they are similarly specific for RA as IgG anti-CCP2. The higher frequency of IgM anti-CCP2 antibodies in early RA suggests that they are mostly generated during the first phase of immune response; nonetheless, their production seems to be sustained in some patients. Further analysis of IgM and IgA anti-CCP2 antibodies may provide insights into the pathogenesis of RA.

Péntek M, Szekanecz Z, Czirják L, Poór G, Rojkovich B, Polgár A, Genti G, Kiss CG, Sándor Z, Májer I, Brodszky V, Gulácsi L. · Pest Megyei Flór Ferenc Kórház, Reumatológiai és Fizioterápiás Osztály, Kistarcsa. · Orv Hetil. · Pubmed #18426720 No free full text.

Abstract: Rheumatoid arthritis (RA) is a chronic, progressive polyarthritis leading to substantial disability. Standardised data on consequences of disease progression are needed for clinical assessments and also for cost-effectiveness models. AIM: To analyse the impact of disease progression on health status, disease specific quality of life and costs in Hungary. METHODS: A cross-sectional survey was performed between April and August, 2004, involving consecutive RA patients of 6 hospital based rheumatology outpatient centres. Self-completed questionnaires were used to assess functional (HAQ) and health status (EQ-5D), quality of life (RAQoL). Disease activity (DAS) and costs were also surveyed, statistical analysis was performed. RESULTS: 255 patients were involved [mean age 55.5 +/- 12.3 years; disease duration 9.0 +/- 9.3 years; HAQ 1.38 +/- 0.76; EQ-5D 0.46 +/- 0.33; RAQoL 16.2 +/- 8.1; DAS 5.09 +/- 1.42; costs 1,043,163 (+/- 844,750) HUF/patient/year, conversion 1 Euro = 250 HUF]. Correlation was significant between the parameters ( p < 0.01): EQ-5D index = 1.014 - 0.25 x HAQ-0.041 x DAS; HAQ = 0.314 + 0.065 x RAQoL. Analysis by disease severity levels (HAQ groups 0.5 difference) revealed that health status worsens (mean EQ-5D: 0.784; 0.576; 0.504; 0.367; 0.211; 0.022) and costs increase (mean 628,280; 888,187; 953,759; 1,291,218; 1,346,112; 1,371,674 HUF/patient/year) with disease progression. Minimally important worsening of functional ability (0.25 HAQ increase) corresponds to -0.0705 EQ-5D and +1.884 RAQoL change. Lower health status difference (EQ-5D -0.05725) was calculated in patients with lower disease activity (DAS < 5.1). CONCLUSIONS: Correlation between disease progression, health status, quality of life and costs does not differ significantly from international results. The amount of costs is much lower in all disease severity levels than in developed European countries. Our study serves baseline data for health economic analysis in RA in Hungary.