bluuebunny/crossref_metadata_2025 huggingface dataset:
Long‐Term Effects of Rituximab in Rheumatoid Arthritis
Authors: Quartuccio Luca , Lombardi Sandra , Fabris Martina , Masolini Paola , Saracco Marta , Pellerito Raffaele , De Vita Salvatore
Published: September 2009

Rituximab selectively targets the B‐cell compartment, including rheumatoid factor‐positive B cells. Short‐term efficacy and safety of rituximab in rheumatoid arthritis (RA) has been established by multicenter randomized placebo‐controlled studies. Results of long‐term follow‐up of the phase II/III clinical trials have confirmed the efficacy and safety of repeated courses of rituximab in the responders. However, mechanisms of action in humans, retreatment regimens, biologic effects on memory B cells and on immunoglobulin levels of prolonged exposure of the immune system to B‐cell depletion over time, and pharmacogenetic aspects remain open and intriguing issues of rituximab therapy. Several studies are ongoing to clarify possible clinical and biologic predictors of response to rituximab in RA and in other autoimmune diseases where rituximab has been proven to be effective. Preliminary clinical and pharmacogenetic results of our cohort of RA patients managed with rituximab from the year 2000 are presented.
Cognitive Functioning in Behçet's Disease
Authors: Cavaco Sara , Da Silva Ana Martins , Pinto Pedro , Coutinho Estér , Santos Ernestina , Bettencourt Andreia , Pinto Cláudia , Gonçalves Alexandra , Silva Susana , Gomes Filomena , Carvalho Luisa , Pereira Cláudia , Martins Berta , Correia João , Vasconcelos Carlos
Published: September 2009

The impact of Behçet's disease on higher cognitive functions is still poorly understood. We proposed (1) to characterize the neuropsychological profile of Behçet's disease patients with (Neuro‐BD) and without (BD) neurological manifestations; (2) to identify which clinical, psychopathological, and genetic variables are related to neuropsychological performance; and (3) to explore the association between cognitive functioning and neuroimaging findings in BD patients. Fifteen Neuro‐BD and 35 BD patients in the nonactive phase of their illness underwent a neurological examination, performed a comprehensive battery of neuropsychological tests, and answered the hospital anxiety and depression scale. Human leukocyte antigen (HLA)‐B*51 genotyping was also performed. Patients’ neuropsychological performances were compared to those of healthy demographically matched subjects. Within one month from the testing date, a subset of 20‐BD patients underwent a magnetic resonance imaging (MRI) scan. Fifty‐three percent of Neuro‐BD and 40% of BD patients were impaired at least on one neuropsychological measure (i.e., digit span–forward). Poorer cognitive functioning in Neuro‐BD was associated with parenchymal involvement, whereas in BD it was related to presence of white matter changes in the frontal lobes, history of headache complaints, or higher levels of anxiety and depression. Current prednisone intake had a positive impact on neuropsychological performance. Disease duration, time since onset of neurological manifestations, or presence of HLA‐B*51 allele had no significant influence. Our results indicate that Behçet's disease may affect cognitive abilities in the absence of overt neurological symptoms. These findings point to an insidious course of neurological involvement.
Antitreponemal Antibodies Leading to Autoantibody Production and Protection from Atherosclerosis in Kitavans from Papua New Guinea
Authors: Agmon‐Levin Nancy , Bat‐sheva Porat Katz , Barzilai Ori , Ram Maya , Lindeberg Staffan , Frostegård Johan , Shoenfeld Yehuda
Published: September 2009

The objective of our study was to determine the prevalence of anti‐infectious agent antibodies and autoantibodies in a unique non‐Westernized population from Kitava, Papua New Guinea (PNG), compared to Western populations. We matched 120 serum samples from Kitavans with 437 samples from four healthy control groups. Sera were tested for the presence of anti‐infectious agent antibodies (treponema, toxoplsmosis, Epstein–Barr virus, cytomegalovirus, rubella) and autoantiobodies [anti‐double‐stranded (ds)DNA, anti‐chromatin, anti‐ribonucleoprotein (RNP), anti‐SSB, anti‐SSA, anti‐Scl‐70, anti‐Smith, anti‐centromer, anti‐SmRNP, anti‐Jo‐1, and anti‐ribosomal‐P] using the Bio‐Rad BioPlex 2200. Antitreponemal antibodies were detected in 87% of PNG sera versus 0–6% of controls (P < 0.0001). Anti‐dsDNA antibodies were detected in 31% of PNG samples, which was significantly higher than in three of the control groups (<10%). The outstanding high rate of antitreponemal antibodies detected in Kitavans possibly represents prior yaws disease. A low prevalence of cardiovascular disease was previously documented in Kitavans and has been attributed, in addition to their diet, to the high prevalence of natural cardioprotective autoantibodies (the IgM‐antiphosphorylcholine antibodies) in this population. Treponemal infection has been shown to induce the appearance of antiphosphorylcholine antibodies. These protective autoantibodies may cross‐react with the pathogenic anti‐dsDNA antibodies. Thus, it is suggested that infection with treponema is associated with the presence of protective as well as pathogenic autoantibodies.
Dysregulation of the Vitamin D Nuclear Receptor May Contribute to the Higher Prevalence of Some Autoimmune Diseases in Women
Authors: Proal Amy D. , Albert Paul J. , Marshall Trevor G.
Published: September 2009

