bluuebunny/crossref_metadata_2025_split huggingface dataset:
The LUNDEX, a new index of drug efficacy in clinical practice: Results of a five‐year observational study of treatment with infliximab and etanercept among rheumatoid arthritis patients in southern Sweden
Authors: Kristensen Lars Erik , Saxne Tore , Geborek Pierre 
Published: January 2006

AbstractObjectiveTo describe the use of the LUNDEX, a new index for comparing the long‐term efficacy and tolerability of biologic therapies in rheumatoid arthritis (RA) patients treated in clinical practice.MethodsPatients (n = 949) with active RA that had not responded to at least 2 disease‐modifying antirheumatic drugs (DMARDs) including methotrexate, in whom biologic therapy was being initiated, were included in a structured clinical followup protocol. The protocol included collection of data on diagnosis, disease duration, previous and ongoing DMARD treatment, and dates on which biologic treatment was started and terminated. In addition, data on efficacy measures used for calculating validated response criteria, i.e., the European League Against Rheumatism and American College of Rheumatology response criteria, were collected at fixed time points. Data were prospectively registered from March 1999 through January 2004. The LUNDEX, a new index combining the proportion of patients fulfilling a selected response criteria set with the proportion of patients adhering to a particular therapy, was designed to compare the efficacy of the different therapies.ResultsEtanercept had higher overall LUNDEX values compared with infliximab, mostly because of a lower rate of adherence to therapy with infliximab. The relationship between the drugs was consistent irrespective of the response criteria used.ConclusionThe LUNDEX is a valuable tool for evaluating drug efficacy in observational studies. It has the advantage of integrating clinical response as well as adherence to therapy in a composite value. Moreover, the LUNDEX has a practical and potentially universal application independent of diagnosis and response criteria.
Signaling pathways regulating intercellular adhesion molecule 1 expression by endothelin 1: Comparison with interleukin‐1β in normal and scleroderma dermal fibroblasts
Authors: Waters Charlotte E. , Shi‐Wen Xu , Denton Chris P. , Abraham David J. , Pearson Jeremy D. 
Published: January 2006

AbstractObjectiveEndothelin 1 (ET‐1) has been implicated in the pathogenesis of fibrotic and inflammatory diseases, including scleroderma. In addition to modulating vascular tone and extracellular matrix turnover, ET‐1 up‐regulates cell surface adhesion molecules including intercellular adhesion molecule 1 (ICAM‐1), which is key to cell–cell and cell–matrix adhesion and leukocyte infiltration. This study was undertaken to delineate the signal transduction pathways utilized by ET‐1 and compare them with those adopted by proinflammatory cytokine interleukin‐1β (IL‐1β) in normal and scleroderma dermal fibroblasts.MethodsProtein expression induced by ET‐1 and IL‐1β on normal dermal fibroblasts, with or without signaling inhibitors, was detected by enzyme‐linked immunosorbent assay, while messenger RNA (mRNA) levels were analyzed by LightCycler polymerase chain reaction. Expression of protein kinase Cδ (PKCδ) and PKCϵ protein in normal dermal fibroblasts and scleroderma dermal fibroblasts was determined by Western blotting, and PKCϵ involvement in ET‐1 signaling was confirmed through transfection of an ICAM‐1 promoter construct into murine PKCϵ−/− fibroblasts. NF‐κB activation was confirmed via electrophoretic mobility supershift assay, and analysis of the ICAM‐1 promoter region was achieved via transfection of deletion constructs into human dermal fibroblasts.ResultsIn normal dermal fibroblasts, ET‐1 induced ICAM‐1 mRNA and surface protein expression in a dose‐ and time‐dependent manner via both receptor subtypes, ETA and ETB; antagonism of both abolished the ET‐1 response. MEK was involved in the signaling cascade, but phosphatidylinositol 3‐kinase and p38 MAPK were not. Key to the cascade was activation of NF‐κB, achieved by ligation of either receptor subtype. PKCϵ activation led to downstream activation of MEK and, in part, NF‐κB. IL‐1β signaling required NF‐κB and MEK activation, along with activation of PKCδ. ET‐1 and IL‐1β each utilized the same ICAM‐1 promoter region and the same NF‐κB site at –157 bp. Responses to ET‐1 and IL‐1β differed in scleroderma dermal fibroblasts, with ET‐1 sensitivity decreasing and IL‐1β responses remaining intact. Expression of PKCϵ and PKCδ in scleroderma dermal fibroblasts was also altered.ConclusionThe findings of this study indicate that differences in sensitivity to ET‐1 and IL‐1β in scleroderma dermal fibroblasts may be explained by altered expression of the PKC isoforms and cytokine receptors.
Risk genotypes in folate‐dependent enzymes and their association with methotrexate‐related side effects in rheumatoid arthritis
Authors: Weisman Michael H. , Furst Daniel E. , Park Grace S. , Kremer Joel M. , Smith Katie M. , Wallace Daniel J. , Caldwell Jacques R. , Dervieux Thierry 
Published: January 2006

