Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
15194098 Transepicondylar line and condylar line as parameters for axial alignment in knee arthropl 2004 Jun In order to investigate the reliability of the transepicondylar line and the condylar line as indicators for lower limb alignment in knee arthroplasty, the femorotibial angle (FTA), and the angle between the transepicondylar line and the tangential line of tibial plateau (angle epsilon) and condylar-plateau angle (CPA) were measured in 107 (78 patients) full-length standing X-ray films of lower limbs. The mean FTA was measured to be 178.0+/-9.3 degrees, the CPA 1.5+/-8.5 degrees and angle epsilon -0.8+/-8.5 degrees. The correlation between FTA and the CPA was analyzed to be significant with a correlation coefficient of 0.63, while another correlation between FTA and angle epsilon was calculated to be significant with a correlation coefficient of 0.81 at the same time. As a result, the correlation of the latter one was highly significant, having a R2 value of 0.648 (P<0.001), while the R2 of the former was only 0.397 (P<0.001). In conclusion, the transepicondylar line could be considered as a more reliable indicator for lower limb alignment, which may play an important role in ligament balancing and improvement of the guiding system in knee arthroplasty.
12236616 Interleukin 1 or tumor necrosis factor-alpha: which is the real target in rheumatoid arthr 2002 Sep Much debate has focused on the relative importance of interleukin 1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) in the pathophysiology of rheumatoid arthritis (RA). The production of these cytokines by synovial macrophages is tightly regulated by cell-cell contact with T cells. During this contact, several surface molecules are implicated in contact mediated cytokine production, including CD40 ligand, CD11b/c, and CD69. Apolipoprotein A-I, an acute phase reactant (APR) that declines during systemic inflammation (reverse APR), inhibits cytokine production by interfering in the T cell-monocyte interaction. Although the effects of IL-1 and TNF-alpha overlap, they have somewhat differing roles in RA on the basis of evidence from several animal models. TNF-alpha appears to play a more important role in triggering events leading to inflammation both locally and systemically, whereas IL-1 is more involved at the local level in processes leading to cartilage and bone destruction and in impeding cartilage repair. However, IL-1 and TNF-alpha strongly synergize in numerous biological functions, both in vitro and in vivo. Blockade of IL-1 and TNF-alpha simultaneously provides favorable effects in collagen and adjuvant induced arthritis, illustrating the importance of both cytokines.
15077259 Measuring quality in arthritis care: methods for developing the Arthritis Foundation's qua 2004 Apr 15 OBJECTIVE: To develop a comprehensive set of explicit process measures to assess the quality of health care for osteoarthritis, rheumatoid arthritis, and analgesics use. METHODS: Potential quality measures and a summary of existing data to support or refute the relationship between the processes of care proposed in the indicators and relevant clinical outcomes were developed through a comprehensive literature review. The proposed measures and literature summary were presented to a multidisciplinary panel of experts in arthritis and pain. Using a modification of the RAND/UCLA Appropriateness Method, the panel rated each proposed measure for its validity as a measure of health care quality. RESULTS: Among 66 proposed indicators, the expert panel rated 51 as valid measures of health care including 14 for osteoarthritis, 27 for rheumatoid arthritis, and 10 for analgesics use. CONCLUSIONS: Sufficient scientific evidence and expert consensus exist to support a comprehensive set of measures to assess the quality of heath care for osteoarthritis, rheumatoid arthritis, and analgesics use. These measures can be used to gain an understanding of the quality of care for patients with arthritis.
14626630 Sonographic study of calcaneal entheses in erosive osteoarthritis, nodal osteoarthritis, r 2003 OBJECTIVE: To establish by ultrasonography (US) the frequency of calcaneal entheses involvement in erosive osteoarthritis (EOA), nodal osteoarthritis (NOA), RA and PsA, and to compare these results in order to aid clinicians in the differential diagnosis among these diseases. A comparison between US results and radiography was also made. METHODS: The heels of 56 consecutive outpatients with EOA, 209 with NOA, 158 with RA and 125 with PsA were studied by US and radiography. A control group of 50 subjects was examined by US. RESULTS: US showed no significant difference in inferior calcaneal enthesophytosis among the four diseases. The frequency of posterioinferior enthesophytosis was lower in RA (34%) in comparison with the other diseases (57% in EOA, 47% in NOA, 49% in PsA). Achilles enthesitis was found in 8% of PsA and in 2% of RA. Retrocalcaneal bursitis was found in 18% of RA and in 6% of PsA. Posterior erosions were present in 12% of RA and 5% of PsA. Inferior erosions were present in 6% of RA and in 1% of PsA. Plantar fasciitis was found in 26% of RA, in 37% of PsA, and in 15% of NOA and 12% of EOA. Subcalcaneal panniculitis was observed in 10% of RA and in 1% of PsA. In the control group, only posterioinferior and inferior enthesophytosis (22% and 18% respectively) were found. Kappa statistics show excellent agreement between US and radiography in detecting posterioinferior (kappa = 0.89) and inferior enthesophytosis (kappa = 0.83), and entheseal erosions (kappa = 0.86). CONCLUSIONS: The calcaneal lesions that could be found in EOA are similar to those observed in NOA. The frequency of calcaneal enthesophytosis is similar in EOA, NOA, and PsA, but inflammatory lesions of calcaneal entheses and of the adjacent bursae are more frequent in RA and in PsA. In terms of heel involvement, EOA seems to be similar to NOA. US shows an excellent concordance with radiography in detecting entheseal cortical bone abnormalities.