Researchers have noted that the incidence of autoimmune diseases, such as Hashimoto's thyroiditis, is markedly higher in women than in men, but to date the reason for this disparity has been unclear. The vitamin D nuclear receptor (VDR) is expressed in the human cycling endometrium. Because the VDR controls expression of the cathelicidin and β‐defensin antimicrobial peptides (AmPs), dysregulation of the receptor greatly compromises the innate immune response. Increasing evidence indicates the presence of a chronic, intraphagocytic, metagenomic microbiota in patients with autoimmune disease that may survive by dysregulating the VDR. VDR dysregulation, in turn, prevents the breakdown of the active vitamin D metabolite 1,25‐hydroxyvitamin D (1,25‐D) by CYP24. In silico data suggest that when 1,25‐D rises above its normal range, it binds the α/β thyroid receptors, the glucocorticoid receptor (GCR), and the androgen receptor (AR), displacing their native ligands and causing an array of hormonal imbalances. If T3 is displaced from α‐thyroid, thyroiditis may result. Because the VDR, GCR, and AR also express multiple families of AmPs, expression of these natural antibiotics further wanes in response to dysregulation by 1,25‐D. The end result is a system‐wide drop in AmP expression that may allow pathogens to spread with greater ease. Because women have an extra site of VDR expression in the endometrium, the drop in AmP expression associated with nuclear receptor dysregulation may disproportionately affect them. This would cause women to accumulate higher bacterial loads than their male counterparts, particularly during early pregnancy when 1,25‐D levels rise by 40%.
Characterization of Antibodies Directed against the Immunoglobulin Light κ Chain Variable Chain Region (VK) of Hepatitis C Virus‐Related Type‐II Mixed Cryoglobulinemia and B‐Cell Proliferations
Authors: De Re Valli , Simula Maria Paola , Pavan Alessandro , Garziera Marica , Marin Dolores , Dolcetti Riccardo , De Vita Salvatore , Sansonno Domenico , Geremia Silvano , Toffoli Giuseppe
Published: September 2009

Autoimmune type‐II cryoglobulinemia (II‐MC) is sustained by hepatitis C virus (HCV) infection and B‐cell (oligo)clones. This is the reason why the disease may be considered an “indolent B‐cell lymphoma (NHL).” B clones show a restricted use of immunoglobulin variable genes (BCR), in particular in the use of the variable κ (VK)3–20/15 light chain, and show a homology between their BCR functional regions and those of autoimmune rheumatoid factors. We underlined the BCR unique repertoire with frequent rheumatoid factor activity also observed in other autoimmune disorders associated with NHL. The immunoglobulin idiotype is a clonal B‐cell marker and an ideal target for immunotherapy. Five monoclonal antibodies were produced in our laboratory toward the VK3–20 of a subject with HCV infection and a II‐MC‐associated NHL. Epitope determination was performed using the epitope excision approach. Monoclonal antibody reactivity was tested in vitro in ELISA, Western blot, and cytofluorimetry. Data confirmed that a panel of antibodies, reactive against shared idiotypes, can be produced from patients with HCV‐associated B‐cell lymphoproliferative diseases, thus obviating the need to produce an anti‐idiotype antibody for each patient.
Autoantibody Detection Using Indirect Immunofluorescence on HEp‐2 Cells
Authors: Sack Ulrich , Conrad Karsten , Csernok Elena , Frank Ingrid , Hiepe Falk , Krieger Thorsten , Kromminga Arno , Von Landenberg Philipp , Messer Gerald , Witte Torsten , Mierau Rudolf ,   for the German EASI (European Autoimmunity Standardization Initiative)
Published: September 2009

The detection of autoantibodies is an important element in the diagnosis and monitoring of disease progression in patients with autoimmune diseases. In laboratory diagnostic tests for connective tissue and autoimmune liver diseases, indirect immunofluorescence on HEp‐2 cells plays a central role in a multistage diagnostic process. Despite the high quality of diagnostics, findings at different laboratories can differ considerably due to a lack of standardization, as well as subjective factors.

The present paper formulates recommendations for the standardized processing and interpretation of the HEp‐2 cell test for the detection of non‐organ‐specific (especially antinuclear) antibodies. It provides requirements regarding the diagnostic tests used, instructions for laboratory procedure and evaluation, and recommendations for interpretation. For an optimal laboratory diagnostic process, it is useful to have an informative, tentative clinical diagnosis and an experienced laboratory diagnostician. In addition, the following key elements are recommended: initial screening using indirect immunofluorescence on carefully chosen HEp‐2 cells beginning with a serum dilution of 1:80 and evaluation under a microscope with powerful illumination; results from a titer of 1:160 upwards being considered positive; internal laboratory quality control; and standardized interpretation. The aim is to improve diagnostic tests and care of patients with autoimmune diseases as a central concern of the European Autoimmunity Standardization Initiative (EASI).
Chemokines as Novel Therapeutic Targets for Inflammatory Bowel Disease
Authors: Nishimura Miyuki , Kuboi Yoshikazu , Muramoto Kenzo , Kawano Tetsu , Imai Toshio
Published: September 2009

The inflammatory bowel diseases (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC) are illness characterized by a chronic clinical course of relapse and remission associated with self‐destructive inflammation of the gastrointestinal tract. In both UC and CD, leukocyte infiltration into the intestine is fundamental event in disease development and progression where the chemokines and their receptors are orchestrating the tissue‐specific and the cell type–selective trafficking of leukocytes. In this review, we will discuss the homeostatic and inflammatory roles of the chemokines and their receptors with their potentials and promise as molecular targets for therapeutic interventions in human IBD, focusing on the recently identified role of the CX3CL1–CX3CR1 axis, as well as the CCL20–CCR6, CCL25–CCR9, and CXCL10–CXCR3 pathways.
Alterations in Cytokine Profile and Dendritic Cells Subsets in Peripheral Blood of Rheumatoid Arthritis Patients before and after Biologic Therapy
Authors: Marti Luciana , Golmia Ricardo , Golmia Andrea Pimentel Fonseca , Paes Ângela Tavares , Guilhen Daiane Donna , Moreira‐Filho Carlos Alberto , Scheinberg Morton
Published: September 2009

