bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relationship between genetic variants in the adenosine pathway and outcome of methotrexate treatment in patients with recent‐onset rheumatoid arthritis
Authors: Wessels Judith A. M. , Kooloos Wouter M. , Jonge Robert De , De Vries‐Bouwstra Jeska K. , Allaart Cornelia F. , Linssen Annelies , Collee Gerard , Sonnaville Peter De , Lindemans Jan , Huizinga Tom W. J. , Guchelaar Henk‐Jan 
Published: August 2006

AbstractObjectiveAmong patients with rheumatoid arthritis (RA), there is a high degree of interindividual variability in the degree of response to methotrexate (MTX) treatment. This study was undertaken to explore polymorphisms in genes contributing to antiinflammatory adenosine release as novel predictors of MTX treatment outcome.MethodsIn 205 patients with newly diagnosed RA, 5 polymorphisms in 5 genes coding for enzymes related to the release of adenosine were analyzed. All patients received standardized MTX treatment (up to 25 mg per week orally), combined with folic acid. MTX efficacy was evaluated by the Disease Activity Score (DAS) and compared among genotypes. The association between MTX‐related adverse events and genotype was also assessed. The following polymorphisms were determined: AMPD1 34C>T, ATIC 347C>G, ITPA 94C>A, MTR 2756A>G, and MTRR 66A>G. When significant differences were found by chi‐square analysis, odds ratios (ORs) and 95% confidence intervals were calculated.ResultsPatients carrying the AMPD1 34T allele, ATIC 347CC, or ITPA 94CC were more likely to have a good clinical response, as defined by a DAS of ≤2.4 (OR [95% confidence interval] 2.1 [1.0–4.5], 2.5 [1.3–4.7], and 2.7 [1.1–8.1], respectively). The likelihood of a good clinical response was increased if patients possessed all 3 favorable genotypes (OR 27.8 [95% confidence interval 3.2–250]). Regarding toxicity, only ATIC G allele carriers experienced a greater frequency of adverse events (OR 2.0 [95% confidence interval 1.1–3.7]).ConclusionPolymorphisms in the AMPD1, ATIC, and ITPA genes are associated with good clinical response to MTX treatment. These findings indicate that genotyping may help in the identification of patients who will benefit most from MTX treatment and may assist clinicians in making treatment decisions regarding patients with recent‐onset RA.
Double‐blind randomized controlled clinical trial of the interleukin‐6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate
Authors: Maini R. N. , Taylor P. C. , Szechinski J. , Pavelka K. , Bröll J. , Balint G. , Emery P. , Raemen F. , Petersen J. , Smolen J. , Thomson D. , Kishimoto T. 
Published: August 2006

AbstractObjectiveTo establish the safety and efficacy of repeat infusions of tocilizumab (previously known as MRA), a humanized anti–interleukin‐6 (IL‐6) receptor antibody, alone and in combination with methotrexate (MTX), for the treatment of rheumatoid arthritis (RA).MethodsThe study group comprised 359 patients with active RA in whom the response to MTX was inadequate. During a stabilization period, these patients received their current dose of MTX for at least 4 weeks. Following stabilization, they were randomized to 1 of 7 treatment arms, as follows: tocilizumab at doses of 2 mg/kg, 4 mg/kg, or 8 mg/kg either as monotherapy or in combination with MTX, or MTX plus placebo.ResultsA 20% response (improvement) according to the American College of Rheumatology criteria (ACR20 response) was achieved by 61% and 63% of patients receiving 4 mg/kg and 8 mg/kg of tocilizumab as monotherapy, respectively, and by 63% and 74% of patients receiving those doses of tocilizumab plus MTX, respectively, compared with 41% of patients receiving placebo plus MTX. Statistically significant ACR50 and ACR70 responses were observed in patients receiving combination therapy with either 4 mg/kg or 8 mg/kg of tocilizumab plus MTX (P < 0.05). A dose‐related reduction in the Disease Activity Score in 28 joints was observed from week 4 onward, in all patients except those receiving monotherapy with 2 mg/kg of tocilizumab. In the majority of patients who received 8 mg/kg of tocilizumab, the C‐reactive protein level/erythrocyte sedimentation rate normalized, while placebo plus MTX had little effect on these laboratory parameters. Tocilizumab was mostly well tolerated, with a safety profile similar to that of other biologic and immunosuppressive therapies. Alanine transaminase and aspartate transaminase levels followed a sawtooth pattern (rising and falling between infusions). There were moderate but reversible increases in the nonfasting total cholesterol and triglyceride levels and reversible reductions in the high‐density lipoprotein cholesterol and neutrophil levels. There were 2 cases of sepsis, both of which occurred in patients who were receiving combination therapy with 8 mg/kg of tocilizumab plus MTX.ConclusionThese results indicate that targeted blockade of IL‐6 signaling is a highly efficacious and promising means of decreasing disease activity in RA.
Endothelin axis polymorphisms in patients with scleroderma
Authors: Fonseca Carmen , Renzoni Elizabeth , Sestini Piersante , Pantelidis Panagiotis , Lagan Anna , Bunn Christopher , McHugh Neil , Welsh Ken I. , Bois Ron M. Du , Denton Christopher P. , Black Carol , Abraham D. 
Published: August 2006