AbstractObjectiveMethotrexate (MTX) is an antifolate agent that is often associated with toxicity. This study investigated whether risk genotypes for folate‐dependent enzymes are associated with the toxicity of MTX in patients with rheumatoid arthritis (RA).MethodsBlood was collected for analysis in a muticenter, cross‐sectional study of RA patients who had been receiving MTX for at least 1 month prior to enrollment, and side effects occurring at the time of a single study visit were recorded. Low‐penetrance risk genotypes in methylenetetrahydrofolate reductase (MTHFR) 677TT, thymidylate synthase (TSER) *2/*2 (variable number of tandem repeats), amino imidazole ribonucleotide transformylase (ATIC) 347GG, and serine hydroxymethyltransferase (SHMT1) 1420CC were measured and summed to constitute the toxicogenetic index specific to each patient. Statistical analyses consisted of logistic regression models with clustered‐center effects, and associations with risk genotypes were expressed as adjusted odds ratios (ORs).ResultsAmong 214 patients enrolled at 4 study sites, a total of 67 patients (31%) presented with a side effect (gastrointestinal event, headache, lethargy, alopecia, cough, or dyspnea). Risk genotypes associated with side effects in the central nervous system were MTHFR 677TT (OR 3.3, P < 0.01) and SHMT1 1420CC (OR 2.4, P < 0.05). ATIC 347GG was associated with gastrointestinal side effects (OR 3.0, P < 0.01), while TSER*2/*2 (OR 5.4, P < 0.01) and SHMT1 1420CC (OR 3.2, P < 0.01) were associated with alopecia. The toxicogenetic index ranged from 0 to 3 (median 1). An index of 3 was associated with an ∼7‐fold higher likelihood of having a side effect compared with an index of 0 (P < 0.01).ConclusionThese data suggest that a composite index of the cumulative risk genotypes in folate‐dependent enzymes may be an effective means of profiling RA patients who develop side effects to MTX.
Reconstitution of peripheral blood B cells after depletion with rituximab in patients with rheumatoid arthritis
Authors: Leandro Maria J. , Cambridge Geraldine , Ehrenstein Michael R. , Edwards Jonathan C. W. 
Published: January 2006

AbstractObjectiveTo study the quantitative and phenotypic reconstitution of peripheral blood B cells and its relationship to the dynamics of clinical response in patients with rheumatoid arthritis (RA) following B cell depletion with rituximab.MethodsTwenty‐four patients with active RA treated with rituximab were studied. Flow cytometry with combinations of monoclonal antibodies to B cell and T cell subsets was used.ResultsThe frequency and total number of CD19+ cells in the peripheral blood decreased a mean of 97% for more than 3 months in all but 1 patient following rituximab therapy. All B cell populations were depleted. More than 80% of residual B cells showed a memory or plasma cell precursor phenotype. B cell repopulation occurred a mean of 8 months after treatment and was dependent on the formation of naive B cells, which showed an increased expression of CD38 and CD5. During repopulation, increased numbers of circulating immature B cells, CD19+,IgD+,CD38high,CD10low,CD24high cells, were identified. Patients who experienced a relapse of RA on return of B cells tended to show repopulation with higher numbers of memory B cells. A small number of T cells and natural killer cells expressed low levels of CD20. These cells were depleted following rituximab therapy and returned to the circulation a mean of 5 months after treatment. No other significant changes were detected in the T cell populations studied.ConclusionRituximab induced a profound depletion of all peripheral blood B cell populations in patients with RA. Repopulation occurred mainly with naive mature and immature B cells. Patients whose RA relapsed on return of B cells tended to show repopulation with higher numbers of memory B cells.
Inflammatory back pain in ankylosing spondylitis: A reassessment of the clinical history for application as classification and diagnostic criteria
Authors: Rudwaleit Martin , Metter Anke , Listing Joachim , Sieper Joachim , Braun Jürgen 
Published: January 2006