12518075 [Diagnostic approach to the rheumatoid wrist from plain radiographs]. 2002 Dec 7 OBJECTIVE: Monitor a reproducible analysis method based on a simple algorithm. DIAGNOSIS OF RHEUMATOLOGIC DISEASE IN WRISTS: The first step is to examine the joint space. When the space is preserved, diagnosis may be established on the presence of bony defects, demineralization or erosions. DIAGNOSIS OF RHEUMATOLOGIC DISEASE IN FINGERS: The first step is to determine whether the patient has degenerative or inflammatory joint disease involving the joint space or bone disease where bony lesions predominate.
12787529 Infections and biological therapy in rheumatoid arthritis. 2003 Apr Infections are common in patients with rheumatic disorders. Reasons for such vulnerability include alterations of immunoregulation, disease severity, debility, co-morbid illnesses and the use of immunosuppressive medications. The advent of new biological agents has precipitated a further examination of the links between infection, the underlying disease and its treatment, resulting in several interesting observations. Interleukin-1 (IL-1) and tumour necrosis factor alpha (TNF-alpha), the major pro-inflammatory cytokines, play important roles in host defence against infection. Inhibition of their activity could therefore be anticipated to augment the risk of infection in patients with pre-existing abnormalities of immune regulation. Slight increases in the rates of infection were noted in the clinical trials of IL-1 receptor antagonist (IL-1Ra). In addition, a small number of opportunistic infections have been observed with the TNF inhibitor, etanercept. However, a marked increase in opportunistic infection, particularly tuberculosis, has occurred with the use of infliximab, an agent that also blocks TNF activity. The precise mechanisms by which these agents predispose to infection are currently being explored. The answers are likely to add significantly to our knowledge of how immune dysfunction contributes both to the pathophysiology of disease and the complications of therapy.
12076504 Electrical stimulation for the treatment of rheumatoid arthritis. 2002 BACKGROUND: Electrical stimulation is one of several rehabilitation interventions suggested for the management of rheumatoid arthritis (RA) to enhance muscle performance. OBJECTIVES: To assess the effectiveness of electrical stimulation for improving muscle strength and function in clients with RA. SEARCH STRATEGY: We searched MEDLINE, Embase, Healthstar, Sports Discus, CINAHL, the Cochrane Controlled Trials Register, the PEDro database, the specialized registry of the Cochrane musculoskeletal group and the Cochrane field of physical and related therapies up to January 2002 according to the sensitive search strategy for RCTs designed for the Cochrane Collaboration. The search was complemented with handsearching of the reference lists. Key experts in the area were contacted for further articles. SELECTION CRITERIA: All randomized controlled trials (RCTs) and controlled clinical trials (CCTs), case-control and cohort studies comparing ES against placebo or another active intervention in patients with RA were selected, according to an a priori protocol. No language restrictions were applied. DATA COLLECTION AND ANALYSIS: Two independent reviewers determined the studies to be included based on a priori inclusion criteria. Data were independently abstracted by the same two reviewers, and checked by a third reviewer using a pre-developed form. The same two reviewers, using a validated scale, independently assessed the methodological quality of the RCTs and CCTs. The data analysis was performed using Peto Odds ratios. MAIN RESULTS: Of the two relevant studies that were identified in the literature, only one RCT met the inclusion criteria. This RCT compared the effects of two electrostimulation (ES) protocols on hand function in general and on the performance of the first dorsal interosseous muscle in particular, in 15 patients with RA and secondary disuse atrophy of the first dorsal interosseous of the dominant hand. The results showed that ES had significant benefit when compared to a control no treatment group in terms of muscle strength and fatigue resistance of the first dorsal interosseous. Most favourable results were obtained by using a patterned stimulation derived from a fatigued motor unit of the first dorsal interosseous in a normal hand rather than a fixed 10 Hz stimulation frequency. Side effects of the ES application were not reported. REVIEWER'S CONCLUSIONS: ES was shown to have a clinically beneficial effect on grip strength and fatigue resistance for RA patients with muscle atrophy of the hand. However, these conclusions are limited by the low methodological quality of the trial included. More well-designed studies are therefore needed to provide further evidence of the benefits of ES in the management of RA.