AbstractObjectiveTo evaluate the distribution of polymorphisms in the endothelin 1 (EDN1), endothelin receptor A (EDNRA) and endothelin receptor B (EDNRB) genes in systemic sclerosis (SSc; scleroderma) and SSc subsets.MethodsTwo hundred five patients with SSc and 255 healthy controls were screened for polymorphisms in EDN1, EDNRA, and EDNRB, using sequence‐specific primer–polymerase chain reaction. The polymorphisms studied were at the following positions: for EDN1, −1370 (T‐1370G) of the promoter, +138 of exon 1 (+138 A/−), +85 of exon 3 (E106E), and +23 of exon 5 (K198N); for EDNRA, −231 of exon 1 (G‐231A), and +69(H323H) and +105 (E335E) of exon 6; for EDNRB, +2841 of exon 2 (EDNRB‐3), −2547 of exon 3 (EDNRB‐2), and −2446 of exon 3 (EDNRB‐1).ResultsNo significant differences between the SSc group as a whole and control subjects were observed for any of the investigated polymorphisms in EDN1, EDNRA, and EDNRB. However, compared with patients with limited cutaneous SSc, patients with diffuse skin involvement had an increased frequency of allele carriage of EDNRB‐1A (76.8% versus 54.4%; P = 0.002), EDNRB‐2A (79.7% versus 60.2%; P = 0.006), and EDNRB‐3G (79.7% versus 56.6%; P = 0.001). Significantly increased carriage frequencies for EDNRA alleles H323H/C and E335E/A were observed in SSc patients with anti–RNA polymerase (anti‐RNAP) antibodies, compared with both anti‐RNAP–negative SSc patients (P < 0.05) and control subjects (P < 0.005).ConclusionThe finding of associations between endothelin receptors A and B and distinct clinical and immunologic SSc subsets supports the role of endothelin and its receptors in the pathogenesis of SSc. However, these findings and their functional significance need to be confirmed and investigated in future studies.
Chimerism occurs twice as often in lupus nephritis as in normal kidneys
Authors: Hovinga Idske C. L. Kremer , Koopmans Marije , Baelde Hans J. , Wal Annemieke M. van der , Sijpkens Yvo W. J. , Heer Emile de , Bruijn Jan A. , Bajema Ingeborg M. 
Published: August 2006

AbstractObjectiveSystemic lupus erythematosus (SLE) is an immune‐mediated disease that particularly affects the kidneys, causing lupus nephritis. In experimental mouse models, lupus nephritis can be mimicked by inducing a chimeric state through the injection of parental T cells in offspring. In humans, pregnancy‐induced chimerism may play a role in the pathogenesis of autoimmune diseases such as SLE, but it is likely that only certain chimeric cells have pathogenic potential. In this study, we investigated whether the distribution of chimeric cells is different in the kidneys of women with SLE from that in normal kidneys, and we examined the phenotype of chimeric cells in women with SLE.MethodsThe presence of chimeric cells was investigated by in situ hybridization targeting the Y chromosome in 57 renal biopsy samples from 49 women with lupus nephritis. Fifty‐one kidney autopsy specimens without histomorphologic lesions served as controls. Double‐staining for the Y chromosome in combination with CD3 and CD34 markers was performed in 5 kidney specimens with lupus nephritis to identify the phenotype of the chimeric cells.ResultsY chromosome–positive cells were found in 27 of 49 patients with lupus nephritis and in 13 of 51 normal controls (P < 0.01). Both CD3+ and CD34+ chimeric cells were identified in lupus nephritis kidney specimens.ConclusionChimeric cells are present significantly more often in kidneys with lupus nephritis than in normal kidneys, and some of these chimeric cells are T cells. This finding is interesting in light of experimental models demonstrating that lupus nephritis is initiated by chimeric T cells.
Identification of fibronectin neoepitopes present in human osteoarthritic cartilage
Authors: Zack Marc D. , Arner Elizabeth C. , Anglin Charles P. , Alston James T. , Malfait Anne‐Marie , Tortorella Micky D. 
Published: August 2006