Rheumatoid arthritis (RA) is an autoimmune disorder characterized by chronic joint inflammation and continuous immune cell infiltration in the synovium. These changes are linked to inflammatory cytokine release, leading to eventual destruction of cartilage and bone. During the last decade new therapeutic modalities have improved the prognosis, with the introduction of novel biological response modifiers including anti‐TNFα CTLA4Ig and, more recently, anti‐IL6. In the present study we looked at the immunological effects of these three forms of therapy. Serum, obtained from patients with RA was analyzed for TNFα, IL6, IL10, IFNγ, and VEGF, and in parallel, circulating plasmacytoid and myeloid dendritic cells (DC) were enumerated before and after three infusions of the respective biological treatments. After treatment with anti‐IL6, we found a significant reduction of IL6 and TNFα levels and the percentage of both DC subsets decreased. Although the results did not reach statistical significance for anti‐TNFα treatment, similar trends were observed. Meanwhile, CTLA4Ig therapy led to the reduction IFNγ levels only. None of the treatments modified significantly VEGF or IL10 levels. These findings may explain why patients with RA improve more rapidly on IL‐6 therapy than with the other two modalities.
TNF‐α Polymorphisms in Primary Biliary Cirrhosis: A Northern and Southern Italian Experience
Authors: Niro Grazia Anna , Poli Francesca , Andriulli Angelo , Bianchi Ilaria , Bernuzzi Francesca , Caliari Lisa , Fontana Rosanna , Gioffreda Domenica , Valvano Maria Rosa , Podda Mauro , Invernizzi Pietro
Published: September 2009

Specific HLA alleles and immunoregulatory genes have been evaluated in primary biliary cirrhosis (PBC), but data are discordant. We determined whether TNF‐α promoter polymorphisms (G‐308A and G‐238A) and alleles of HLA class II (HLA‐DRB1) might be associated either with PBC occurrence and severity in Italian populations from two distinct areas. The distribution of TNF1 (G/G) genotype did not differ either between patients and controls or between patients from Northern and Southern Italy. Contrariwise, the HLA‐DRB1*08 appeared positively linked to the occurrence of disease (8.4% in patients vs. 2.5% in controls, P= 0.003), whereas the HLA‐DRB1*13 appeared to be protective, being more frequent in controls (12.8%) than in patients (7%) (P= 0.038). Neither positively nor negatively associated alleles of the two genomic loci had an effect on disease progression. We report a distinct genetic risk of developing PBC in the Italian population, with no interaction between the HLA and TNF alleles.
Rituximab in Severe Pemphigus
Authors: Schmidt Enno , Goebeler Matthias , Zillikens Detlef
Published: September 2009

Pemphigus is a life‐threatening autoimmune bullous disorder that requires long‐term treatment with systemic corticosteroids mostly in conjunction with further immunosuppressants. Rituximab has opened a new avenue for severe and refractory pemphigus patients. In 95% of the 136 pemphigus patients reported to date in the English, French, and German literature, at least a partial remission has been achieved. In about two‐thirds of communicated cases, application of rituximab resulted in the healing of all lesions. A controlled prospective study, however, has only recently being initiated. In pemphigus, rituximab is aimed at resetting the immune system to a condition in which autoreactive B lymphocytes are eliminated or sufficiently controlled. Here, we review mechanisms of action, different treatment protocols, clinical responses, and the safety profile of rituximab.
Effects of Low‐Molecular‐Weight Heparin on Adhesion and Vesiculation of Phospholipid Membranes
Authors: Frank Mojca , Sodin‐Šemrl Snežna , Rozman Blaž , Potočnik Marko , Kralj‐Iglič Veronika
Published: September 2009

Heparins represent an efficient treatment of acute thrombosis and obstetric complications in antiphospholipid syndrome (APS). Enhanced microvesiculation of cell membranes, as detected by reduced membrane adhesion, can contribute to hypercoagulability in APS. Healthy donor IgG antibodies significantly increased β2‐glycoprotein I (β2‐GPI)‐induced membrane adhesion, indicating that IgG antibodies might supplement the role of β2‐GPI in the regulation of membrane microvesiculation in healthy individuals. Anti‐β2‐GPI IgG antibodies significantly reduced β2‐GPI‐induced membrane adhesion, suggesting a direct role of anti‐β2‐GPI antibodies in enhancing membrane microvesiculation in APS. Therapeutic concentration of nadroparin completely restored β2‐GPI‐induced membrane adhesion in the presence of anti‐β2‐GPI IgG antibodies. A novel anticoagulant mechanism of nadroparin in APS is suggested that supplements its direct effect on the coagulation cascade. Restoration of adhesion between negatively charged membranes in the presence of nadroparin might decrease shedding of microvesicles into the surrounding solution and could thus contribute to the efficacy of heparin treatment in APS.
Anti‐C1q Autoantibodies in Lupus Nephritis
Authors: Sinico Renato Alberto , Rimoldi Laura , Radice Antonella , Bianchi Laura , Gallelli Beniamina , Moroni Gabriella
Published: September 2009

