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      Biological Treatments in Behçet's Disease: Beyond Anti-TNF Therapy

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          Abstract

          Behçet's disease (BD) is universally recognized as a multisystemic inflammatory disease of unknown etiology with chronic course and unpredictable exacerbations: its clinical spectrum varies from pure vasculitic manifestations with thrombotic complications to protean inflammatory involvement of multiple organs and tissues. Treatment has been revolutionized by the progressed knowledge in the pathogenetic mechanisms of BD, involving dysfunction and oversecretion of multiple proinflammatory molecules, chiefly tumor necrosis factor- (TNF-) α, interleukin- (IL-) 1 β, and IL-6. However, although biological treatment with anti-TNF- α agents has been largely demonstrated to be effective in BD, not all patients are definite responders, and this beneficial response might drop off over time. Therefore, additional therapies for a subset of refractory patients with BD are inevitably needed. Different agents targeting various cytokines and their receptors or cell surface molecules have been studied: the IL-1 receptor has been targeted by anakinra, the IL-1 by canakinumab and gevokizumab, the IL-6 receptor by tocilizumab, the IL12/23 receptor by ustekinumab, and the B-lymphocyte antigen CD-20 by rituximab. The aim of this review is to summarize all current experiences and the most recent evidence regarding these novel approaches with biological drugs other than TNF- α blockers in BD, providing a valuable addition to the actually available therapeutic armamentarium.

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          Most cited references110

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          Treating inflammation by blocking interleukin-1 in humans.

          IL-1 is a master cytokine of local and systemic inflammation. With the availability of specific IL-1 targeting therapies, a broadening list of diseases has revealed the pathologic role of IL-1-mediated inflammation. Although IL-1, either IL-1α or IL-1β, was administered to patients in order to improve bone marrow function or increase host immune responses to cancer, these patients experienced unacceptable toxicity with fever, anorexia, myalgias, arthralgias, fatigue, gastrointestinal upset and sleep disturbances; frank hypotension occurred. Thus it was not unexpected that specific pharmacological blockade of IL-1 activity in inflammatory diseases would be beneficial. Monotherapy blocking IL-1 activity in a broad spectrum of inflammatory syndromes results in a rapid and sustained reduction in disease severity. In common conditions such as heart failure and gout arthritis, IL-1 blockade can be effective therapy. Three IL-1blockers have been approved: the IL-1 receptor antagonist, anakinra, blocks the IL-1 receptor and therefore reduces the activity of IL-1α and IL-1β. A soluble decoy receptor, rilonacept, and a neutralizing monoclonal anti-interleukin-1β antibody, canakinumab, are also approved. A monoclonal antibody directed against the IL-1 receptor and a neutralizing anti-IL-1α are in clinical trials. By specifically blocking IL-1, we have learned a great deal about the role of this cytokine in inflammation but equally important, reducing IL-1 activity has lifted the burden of disease for many patients.
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            Criteria for diagnosis of Behcet's disease

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              HLA-B51/B5 and the risk of Behçet's disease: a systematic review and meta-analysis of case-control genetic association studies.

              To quantify by meta-analysis the genetic effect of the HLA-B5 or HLA-B51 (HLA-B51/B5) allele on the risk of developing Behçet's disease (BD) and to look for potential effect modifiers. Relevant studies were identified using the PubMed Medline database and manual searches of the literature. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by using the random-effects model. Subgroup meta-analyses and meta-regression analyses were undertaken to investigate the effects of selected study-level parameters on the pooled OR. Heterogeneity was assessed using the I2 statistic. Pooled results were used to calculate population-attributable risks (PAR) for BD in relationship to HLA-B51/B5. A total of 4,800 patients with BD and 16,289 controls from 78 independent studies (published 1975-2007) were selected. The pooled OR of HLA-B51/B5 allele carriers to develop BD compared with noncarriers was 5.78 (95% CI 5.00-6.67), with moderate between-study heterogeneity (I2 = 61%). The subgroup analyses stratifying studies by geographic locations (Eastern Asia, Middle East/North Africa, Southern Europe, Northern/Eastern Europe) yielded consistent OR ranges (5.31-7.20), with I2 ranges of 52-70%. Univariate random-effects meta-regression indicated the percentage of male BD cases (P = 0.008) as a source of heterogeneity. The PAR within the various geographic areas were estimated at 32-52%. The strength of the association between BD and HLA-B51/B5, and its consistency across populations of various ethnicities, lends further support to this allele being a primary and causal risk determinant for BD. Variations according to sex support an interaction of this allele with BD characteristics.
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                Author and article information

                Journal
                Mediators Inflamm
                Mediators Inflamm
                MI
                Mediators of Inflammation
                Hindawi Publishing Corporation
                0962-9351
                1466-1861
                2014
                30 June 2014
                : 2014
                : 107421
                Affiliations
                1Interdepartmental Research Center of Systemic Autoimmune and Autoinflammatory Diseases, Rheumatology Unit, Policlinico Le Scotte, University of Siena, Viale Bracci 1, 53100 Siena, Italy
                2Rheumatology Unit, Department of Medicine DIMED, University of Padova, Via Giustiniani 2, 35128 Padova, Italy
                3Rheumatology Unit, Department of Clinical Medicine and Surgery, University Federico II, Via S. Pansini 5, 80131 Naples, Italy
                4Institute of Pediatrics, Cattolica Sacro Cuore University, Largo Agostino Gemelli 8, 00168 Rome, Italy
                5La Sapienza University, Viale del Policlinico 155, 00161 Rome, Italy
                6Department of Pediatrics, Rheumatology Unit, Anna Meyer Children's Hospital and University of Florence, Viale Pieraccini 24, 50139 Florence, Italy
                7Rheumatology Service, Hospital Regional Universitario Carlos Haya, University of Màlaga, Avenida Carlos Haya s/n, 29010 Màlaga, Spain
                Author notes

                Academic Editor: Chiara De Luca

                Author information
                http://orcid.org/0000-0002-8928-2520
                http://orcid.org/0000-0001-7032-7779
                http://orcid.org/0000-0002-3314-0814
                http://orcid.org/0000-0002-0346-3268
                http://orcid.org/0000-0002-7352-1275
                Article
                10.1155/2014/107421
                4100257
                25061259
                dfbb4df4-70ae-45a4-a280-3ac34348d72c
                Copyright © 2014 Francesco Caso et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 16 January 2014
                : 17 April 2014
                : 1 May 2014
                Categories
                Review Article

                Immunology
                Immunology

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