AbstractObjectiveFibronectin fragments are present at high concentrations in the cartilage of patients with rheumatoid arthritis and patients with osteoarthritis (OA) and have been shown to promote cartilage catabolism in human cartilage cultures, suggesting that fibronectin fragments participate in the initiation and progression of arthritic disease. This study was undertaken to 1) identify the major fibronectin fragments in human OA cartilage and confirm their ability to elicit cartilage catabolism, 2) identify the cleavage sites in fibronectin and generate the corresponding neoepitope antibodies, and 3) explore the utility of fibronectin neoepitopes as biomarkers.MethodsFibronectin fragments were purified from human OA cartilage using affinity chromatography; their N‐termini were then identified by sequencing. Bovine nasal cartilage was treated with affinity‐purified fibronectin fragments and assayed for aggrecan breakdown by monitoring the release of glycosaminoglycans and the aggrecan neoepitope 1771AGEG. Fibronectin neoepitopes were detected by Western blotting in cytokine‐treated media of human cartilage explants, and by immunohistochemical analyses of human OA cartilage.ResultsMultiple fibronectin fragments were isolated from human OA cartilage, and all contained the N‐terminus 272VYQP. These fragments induced aggrecanase‐mediated cartilage catabolism in bovine cartilage explants. Fibronectin fragments with the N‐terminus 272VYQP and fragments with the C‐terminus VRAA271 were detected following cytokine treatment of human cartilage extracts. These neoepitopes localized with areas of aggrecan loss in OA cartilage.ConclusionHuman OA cartilage contains fibronectin fragments with catabolic activity and a major cleavage site within fibronectin. This study is the first to characterize fibronectin neoepitopes in OA cartilage, suggesting that they may represent a novel biomarker of arthritis.
Long‐term comparison of rituximab treatment for refractory systemic lupus erythematosus and vasculitis: Remission, relapse, and re‐treatment
Authors: Smith K. G. C. , Jones R. B. , Burns S. M. , Jayne D. R. W. 
Published: August 2006

AbstractObjectiveCurrent treatments for systemic lupus erythematosus (SLE) and vasculitis contribute to mortality and incapacity and are only partially effective; thus, newer therapies are clearly needed. Depletion of B cells has led to disease control in patients with autoimmune disorders. We sought to assess the long‐term efficacy and safety of a B cell–depleting therapy in patients with SLE and patients with vasculitis.MethodsIn a prospective study with a median followup of 24 months, 11 patients with active or refractory SLE and 11 patients with active or refractory antineutrophil cytoplasmic antibody–associated vasculitis (AAV) received a course of therapy with rituximab (an anti‐CD20 monoclonal antibody) along with a single dose of intravenous cyclophosphamide.ResultsRemission followed rapid B cell depletion, with response rates of 100% among the 11 patients with SLE (6 patients had a complete response, and 5 patients had a partial response) and 91% among the 11 patients with AAV (9 patients had a complete response, and 1 patient had partial remission). A renal response occurred in all 6 patients with lupus nephritis. Clinical improvement was accompanied by significant reductions in the daily dose of prednisolone. Relapse occurred in 64% of the patients with SLE and in 60% of those with AAV. B cell return preceded relapse in the majority of patients, and further treatment with rituximab proved effective. IgG and IgM levels were maintained in the normal range. The incidence of infective complications was low; however, infusion reactions were common, and human antichimeric antibodies developed in 5 of 14 patients.ConclusionB cell depletion offers the prospect of sustained disease remission and improved disease control combined with low toxicity in patients with active or refractory SLE or AAV. Relapse following treatment is common, but re‐treatment is rapidly effective.
Dysregulation of interleukin‐10–dependent gene expression in rheumatoid arthritis synovial macrophages
Authors: Antoniv Taras T. , Ivashkiv Lionel B. 
Published: August 2006