AbstractObjectiveBack pain associated with ankylosing spondylitis (AS) is referred to as inflammatory back pain (IBP). The value of the clinical history in differentiating IBP from mechanical low back pain (MLBP) has been investigated in only a few studies. In this exploratory study, we sought to evaluate the individual features of IBP and to compose and compare various combinations of features for use as classification and diagnostic criteria.MethodsWe assessed the clinical history of 213 patients (101 with AS and 112 with MLBP) younger than 50 years who had chronic back pain. Single clinical parameters and combinations of parameters were compared between the AS and MLBP patient groups.ResultsMorning stiffness of >30 minutes' duration, age at onset of back pain, no improvement in back pain with rest, awakening because of back pain during the second half of the night only, alternating buttock pain, and time period of the onset of back pain were identified as independent contributors to IBP. Importantly, none of the single parameters sufficiently differentiated AS from MLBP. In contrast, several sets of combined parameters proved to be well balanced between sensitivity and specificity. Among these, a new candidate set of criteria for IBP, which consisted of morning stiffness of >30 minutes' duration, improvement in back pain with exercise but not with rest, awakening because of back pain during the second half of the night only, and alternating buttock pain, yielded a sensitivity of 70.3% and a specificity of 81.2% if at least 2 of these 4 parameters were fulfilled (positive likelihood ratio 3.7). If at least 3 of the 4 parameters were fulfilled, the positive likelihood ratio increased to 12.4.ConclusionA new set of criteria for IBP performed better than previous criteria in AS patients with established disease. A prospective study is needed to validate the diagnostic properties of the new candidate criteria set in patients with early disease.
Association between a variation in LRCH1 and knee osteoarthritis: A genome‐wide single‐nucleotide polymorphism association study using DNA pooling
Authors: Spector Tim D. , Reneland Richard H. , Mah Steven , Valdes Ana M. , Hart Deborah J. , Kammerer Stefan , Langdown Maria , Hoyal Carolyn R. , Atienza Josephine , Doherty Michael , Rahman Proton , Nelson Matthew R. , Braun Andreas 
Published: January 2006

AbstractObjectiveTo perform a large‐scale association analysis of single‐nucleotide polymorphisms (SNPs) in patients with radiographically defined osteoarthritis (OA) of the knee.MethodsWe examined >25,000 SNPs located within ∼14,000 genes for associations with radiographically defined knee OA, using polymerase chain reaction and MassExtend amplification techniques. Allele frequencies were estimated initially in DNA pools from 335 female patients with knee OA and 335 asymptomatic and radiographically negative female control subjects. All were of northern European ancestry. Significant allele frequency differences were validated by genotyping of individual DNA samples. Confirmed significant findings were verified in 2 additional case–control samples from the UK (443 cases and 303 controls) and Newfoundland (346 cases and 264 controls). Chondrosarcoma cell lines were used to test for potential differences in gene expression.ResultsThe marker most strongly associated with the risk of knee OA was rs912428, a C/T polymorphism in intron 1 of LRCH1, a gene on chromosome 13q14 that encodes a novel protein of as‐yet‐unknown function. The frequency of the T allele compared with controls was consistently increased by 40% across all 3 case–control groups. Additional subanalyses in case–control samples with hip OA and hand OA suggested similar trends, but did not reach statistical significance. Association fine‐mapping using 10 additional SNPs in LRCH1 confirmed intron 1 as the region of highest association but failed to reveal variations with significance stronger than the marker SNP, as did the haplotype analysis. LRCH1 was not up‐regulated or overexpressed in chondrosarcoma cell lines exposed to inflammatory stimuli, suggesting a possible structural role.ConclusionA genetic variant in LRCH1 was consistently associated with knee OA in 3 samples from 2 populations. Our results also suggest that the same association with OA may exist at other sites. Additional genetic and experimental work is needed to elucidate the precise mechanism by which the LRCH1 gene influences OA risk.
Activation of p38 MAPK is a key step in tumor necrosis factor–mediated inflammatory bone destruction
Authors: Zwerina Jochen , Hayer Silvia , Redlich Kurt , Bobacz Klaus , Kollias Giorgos , Smolen Josef S. , Schett Georg 
Published: January 2006