13130463 Activin A induces cell proliferation of fibroblast-like synoviocytes in rheumatoid arthrit 2003 Sep OBJECTIVE: To investigate the expression of activin A and its receptors in rheumatoid arthritis (RA) synovial tissues, and to determine the effect of activin A on cultured fibroblast-like synoviocytes (FLS). METHODS: The localization of activin A and activin type II receptor (ARII) in synovial tissues of RA patients was analyzed by immunohistochemistry. The expression of activin A and activin receptors in human cultured FLS was examined by reverse transcriptase-polymerase chain reaction and Western blotting. Enzyme-linked immunosorbent assay was used to measure activin A in culture supernatants. The cell growth of FLS was determined by (3)H-thymidine incorporation and MTT assay. RESULTS: Immunohistochemical analysis confirmed the up-regulation of activin A in rheumatoid synovium as compared with osteoarthritis or normal joint tissues. CD68+ macrophage-lineage cells and vimentin-positive FLS were identified as activin-producing cells in rheumatoid synovium. Both cell types also expressed ARII. The expression of activin A and ARII on cultured FLS was confirmed at the protein and messenger RNA levels. Interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha, and transforming growth factor beta activated FLS to secrete activin A. Recombinant activin A accelerated the proliferation of FLS, while follistatin, an endogenous activin antagonist, partially inhibited FLS proliferation induced by IL-1 beta. CONCLUSION: These results suggest that activin A acts as a growth factor of FLS in RA.
12228167 Low levels of apoptosis and high FLIP expression in early rheumatoid arthritis synovium. 2002 Oct OBJECTIVES: To define synovial apoptosis with respect to disease duration, inflammatory cell type, FLIP (FLICE-like inhibitory protein), and cytokines expression in patients with rheumatoid arthritis (RA). METHODS: Synovial biopsy specimens from 11 patients with longstanding RA (median disease duration 21 years) and eight with early RA (median disease duration five months) were investigated. Apoptosis (TUNEL method combined with morphological analysis), cell surface markers (CD3, CD68), cytokines (interleukin (IL) 1alpha, IL1beta, tumour necrosis factor alpha, and IL6), and FLIP expression were evaluated. Computer assisted image analysis was used for quantification. RESULTS: The apoptosis level in RA synovium was significantly higher in the group of patients with longstanding RA than in the patients with early RA (8.8% v 0.6%, p=0.001), while the number of macrophages and FLIP expression were higher in the group with early disease than in the group with longstanding RA (16.2% v 8.3%, p=0.02 and 31.1% v 0.2%, p=0.001 respectively). All three markers correlated significantly with disease duration (R=-0.7, p<0.001 for FLIP, R=0.6, p=0.001 for apoptosis, and R=-0.5, p<0.05 for CD68). Cytokine expression and T cell score were not significantly different in early RA from longstanding RA. No differences were seen between patients treated or not treated with corticosteroids or between patients treated or not treated with disease modifying antirheumatic drugs. CONCLUSIONS: The findings suggest that RA synovial macrophages are resistant to apoptosis in early RA and express high levels of FLIP. During natural or drug modified disease progression the apoptotic mechanism may be restored with a specific increase of synovial apoptosis in patients with longstanding arthritis.
12632419 Specific increase in enzymatic activity of adenosine deaminase 1 in rheumatoid synovial fi 2003 Mar OBJECTIVE: Adenosine deaminase (ADA; EC 3.5.4.4) activity is elevated in the synovial fluid (SF) of patients with rheumatoid arthritis (RA). Since the antiinflammatory effect of methotrexate is reportedly associated with increased levels of extracellular adenosine, the present study was undertaken to clarify the role of 2 ADA isozymes, ADA1 and ADA2, in the pathogenesis of RA. METHODS: The activities of ADA1 and ADA2 were measured in SF from RA and osteoarthritis (OA) patients, in sera from RA patients, and in lysates prepared from mononuclear and polymorphonuclear cells from SF from RA patients, peripheral blood from RA patients, and fibroblast-like synoviocytes (FLS) from RA and OA patients. Also measured were the effects of proinflammatory cytokines on ADA1 activity and ADA messenger RNA (mRNA) expression in RA FLS, as determined using real-time polymerase chain reaction. The adenosine concentration in RA SF was measured by radioimmunoassay. RESULTS: The adenosine concentration in RA SF ranged from 0.027 microM to 0.508 microM (mean +/- SD 0.156 +/- 0.132 microM). At those concentrations, ADA1 would be expected to be functionally dominant due to its higher affinity for adenosine. ADA1 activity in RA SF (mean +/- SD 14.4 +/- 8.5 IU/liter) was significantly higher than that in OA SF (3.0 +/- 1.1 IU/liter) or RA sera (3.0 +/- 0.6 IU/liter); moreover, ADA1 activity in RA FLS lysate was the highest among the cell lysates tested. Proinflammatory cytokines did not affect ADA1 activity or ADA mRNA expression in RA FLS. CONCLUSION: Elevated ADA1 activity is an intrinsic characteristic of RA FLS, which likely contributes to the pathogenesis of RA by neutralizing the antirheumatic properties of endogenous adenosine.