AbstractObjectiveThe inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin‐1 (IL‐1) are produced by activated macrophages, are key mediators of pathogenesis, and are validated therapeutic targets in rheumatoid arthritis (RA) and seronegative spondylarthritis (SpA). IL‐10 is a potent antiinflammatory cytokine that suppresses macrophage TNFα and IL‐1 production, yet is not effective in suppressing inflammatory arthritis. To gain insight into IL‐10 responses in inflammatory arthritis, we used microarray analysis to determine the patterns of IL‐10–inducible gene expression in freshly isolated RA and seronegative SpA synovial macrophages.MethodsMacrophages from the synovial fluid of 5 patients with RA and 3 with seronegative SpA (2 with psoriatic arthritis and 1 with ankylosing spondylitis) were isolated by positive selection and stimulated ex vivo with IL‐10 or interferon‐γ (IFNγ). Gene expression was analyzed using Affymetrix microarrays and protocols. Real‐time polymerase chain reaction was used to confirm changes in gene expression.ResultsThe number of genes induced by IL‐10 in arthritic macrophages was markedly smaller than that induced in control macrophages, and the strength of induction was lower in arthritic macrophages for most genes. The residual response of arthritic macrophages to IL‐10 stimulation was qualitatively altered, such that IL‐10 preferentially increased expression of IFNγ‐inducible genes. In contrast, arthritic macrophages expressed many IFNγ‐inducible genes prior to stimulation, and their response to IFNγ remained mostly intact.ConclusionThese results demonstrate that IL‐10 responses are dysregulated in RA synovial macrophages. An altered biologic response to IL‐10, with attenuation of its antiinflammatory function and a concomitant retention of IFNγ‐like activating functions, provides a basis for the lack of efficacy of IL‐10 in suppressing inflammatory arthritis.
Cappuccino mutation in an autoimmune‐prone strain of mice suggests a role of platelet function in the progression of immune complex crescentic glomerulonephritis
Authors: Yoshida Minako , Saiga Kan , Hato Takaaki , Iwaki Shoko , Niiya Toshiyuki , Arita Norimasa , Komori Hiroaki , Tsubaki Takahito , Furukawa Hiroshi , Terada Miho , Maeyama Kazutaka , Nemoto Kyuichi , Nose Masato , Ono Masao 
Published: August 2006

AbstractObjectiveCrescent formation in the renal glomerulus is a typical manifestation of progressive glomerulopathy associated with fatal renal failure; therefore, its prevention is of clinical importance. Little is known about the pathogenic mechanism for crescent formation. This study was undertaken in an attempt to identify the events that are critical for crescent formation in immune complex crescentic glomerulonephritis (CGN) by analyzing a novel mutant strain of mice.MethodsA spontaneous mutant strain of mice was isolated from the autoimmune‐prone strain EOD, which stably develops fatal CGN. The mutant phenotypes were assessed histopathologically, hematologically, and immunologically. The mutation was searched for with positional cloning using microsatellite markers.ResultsCompared with wild‐type EOD (WT‐EOD) mice, mutant EOD (mut‐EOD) mice showed marked improvement in CGN in conjunction with an improvement in spontaneous mortality. In WT‐EOD mice, an inverse correlation between blood urea nitrogen concentration and blood platelet count and massive accumulation of platelets in the glomerulus were evident, suggesting that an accumulation of platelets in the glomerulus contributes to the progression of CGN. The mutant platelets showed an abnormal aggregation in response to collagen and thrombin, associated with a bleeding tendency in mut‐EOD mice. Genetic analysis revealed a deleterious mutation in the cappuccino gene (cno), which encodes a protein that belongs to a complex called the biogenesis of lysosome‐related organelle complex 1 and is profoundly involved in platelet function. Morphologic examination revealed a partial defect in dense body formation in the δ‐granule of platelets.ConclusionThe present findings suggest that platelet functions have a critical role in crescent formation in autoimmune GN.
Immunohistologic analysis of zygapophyseal joints in patients with ankylosing spondylitis
Authors: Appel Heiner , Kuhne Maren , Spiekermann Simone , Ebhardt Harald , Grozdanovic Zarko , Köhler Dorothee , Dreimann Marc , Hempfing Axel , Rudwaleit Martin , Stein Harald , Metz‐Stavenhagen Peter , Sieper Joachim , Loddenkemper Christoph 
Published: August 2006