Anti‐C1q antibodies are found in a variety of diseases, in addition to systemic lupus erythematosus (SLE), and in 3–5% of normal individuals. In particular, anti‐C1q antibodies are detected at a high titer in 100% of patients with hypocomplementemic urticarial vasculitis and in 30–48% of SLE patients. Their titer correlates with active renal disease with a sensitivity of 44–100% and a specificity of 70–92%. An increase in anti‐C1q antibody titer has been suggested to be able to predict renal flares in lupus nephritis so that monitoring anti‐C1q might be valuable for the clinical management of SLE patients as a noninvasive biological marker. Recently our group studied 228 patients affected by lupus nephritis and found that the association of anti‐C1q, C3, and C4, in a multivariate analysis, provided the best prediction of renal flares, particularly in patients with focal and diffuse proliferative lupus nephritis and in the absence of antiphospholipid antibodies.
Natural Antibodies against Phosphorylcholine in Cardiovascular Disease
Authors: De Faire Ulf , Frostegård Johan
Published: September 2009

Atherosclerosis is a chronic inflammatory disease characterized by the presence of activated immune‐competent cells in the lesions, producing mainly proinflammatory cytokines. Atherosclerosis is the underlying cause of cardiovascular disease (CVD), to a large extent occurring after damage and/or rupture of the atherosclerotic plaques. One major factor implicated as a cause of this immune activation is modified low‐density lipoproteins (LDL), especially oxidized forms (oxLDL), which are abundant in plaques, both in foam cells and in the necrotic core. The LDL‐oxidation process is very complex, and the nature of the antigens has been difficult to identify. We and others have focused on the phospholipids (PL) in oxLDL, especially oxidized forms of PL, including platelet‐activating factor (PAF)‐like lipids and lysophosphatidylcholine (LPC), and demonstrated that these could play a major role through proinflammatory effects. One common epitope is phosphorylcholine (PC), which is also exposed on some microorganisms (including Streptococcus pneumoneae) and on apoptotic cells. Natural IgM antibodies against PC (anti‐PC) have been known for a long time, but little has been reported about their role in human disease, especially in CVD. We have demonstrated that anti‐PC IgM are negatively associated with atherosclerosis development in hypertensive individuals and that low levels of anti‐PC independently predict development of CVD. Anti‐PC IgM could, therefore, be a novel risk marker in CVD. Animal experiments indicate that both active immunization with PC and passive immunization with anti‐PC ameliorate atherosclerosis development. The possibility that anti‐PC could be used therapeutically in humans deserves further study.
Development of Recombinant Human IgA for Anticardiolipin Antibodies Assay Standardization
Authors: Knappik Achim , Capuano Francesco , Frisch Christian , Ylera Francisco , Bonelli Fabrizio
Published: September 2009

Controls and calibrators in autoimmune assays are typically developed from patient sera. However, the use of sera is accompanied by a number of disadvantages, such as lack of monospecificity, lack of assay comparability, and supply limitations. Ideally, the control reagent would be an antigen‐specific human monoclonal antibody preparation that is defined and pure, easy to produce without any supply limitations, and of defined isotype (IgG, IgM, or IgA). The generation of antigen‐specific human monoclonal antibodies has been complicated, but recent advances in development of fully human antibodies by means of in vitro antibody gene library selection has opened a way for the isolation of human antibodies to virtually any antigen, including self‐antigens. Such antibodies can be converted to any isotype by gene cloning. Here we developed a set of human monoclonal IgA antibodies specific for the cardiolipin–β2‐glycoprotein 1 complex, using the HuCAL® technology. We evaluated the IgA variants of those antibodies for their use as standards in IgA anticardiolipin antibody assays and compared these reagents with serum controls. Such recombinant antibodies may ultimately replace patient sera as assay control and calibration reagents.
DNA‐Bound Lactoferrin Is the Major Target for Antineutrophil Perinuclear Cytoplasmic Antibodies in Ulcerative Colitis
Authors: Teegen Bianca , Niemann Stephanie , Probst Christian , Schlumberger Wolfgang , Stöcker Winfried , Komorowski Lars
Published: September 2009

Lactoferrin has repeatedly been proposed to be a target for antineutrophil perinuclear cytoplasmic antibodies (P‐ANCA), which are present in 67% of ulcerative colitis (UC) cases. However, this high prevalence has not been achieved with either Western blots or monospecific ELISA on the basis of purified lactoferrin bound to the solid phase. We reevaluated autoantibodies against lactoferrin by indirect immunofluorescence (IIF), using a lactoferrin‐tuned granulocyte substrate. Slides with ethanol‐fixed human granulocytes were stripped of their P‐ANCA targets by high‐salt treatment and then reconstituted with human lactoferrin (LFR granulocytes). The slides were then subjected to IIF with a panel of sera (39 UC, 10 antimyeloperoxidase‐positive vasculitis, 50 healthy blood donors). The human sera were also analyzed with antilactoferrin ELISA. In 28 of 39 (71.8%) sera from UC patients, antibodies could be determined that bound exclusively to LFR granulocytes. Nuclease‐treated cells failed to show this reactivity. ELISA detected antilactoferrin antibodies in only two UC sera. Lactoferrin is a major P‐ANCA target in UC but requires DNA to present the epitopes relevant for the reaction with the autoantibodies. Antigen‐stripped and lactoferrin‐reconstituted granulocytes can be used in IIF to diagnose antilactoferrin antibodies in UC more reliably than with existing ELISA systems.
Immmunopathogenesis of Rheumatoid Arthritis
Authors: Hoffmann Markus , Hayer Silvia , Steiner Guenter
Published: September 2009