AbstractObjectiveTo investigate whether activation of p38 MAPK is a crucial signaling factor in inflammatory bone destruction mediated by tumor necrosis factor (TNF). Mice overexpressing TNF were treated with 2 different inhibitors of p38 MAPK, and the effect of this treatment on joint inflammation and structural damage was assessed.MethodsHuman TNF‐transgenic mice received systemic treatment with 2 different p38 MAPK inhibitors (RO4399247 and AVE8677). Treatment was started at the time of symptom onset and lasted for 6 weeks. Mice were assessed for clinical signs of arthritis, bone erosion, and cartilage damage. In addition, the effect of these inhibitors on osteoclast generation in vitro and in vivo was assessed.ResultsBoth p38 MAPK inhibitors significantly reduced clinical signs of TNF‐mediated arthritis. This was attributable to reducing synovial inflammation by 50% without affecting the cellular composition of the infiltrate. Synovial expression of interleukin‐1 and RANKL was reduced upon p38 MAPK blockade, and activation of the molecular target MAPK‐activated protein kinase 2 (MAPKAP‐2) was also inhibited. Proteoglycan loss of articular cartilage was reduced by 50%, although p38 MAPK inhibition did not change matrix molecule synthesis by cultivated chondrocytes. Importantly, bone loss was almost completely prevented by p38 MAPK inhibition. The numbers of synovial osteoclasts and precursors were dramatically reduced, and both p38 MAPK inhibitors also inhibited in vitro osteoclastogenesis at micromolar concentrations and blocked activation of MAPKAP‐2 as well as differentiation markers in cultured osteoclast precursors.ConclusionThese results suggest the major importance of p38 MAPK for TNF‐mediated inflammatory bone destruction in arthritis and suggest that inhibition of p38 MAPK might be an important tool for reducing structural damage in rheumatoid arthritis.
Platelet C4d is highly specific for systemic lupus erythematosus
Authors: Navratil Jeannine S. , Manzi Susan , Kao Amy H. , Krishnaswami Shanthi , Liu Chau‐Ching , Ruffing Margie J. , Shaw Penny S. , Nilson Abbey C. , Dryden Emily R. , Johnson Jeffrey J. , Ahearn Joseph M. 
Published: January 2006

AbstractObjectiveComplement‐activation product C4d is deposited on normal erythrocytes, while abnormal levels have been observed on the surface of erythrocytes of patients with systemic lupus erythematosus (SLE). This study examines whether C4d also deposits on human platelet surfaces, and whether platelet‐bound C4d may provide a biomarker for SLE.MethodsWe conducted a cross‐sectional study of 105 patients with SLE, 115 patients with other diseases, and 100 healthy controls. Levels of C4d on the surface of platelets were examined by flow cytometry and scanning confocal microscopy. Statistical analyses were performed to determine the clinical variables associated with platelet C4d.ResultsAbnormal levels of platelet C4d were found to be highly specific for SLE. Platelet C4d was detected in 18% of patients with SLE, being 100% specific for a diagnosis of SLE compared with healthy controls and 98% specific for SLE compared with patients with other diseases (P < 0.0001). In addition, platelet C4d was significantly associated with positivity for lupus anticoagulant (P < 0.0001) and anticardiolipin antibodies of the IgG (P = 0.035) or the IgM (P = 0.016) isotype. Platelet C4d was also significantly associated with SLE disease activity according to the SLE Disease Activity Index (P = 0.039), low serum C4 (P = 0.046), an elevated erythrocyte sedimentation rate (P = 0.006), and abnormal levels of C4d on erythrocytes (P < 0.0001).ConclusionThis observation suggests that platelet‐bound C4d may be a useful biomarker for SLE and may be a clue to the pathogenic mechanisms responsible for the myriad thrombotic and vascular complications of lupus associated with antiphospholipid antibodies.
Incidence of noncardiac vascular disease in rheumatoid arthritis and relationship to extraarticular disease manifestations
Authors: Liang Kimberly P. , Liang Kelly V. , Matteson Eric L. , McClelland Robyn L. , Christianson Teresa J. H. , Turesson Carl 
Published: January 2006

AbstractObjectiveTo investigate the incidence of noncardiac vascular disease in patients with rheumatoid arthritis (RA) and its relationship to systemic extraarticular disease in a community‐based cohort.MethodsA retrospective medical record review of 609 patients with incident RA diagnosed during 1955–1994 was carried out in Olmsted County, Minnesota. Patients were followed up from 1955 to 2000 (median followup 11.8 years). Incident noncardiac vascular disease and severe extraarticular RA manifestations (including pericarditis, pleuritis, and vasculitis) were recorded according to predefined criteria, and incidence rates were estimated. Using Cox proportional hazards models, the risk (hazard ratio [HR]) of developing vascular events was assessed in patients with and without severe extraarticular RA.ResultsCerebrovascular and peripheral arterial events occurred in 139 patients (22.8%). The 30‐year cumulative incidence rates of peripheral arterial events, cerebrovascular events, and venous thromboembolic events were estimated to be 19.6%, 21.6%, and 7.2%, respectively. The presence of severe extraarticular RA manifestations was found to be associated with all subgroups of noncardiac vascular disease except cerebrovascular disease alone (HR 2.3, 95% confidence interval [95% CI] 1.2–4.3 for peripheral arterial events; HR 3.7, 95% CI 1.3–10.3 for venous thromboembolic events; HR 1.5, 95% CI 0.7–3.2 for cerebrovascular events) after adjusting for age, sex, body mass index, smoking, and rheumatoid factor status.ConclusionThis is the first study to assess the incidence of noncardiac vascular disease in RA. Severe extraarticular RA was associated with all forms of noncardiac vascular disease except cerebrovascular disease alone. Similar to cardiac disease, the excess risk of noncardiac vascular disease in RA is likely to be related, in part, to the systemic inflammation associated with the extraarticular manifestations of RA.
A new classification of HLA–DRB1 alleles differentiates predisposing and protective alleles for rheumatoid arthritis structural severity
Authors: Gourraud Pierre‐Antoine , Boyer Jean‐Frédéric , Barnetche Thomas , Abbal Michel , Cambon‐Thomsen Anne , Cantagrel Alain , Constantin Arnaud 
Published: January 2006