AbstractObjectiveZygapophyseal joints of the spine are often affected in ankylosing spondylitis (AS). In this study, we undertook a systematic immunohistologic evaluation of the immunopathology of the zygapophyseal joints in patients with advanced AS.MethodsWe obtained zygapophyseal joints from 16 AS patients undergoing polysegmental correction of kyphosis and from 10 non‐AS controls (at autopsy). Immunohistologic analysis of the bone marrow was performed by analyzing the number of infiltrating T cells (CD3, CD4, CD8), B cells (CD20), osteoclasts (CD68), bone marrow macrophages (CD68), and microvessel density (CD34) per high‐power field.ResultsZygapophyseal joints from 6 of 16 AS patients, but from none of the controls, exhibited 2 or more CD3+ T cell aggregates, signifying persistent inflammation. Interstitial CD4+ and CD8+ T cells were significantly more frequent in AS patients compared with non‐AS controls (P = 0.002 and P = 0.049, respectively). While there was no clear difference between the number of CD20+ B cells in AS patients overall compared with controls, there was a significant difference when persistently inflamed joints from patients with AS were compared with joints without active inflammation from patients with AS or joints from controls (both P = 0.03). Microvessel density in bone marrow from AS patients with active inflammation was significantly higher than that in bone marrow from controls.ConclusionThis immunohistologic study of bone marrow from zygapophyseal joints demonstrates persistent inflammation in the spine of patients with AS, including those with longstanding disease. The findings of increased numbers of T cells and B cells and neoangiogenesis suggest that these features play a role in the pathogenesis of AS.
Vascular amine oxidases are needed for leukocyte extravasation into inflamed joints in vivo
Authors: Marttila‐Ichihara Fumiko , Smith David J. , Stolen Craig , Yegutkin Gennady G. , Elima Kati , Mercier Nathalie , Kiviranta Riku , Pihlavisto Marjo , Alaranta Sakari , Pentikäinen Ulla , Pentikäinen Olli , Fülöp Ferenc , Jalkanen Sirpa , Salmi Marko 
Published: August 2006

AbstractObjectiveLeukocyte traffic from the blood to the joints is crucial in the pathogenesis of arthritis. A bifunctional endothelial cell–surface glycoprotein, AOC3 (amine oxidase, copper‐containing 3; also known as vascular adhesion protein 1), has both adhesive and enzymatic properties. We undertook this study to determine the contribution of AOC3 and its oxidase activity to leukocyte trafficking into inflamed joints in vivo.MethodsWe used gene‐modified animals, molecular modeling, an AOC3 enzyme inhibitor, oxidase assays, and arthritis models (adjuvant‐induced arthritis [AIA] in rats and anti–type II collagen antibody–induced arthritis in mice) to dissect the importance of AOC3 in vivo.ResultsThe AOC3 inhibitor fitted well with a covalent binding mode into the active site of the AOC3 crystal structure. It selectively blocked the oxidase activity of AOC3 in enzyme assays. Intraperitoneal and oral administration of the AOC3 inhibitor significantly ameliorated rat AIA. In anti–type II collagen antibody–induced arthritis in mice, the AOC3 inhibitor also improved the outcome of the joint inflammation. The acute semicarbazide‐sensitive amine oxidase blockade by the inhibitor had even more pronounced effects than genetic deletion of AOC3. Enzymatic analyses showed that the inhibitor also blocked 2 other structurally very closely related AOCs, but not any of more than 100 other enzymes tested.ConclusionThese are the first data to demonstrate that the enzymatic activity of the atypical endothelial adhesion molecule AOC3, and possibly that of other closely related ecto‐oxidases, is crucial for leukocyte exit from the vessels in inflamed joints in vivo.
Safety of the selective costimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease‐modifying antirheumatic drugs: A one‐year randomized, placebo‐controlled study
Authors: Weinblatt M. , Combe B. , Covucci A. , Aranda R. , Becker J. C. , Keystone E. 
Published: August 2006

AbstractObjectiveTo assess the safety of abatacept, a selective costimulation modulator, in patients with active rheumatoid arthritis (RA) who had been receiving ≥1 traditional nonbiologic and/or biologic disease‐modifying antirheumatic drugs (DMARDs) approved for the treatment of RA for at least 3 months prior to entry into the study.MethodsThis was a 1‐year, multicenter, randomized, double‐blind, placebo‐controlled trial. Patients were randomized 2:1 to receive abatacept at a fixed dose approximating 10 mg/kg by weight range, or placebo.ResultsThe abatacept and placebo groups exhibited similar frequencies of adverse events (90% and 87%, respectively), serious adverse events (13% and 12%, respectively), and discontinuations due to adverse events (5% and 4%, respectively). Five patients (0.5%) in the abatacept group and 4 patients (0.8%) in the placebo group died during the study. Serious infections were more frequent in the abatacept group than in the placebo group (2.9% versus 1.9%). Fewer than 4% of patients in either group experienced a severe or very severe infection. The incidence of neoplasms was 3.5% in both groups. When evaluated according to background therapy, serious adverse events occurred more frequently in the subgroup receiving abatacept plus a biologic agent (22.3%) than in the other subgroups (11.7–12.5%).ConclusionAbatacept in combination with synthetic DMARDs was well tolerated and improved physical function and physician‐ and patient‐reported disease outcomes. However, abatacept in combination with biologic background therapies was associated with an increase in the rate of serious adverse events. Therefore, abatacept is not recommended for use in combination with biologic therapy.