Rheumatoid arthritis (RA) is a severe autoimmune disorder of unknown etiology. Major autoantigens include immunoglobulin G (which is targeted by rheumatoid factor), citrullinated proteins, and the heterogeneous nuclear ribonucleoprotein (hnRNP) A2. To obtain more insight into the pathogenic role of arthritogenic autoantigens, we studied autoimmune responses in two animal models of RA, which are independent of immunization with exogenous antigens, namely human tumor necrosis factor‐α (TNF‐α)‐transgenic (hTNFtg) mice and rats with pristane‐induced arthritis (PIA). Serologic and cellular studies revealed autoantibodies to hnRNP‐A2 in these animals and pronounced T‐cell reactivity to hnRNP‐A2 and the presence of rheumatoid factor in PIA, while citrullinated antigens were not targeted. Furthermore, hnRNP‐A2 was found to be highly overexpressed in the joints of mice and rats affected by arthritis. Thus, unspecific proinflammatory stimuli, such as TNF‐α or pristane, may induce pathogenic autoimmune reactions that may drive an inflammatory process, leading to the development of erosive arthritis.
HLA‐B27 and HLA‐B51 Determination in Tunisian Healthy Subjects and Patients with Suspected Ankylosing Spondylitis and Behçet's Disease
Authors: Sakly Nabil , Boumiza Radhia , Zrour‐Hassen Saoussen , Hamzaoui Amira , Yahia Salim Ben , Amara Hamida , Khairallah Moncef , Mahjoub Sylvia , Bergaoui Naceur , Ghedira Ibtissem
Published: September 2009

The aim of this retrospective study is to assess the frequency of HLA‐B27 and HLA‐B51 in healthy subjects from the center of Tunisia and to investigate their usefulness in the diagnosis of ankylosing spondylitis (AS) and Behçet's disease (BD), respectively. Microlymphocytotoxicity test was used to perform serologic HLA typing in a group of 124 healthy volunteers and a group of 365 patients suffering from clinical manifestations of AS and/or BD. HLA‐B27 was found in 3.2% of healthy subjects and in 42.9% of patients with AS (P < 0.00006). HLA‐B51 is, however, found in 16.1% of healthy subjects and in 30.0% of patients with BD (P > 0.05). Unlike HLA‐B51, which seems to be as frequent in Tunisian patients with BD as in healthy subjects, HLA‐B27 is more frequent in patients with AS than in controls. This highlights the usefulness of HLA‐B27, rather than that of HLA‐B51, in the diagnosis of the respective diseases.
HE3286: A Novel Synthetic Steroid as an Oral Treatment for Autoimmune Disease
Authors: Ahlem C. , Auci D. , Mangano K. , Reading C. , Frincke J. , Stickney D. , Nicoletti F.
Published: September 2009

HE3286 (17α‐ethynyl‐5‐androstene‐3β, 7β, 17β‐triol) is a synthetic derivative of a natural anti‐inflammatory steroid, β‐AET (5‐androstene‐3β, 7β, 17β‐triol). HE3286 is orally bioavailable and treats established disease in models of ulcerative colitis, collagen‐induced arthritis, and collagen antibody‐induced arthritis, reducing clinical signs of disease and proinflammatory signals, including IL‐6 and matrix metallopeptidase 3. HE3286 modulates nuclear factor κB through an unknown mechanism but does not interact with any of the steroid‐binding nuclear hormone receptors and is not immune suppressive. HE3286 was safe and well tolerated in phase I studies and is under evaluation in multicenter phase I/II clinical trials for ulcerative colitis and arthritis. HE3286 may provide a new treatment option for patients with inflammatory and autoimmune diseases.
Enhancing the Action of Rituximab in Chronic Lymphocytic Leukemia by Adding Fresh Frozen Plasma
Authors: Klepfish Abraham , Gilles Lugassy , Ioannis Kotsianidis , Eliezer Rachmilewitz , Ami Schattner
Published: September 2009

Many patients with chronic lymphocytic leukemia (CLL) develop progressive treatment‐resistant disease. Rituximab (RTX), a monoclonal antibody targeting CD20 on B lymphocytes and widely used in other indolent B‐cell neoplasms is less efficacious in CLL, possibly because of associated complement deficiencies. Initial in vitro and in vivo observations support the central role of complement in rituximab‐mediated loss of CD20+ cells in CLL. In an open trial conducted in outpatient hematology clinics in Israel and Greece, we examined whether providing complement by concurrent administration of fresh frozen plasma (FFP) would enhance the effect of RTX in CLL. Five patients with severe treatment‐resistant CLL were included in the trial. All had been previously treated with fludarabine, and three also failed treatment with RTX. Each patient was treated with two units of FFP followed with RTX 375 mg/m2 as a single agent, repeated every 1–2 weeks as needed. A rapid and dramatic clinical and laboratory response was achieved in all patients. Lymphocyte counts dropped markedly followed by shrinkage of lymph nodes and spleen and improvement of the anemia and thrombocytopenia. This could be maintained over 8 months (median) with additional cycles if necessary. Treatment was well tolerated in all cases. In conclusion, adding FFP to RTX may provide a useful therapeutic option in patients with advanced CLL resistant to treatment. Further studies are needed to confirm and study the efficacy of the FFP/RTX combination in advanced CLL, establish the mechanisms, and possibly extend its use to other B‐cell‐dependent pathologies, such as treatment‐refractory autoimmune diseases.
Autoantibody Screen in Inflammatory Myopathies High Prevalence of Antibodies to Gliadin
Authors: Orbach Hedi , Amitai Nimrod , Barzilai Ori , Boaz Mona , Ram Maya , Zandman‐Goddard Gisele , Shoenfeld Yehuda
Published: September 2009