AbstractObjectiveA new classification of HLA–DRB1 alleles supporting the shared epitope hypothesis of rheumatoid arthritis (RA) susceptibility was recently introduced. We investigated the relevance of this classification in terms of the structural severity of RA.MethodsThe study group comprised 144 patients who were included in a prospective longitudinal cohort of French Caucasoid patients with early RA. Progression of the total radiographic damage score (Sharp/van der Heijde method) was used to quantify the structural severity of RA after 4 years of followup. HLA–DRB1 typing and subtyping were performed by polymerase chain reaction, using a panel of sequence‐specific oligonucleotide probes. HLA–DRB1 alleles were classified according to the above‐mentioned new system. The association between the HLA–DRB1 allele groups (S1, S2, S3P, S3D, and X) and the structural severity of RA was analyzed with nonparametric statistical tests.ResultsThe presence of S2 alleles (HLA–DRB1*0401 and HLA–DRB1*1303) was associated with severe forms of RA (P = 0.004); a significant dose effect was observed (P = 0.01). The presence of S3D alleles (HLA–DRB1*11001, HLA–DRB1*1104, HLA–DRB1*12, and HLA–DRB1*16) was associated with benign forms of RA (P < 0.0001), and a significant dose effect was observed (P < 0.01).ConclusionThe studied classification of HLA–DRB1 alleles is relevant in terms of RA outcomes. Compared with a previously described classification system, this system differentiates predisposing (S2) and protective (S3D) alleles for RA structural severity, which, respectively, correspond to KRRAA and DRRAA amino acid patterns at position 70–74 of the third hypervariable region of the HLA–DRβ chain.
Early cytokine profiles in the joint define pathogen clearance and severity of arthritis in Chlamydia‐induced arthritis in rats
Authors: Inman Robert D. , Chiu Basil 
Published: January 2006

AbstractObjectiveAlthough Chlamydia trachomatis–induced arthritis is among the most common rheumatic diseases having an identified infectious trigger, the pathogenesis of this arthritis is not well defined. We sought to investigate the host–microbe interactions that contribute to the severity of arthritis initiated by chlamydial infection.MethodsWe established an experimental rat model of C trachomatis–induced arthritis that recapitulates many pathologic features of the clinical disease. The severity of the arthritis was defined using an established histopathologic scoring system. Host clearance of the pathogen and local cytokine production were examined by enzyme‐linked immunosorbent assays.ResultsLewis rats were susceptible to C trachomatis–induced arthritis, whereas BN rats were relatively resistant to this disease. Significant differences in the histopathologic severity of arthritis were originally observed on day 21, and this prompted an examination of the acute phase of the arthritis. As early as day 5 after the onset of the arthritis, pathologic changes in Lewis rats were more severe than those in BN rats. An evaluation of the role of complement using cobra venom factor treatment excluded complement as being the key to differential sensitivity, because decomplementation did not eliminate the differences in arthritis severity between Lewis and BN rats. Host clearance, in contrast, was significantly different between the rat strains, with BN rats showing more prompt and effective clearance of the pathogen from both synovial tissues and spleen compared with Lewis rats. Local cytokine profiles demonstrated that host resistance was characterized by enhanced synovial expression of tumor necrosis factor α, interferon‐γ (IFNγ), and interleukin‐4.ConclusionThese studies demonstrated that cytokines thought to be proinflammatory in nature can play an important role in host defense in infection‐triggered arthritis and serve to highlight the dynamic cytokine relationships that constitute effective host–pathogen interactions.