Background: Inflammatory myopathies (IM) are associated with autoimmune diseases. Aim: To evaluate the titers of auto‐antibodies specific to various autoimmune diseases in patients with IM compared with controls. Methods: Sera from 99 IM patients and 100 healthy controls were tested for autoantibodies for vasculitis (myeloperoxidase, PR3, and glomerular basement membrane) and autoimmune gastrointestinal diseases (IgA and IgG antigliadin, antitissue transglutaminase, and Saccharomyces cerevisiae) utilizing the BioPlex 2200 Multiplexed Immunoassay method (Biorad). Results: Antigliadin IgA levels were significantly elevated in IM patients compared with controls (0.37 units ± 0.44 vs. 0.24 units ± 0.15, P= 0.017). Antitissue transglutaminase IgA was marginally increased in IM patients versus controls (0.36 units ± 1.12 vs. 0.2 units ± 0.0, P= 0.08). Conclusions: Antibodies to gliadin and tissue transglutaminase characteristic for celiac disease were elevated in patients with IM compared with controls. This may indicate a higher prevalence of gluten sensitivity or celiac disease in IM.
Infections May Have a Protective Role in the Etiopathogenesis of Celiac Disease
Authors: Plot Leeor , Amital Howard , Barzilai Ori , Ram Maya , Nicola Bizzaro , Shoenfeld Yehuda
Published: September 2009

Infectious agents have been implicated in the pathogenesis of many autoimmune diseases via various pathogenic mechanisms, such as molecular mimicry, resulting in modulation of the host's immune tolerance. In the following article we examine the association between serological evidence of past infection with Toxoplasma gondii, rubella virus, cytomegalovirus, Treponema pallidum, and Epstein–Barr virus, and the co‐existence of celiac disease. Our results imply that certain infections may generate an immunological environment that disfavors future appearance of certain autoimmune conditions such as celiac disease.
Toll‐like Receptors in Multiple Sclerosis Mouse Experimental Models
Authors: Marta Monica
Published: September 2009

Certain pathogen molecules trigger innate immune responses and drive subsequent adaptive immune responses toward an antigen presented simultaneously. Such bacterial or viral molecules constitute pathogen‐associated molecular patterns (PAMPs) that bind to pattern‐recognition receptors such as toll‐like receptors (TLRs). Recently, endogenous molecules were identified that ligate the same receptors. The role of these receptors' response to complete Freund's adjuvant during initiation of CD4 T cell responses in EAE, the animal model for multiple sclerosis, is here discussed. Myeloid differentiation primary response gene 88 (MyD88) is necessary for the induction of experimental autoimmune encephalomyelitis (EAE), and it is required for the activation of myeloid dendritic cells and differentiation of T helper 17 cells. The role of individual TLR, in particular TLR3, TLR4, and TLR9, signaling in modulation of EAE inflammation varies with the experimental model employed and the immune cells that drive pathology. The TLR‐dependent production of proinflammatory cytokines is regulated by mechanisms that dampen the pathway and prevent excess damage. Development of TLR antagonists to treat autoimmune diseases must acknowledge the possibility of interference with regulatory mechanisms.
IL‐6 during Viral‐induced Chronic Autoimmune Myocarditis
Authors: Poffenberger Maya C. , Horwitz Marc S.
Published: September 2009

Interleukin (IL)‐6 is a pleiotropic cytokine that plays a key role in a wide variety of diseases. Based on a number of adjuvant‐induced experimental models, IL‐6 is critical to the development of autoimmune diseases including experimental autoimmune encephalomyelitis, adjuvant‐induced arthritis, and experimental autoimmune myocarditis. However, whether it plays a pathogenic role in viral‐induced autoimmune myocarditis has been less well defined. While experimental models of myocarditis have clearly linked IL‐6 to the generation of pathogenic autoreactive T cells, IL‐6 has exhibited a protective role in autoimmune disease development in viral‐induced disease models. As pathogen infection has been linked to the majority of myocarditis patients, treatments aimed at decreasing IL‐6 levels in the hopes of limiting the autoimmune response run the risk of increasing disease severity.
Effector Functions of Antiaquaporin‐4 Autoantibodies in Neuromyelitis Optica
Authors: Cayrol Romain , Saikali Philippe , Vincent Thierry
Published: September 2009

NMO‐IgG autoantibody is now considered a useful serum biomarker of neuromyelitis optica (NMO). A series of clinical and pathological observations suggest that NMO‐IgG may play a central role in NMO physiopathology. Although the exact role and function of NMO‐IgG in vivo remain to be determined, recent reports suggest that this antibody that targets the aquaporin‐4 (AQP‐4) water channel expressed by astrocytes is able to destabilize the blood–brain barrier and contribute to astrocyte and oligodendrocyte damage. This review summarizes the latest molecular effector functions attributed to the NMO‐IgG/anti‐AQP4 antibody and discusses their potential role in NMO pathology.
White Blood Cell Count Abnormalities and Infections in One‐year Follow‐up of 124 Patients with SLE
Authors: Dias Ana Margarida Brito , Do Couto Maura Cristina Medeiros , Duarte Cátia Cristina Marques , Inês Luís Pedro Bolotinha , Malcata Armando Boavida
Published: September 2009

The purpose of our study was to evaluate the frequency of leukocyte count abnormalities in a large cohort of SLE patients and its association with infection. To make this evaluation, we studied consecutive patients with SLE diagnosis and prospectively followed them in the Coimbra Lupus Cohort. Data about white blood cell count abnormalities and infection during one‐year follow‐up were obtained. The presence of leukopenia, lymphopenia, and neutropenia was registered for one‐year period. Infections were classified as severe or mild. We found that of the 124 patients who were included (91.1% female, mean age 41.2, mean disease duration 11.1), mild infections occurred in 43.5%, and severe in 3.2% of the patients. Twelve percent, 41.1%, and 4.8% of the patients had persistent leukopenia, lymphopenia, and neutropenia, respectively. Fourteen percent received a pneumococcal vaccination. Patients with neutropenia had a significantly higher number of infections (P= 0.033). Thus, our study showed that neutropenia was associated with an increased risk of infection during this one‐year follow‐up. Infections were frequent, but most of them were mild.
Hyperactivity Induced by Antiphospholipid Syndrome Serum
Authors: Menachem Assaf , Chapman Joab , Katzav Aviva
Published: September 2009

Antiphospholipid syndrome (APS) is a multisystem disorder characterized by arterial and venous thrombosis, pregnancy morbidity, and neuropsychiatric manifestations. Antiphospholipid IgG injected intracerebro‐ventricularly (ICV) cause behavioral hyperactivity in mice. In the present study we investigated the effects of APS whole‐serum ICV administration in female Balb/C mice. Control mice were injected with serum derived from healthy subjects or saline solution. Behavior was assessed by the staircase apparatus which combines locomotor (stair‐climbing) exploratory activities and rearing as a measure of anxiety. Mice injected with serum from APS patients or serum from normal subjects showed a trend to an increase in the number of stairs climbed in the APS group. The results suggest a differential effect of specific IgG and other serum components in the CNS manifestations of APS.
Complement Cascade in Systemic Lupus Erythematosus
Authors: Ceribelli Angela , Andreoli Laura , Cavazzana Ilaria , Franceschini Franco , Radice Antonella , Rimoldi Laura , Sinico Renato Alberto , Carlsson Malin , Wieslander Jorgen , Tincani Angela
Published: September 2009

The complement (C') cascade is an important part of the innate immunity. It acts through three major pathways: classical (CP), alternative (AP) and mannose‐binding‐lectin (MP). C' reduction is a key feature in systemic lupus erythematosus (SLE), for its pathogenesis and for disease relapse. The aims of our study are to correlate C' variations with disease activity and verify the presence of C' deficiencies. We tested for three C' pathways 52 sera from 20 patients affected by SLE. A significant correlation between the ECLAM score and the degree of activation of the CP (Mann‐Whitney; P= 0.001) was recorded, while the correlation with anti‐dsDNA antibodies did not reach statistical significance (Mann‐Whitney; P > 0.05). In conclusion, the ELISA assay can be considered well suited for testing SLE samples. We detected a significant link between the phases of lupus activity and the reduction of the CP.
The present role of corticosteroids in uveitis
Authors: KHAIRALLAH M
Published: September 2009

Corticosteroids are the most widely used anti‐inflammatory and immunosuppressant drugs in ophthalmology in general, and remain the mainstay of therapy for patients with uveitis.An infectious etiology for intraocular inflammation should be adequately excluded or appropriately covered with anti‐infectious therapy before administration of corticosteroid therapy. Topical corticosteroids alone are usually effective in the management of anterior uveitis and have little activity against intermediate or posterior uveitis. Ocular adverse effects of topical steroid therapy mainly include ocular hypertension and cataract. The use of periocular steroid injections (subconjunctival, anterior or posterior subtenon, orbital floor) are important modalities in the management of anterior uveitis refractory to topical treatment and intermediate or posterior uveitis, particularly unilateral cases. Systemic corticosteroids remain the initial drug of choice for most patients with severe bilateral intermediate or posterior uveitis. Therapy is initiated with 1.0 to 2.0 mg/Kg of oral prednisone or prednisolone as a single morning dose, followed by a slow taper. Use of intravenous pulse steroid therapy is an important option in acute, severe, bilateral posterior segment inflammation. In several cases, the level of systemic steroid required to control the inflammation is too high and unacceptable. Immunosuppressive drugs as steroid‐sparing agents are indicated is such cases. Intravitreal injection of triamcinolone acetonide and slow‐release intraocular devices are therapeutic options that can be used in selected uveitis cases refractory to conventional therapy and biologic agents.
Traditional immunosuppressants for uveitis
Authors: DE SMET M
Published: September 2009

Abstract not provided
Mycophenolate mofetil in uveitis
Authors: NERI P
Published: September 2009

Purpose To review the current Literature and to describe the experience of a tertiary referral centre on the use of mycophenolate mofetil (MMF) treatment in uveitis.

Methods The current literature is reviewed and the experience of a tertiary referral centre is reported.

Results The long‐lasting remission in several systemic diseases, such as Crohn’s disease, severe atopic dermatitis, Wegener’s granulomatosis and microscopic polyangioitis, rheumatoid arthritis, pemphigus vugaris, and psoriasis, have been proven. Recent publications have have recently confirmed the satisfactory control of uveitis with MMF in a large cohort of patients. Moreover, the long‐term control of cystoid macular oedema (CMO) unresponsive to the traditional therapy has been described, as well as for the choroidal neovascularization (CNV).

Conclusion Non‐infectious uveitis is one of the leading causes of visual impairment in ophthalmology. Steroids can control such disease, even though a long‐term treatment is not recommended: several complications, such as high blood sugar level, osteoporosis, blood cell abnormalities, cataract and glaucoma, can occur. MMF is a reversible, non competitive, selective inhibitor of the de‐novo pathway of purine synthesis; mycophenolic acid has a strong effect to Type II isoform of inosine monophosphate dehydrogenase enzyme, providing a stronger cytostatic effect on lymphocytes than on other cells types, with minor action to Type I expressed in most other cells. The specific action of MMF on selected targets makes it a promising drug for the control of non‐infectious intraocular inflammations.
Optimised monitoring of inflammation suppressive therapy (IST) in uveitis
Authors: HERBORT CP
Published: September 2009

Purpose The array of inflammation suppressive therapies (IST) has increased trumendously in the last two decades including the availability of biological molecules with potent immunomodulatary activities as well as new immunosuppressive agents. In parallel measuring methods for intraocular inflammation have become available allowing much more acurate monitoring of the evolution of inflammation and its response to therapy. In addition to the traditionally used fluorescein angiography (FA), laser flare photometrry (LFP), indocyanine green angiography ICGA) and optical coherence tomography (OCT) are among the new investigational methods that have become available, each of them allowing us to establish inflammatory activity with increased precision and to explore compartments previously poorly accessible.

Methods The advantages of each method will be put forward. Illustrative cases will be taken as examples to show the degree of precision obtained by combining the different methods presently at our disposal for the follow‐up and monitoring of inflammation suppressive treatment.

Results These cases will show that the presently available tools for optimal monitoring of intraocular inflammation allow the clinician to be better aware of the level of inflammatory activity and to better adapt his treatment.

Conclusion Not only he availability of potent new therapies but also the possibility to follow more precisely intraocular inflammation with new precise devices has certainly changed the outcome of uveitis cases in recent years.
Pitfalls in statistics and how to avoid them ‐ part 1
Authors: KIVELÄ T
Published: September 2009

Purpose To highlight some pearls and pitfalls in reporting summary statistics and in using common statistical tests.

Methods Personal experience of the author as a writer, reviewer and editorial board member especially for the EVER Journal, Acta Ophthalmologica, is used to highlight some of the most common possibilities for improvement in using basic statistics.

Results The items discussed, based on examples from the literature, include: 1. how to avoid giving a false impression of precision when reporting key results and how to communicate effect size; 2. how to differentiate statistical from clinical significance and how to communicate statistically nonsignificant results when writing the manuscript; 3. recognising the common problem of making multiple comparisons and adjusting for them; and 4. differentiating ordered and unordered categorical data and choosing the proper statistical test accordingly.

Conclusion Clear reporting and analysis of basic statistics is not difficult as long as one is aware of a few basic rules, which will be discussed in this talk. Putting them into action may improve your manuscripts.
Pitfalls in statistics and how to avoid them ‐ part 2
Authors: KIVELÄ T
Published: September 2009

Purpose To highlight some pearls and pitfalls in reporting statistics related to the eye.

Methods Personal experience of the author as a writer, reviewer and editorial board member especially for the EVER Journal, Acta Ophthalmologica, is used to highlight common issues specific for reporting eye‐related statistics.

Results The items discussed, based on examples from the literature, include: 1. proper ways of summarising and comparing visual acuities; and 2. proper ways of analysing data collected from both eyes of the patients. The need to find a statistician well versed in ophthalmic research at the planning stage of a study is stressed

Conclusion Correct reporting and analysis of data related to the eye is not difficult as long as one is aware of a few basic rules, which will be discussed in this talk. Putting them into action helps to ensure that the conclusions the readers draw from your study are proper.
Diabetic retinopathy
Authors: POURNARAS CJ , MENDRINOS E
Published: September 2009

Purpose To describe the clinical stages of diabetic retinopathy (DR) and diabetic macular edema (DME), their complications and treatment.

Methods Diabetic retinopathy is currently classified into several groups: minimal non‐proliferative, moderate non‐proliferative, severe non‐proliferative and proliferative with or without high‐risk characteristics. To characterize the severity of DME and for treatment guidelines, the term clinically significant macular edema (CSME) is used. CSME is further classified into focal or diffuse.

Results The role of panretinal photocoagulation in reducing the risk of severe visual loss related to proliferative diabetic retinopathy has been demonstrated by prospective large scale randomized studies (DRS, ERTDS). Similarly, the ETRDS study showed the benefit of focal/grid laser photocoagulation in reducing the risk of moderate visual loss in CSME. In the last years, promising results have been published on the use of intravitreal (IVT) injections of triamcilone acetonide, anti‐VEGF agents, and on the use injectable sustained release steroid implants in terms of visual gain and reduction of central macular thickness. Laser photocoagulation was demonstrated more effective that IVT triamcinolone alone for the treatment of diabetic macular oedema. The risks and benefits of novel treatment modalities and their efficacy and safety should be further evaluated in prospective well designed studies. Vitrectomy is indicated in selected cases.

Conclusion Diabetic retinopathy is characterized by gradually progressive alterations in the retinal microvasculature leading to neovascularization, vitreous hemorrhage, retinal detachment and macular edema. Several treatment modalities are still investigated. Laser photocoagulation is the standard of care.
Pigmented lesions
Authors: DESJARDINS L
Published: September 2009

Purpose The aim of the course is to describe symptoms , clinical findings and main diagnostic procedures for pigmented fundus lesions

Methods Asymptomatic lesions include choroidal naevi , melanocytomas and congenital hypertrophy of the pigment epithelium . Symptomatic lesions include combined hamartomas of the retina and pigment epithelium, suspicious choroidal naevi , choroidal melanomas and subretinal hematomas

Results For each of the lesions fundus aspects will be described as well as the results of ultrasonography , fluorescein angiograms , OCT and MRI With the symptoms, clinical findings and results of ancillary tests diagnosis and differential diagnosis will be discussed