15940553 Prevalence of rheumatoid arthritis in Antalya, Turkey. 2005 Jun The aim of this study was to evaluate the prevalence of rheumatoid arthritis (RA) in Antalya, Turkey. A cross-sectional study was performed face-to-face using a structured interview. Subjects were asked whether they had arthritis at present or previously. Subjects suspected of having RA were invited to the hospital for physical examination and laboratory investigations. Diagnosis of RA was confirmed if the patient fulfilled 1987 American College of Rheumatology (ACR) criteria for RA. A total of 3173 subjects were interviewed. The diagnosis of RA was established in 12 subjects. The prevalence of RA was determined as 0.38% [95% confidence interval (CI): 0.16-0.59]. The mean age was 49.92+/-11.56 years in subjects with RA and greater than that of other subjects (p<0.001). Of 12 subjects with RA, 9 had previously been diagnosed with the disease. Rheumatoid factor was detected in the sera of eight subjects. RA is less frequent in Turkey than in Northern Europe. Different genetic and environmental factors may have a role in this result.
12193736 The role of matrix metalloproteinase-2 and matrix metalloproteinase-9 in antibody-induced 2002 Sep 1 Matrix metalloproteinases (MMPs) are a large group of enzymes responsible for matrix degradation. Among them, the family of gelatinases (MMP-2/gelatinase A and MMP-9/gelatinase B) is overproduced in the joints of patients with rheumatoid arthritis. Because of their degradative effects on the extracellular matrix, gelatinases have been believed to play an important role in progression and cartilage degradation in this disease, although their precise roles are yet to be defined. To clarify these roles, we investigated the development of Ab-induced arthritis, one of the murine models of rheumatoid arthritis, in MMP-2 or MMP-9 knockout (KO) mice. Surprisingly, the MMP-2 KO mice exhibited severe clinical and histologic arthritis than wild-type mice. The MMP-9 KO mice displayed milder arthritis. Recovery from exacerbated arthritis in the MMP-2 KO mice was possible by injection of wild-type fibroblasts. These results indicated a suppressive role of MMP-2 and a pivotal role of MMP-9 in the development of inflammatory joint disease.
15226517 Inducible but not endothelial nitric oxide synthase polymorphism is associated with suscep 2004 Sep OBJECTIVE: To assess the influence of inducible and endothelial nitric oxide synthase (iNOS and eNOS) polymorphisms in susceptibility to rheumatoid arthritis (RA). METHODS: Two hundred RA patients fulfilling the 1987 American College of Rheumatology classification criteria followed at the out-patient rheumatology clinic of the Hospital Xeral-Calde (Lugo, Spain) and 251 ethnically matched controls were studied. Patients and controls were genotyped by PCR-based techniques for a multiallelic (CCTTT)(n) repeat in the promoter region of the iNOS gene and for a T/C polymorphism at position -786 in the promoter region and a polymorphism in exon 7 (298Glu/Asp or 5557G/T) of the eNOS gene. RESULTS: No significant difference in allele or genotype frequencies for either polymorphism in the eNOS gene was observed between RA patients and controls. The overall iNOS CCTTT(n) allelic or genotypic distribution did not show statistical significant differences between RA patients and controls. Interestingly, when we stratified the iNOS alleles into short (8-11) and long (12-16) repeats, significant differences were observed between RA patients and controls (P = 0.021; odds ratio = 1.37, 95% confidence interval 1.04-1.81). Of note, individuals carrying two alleles with a repeat number less than 12 (fewer than 196 base pairs) exhibited a double risk of developing RA (P = 0.005, odds ratio 2.26, 95% confidence interval 1.25-4.08). CONCLUSIONS: Significant differences in the iNOS promoter polymorphism genotype frequency between northwest Spanish RA patients and controls suggest a potential role for this polymorphism in susceptibility to RA.
15529351 Do breast-feeding and other reproductive factors influence future risk of rheumatoid arthr 2004 Nov OBJECTIVE: To explore the contribution of female hormonal factors occurring prior to the onset of rheumatoid arthritis (RA), such as age at menarche, parity, age at first birth, breast-feeding, use of oral contraceptives (OCs), irregular menstrual cycles, and postmenopausal hormone (PMH) use, to the subsequent development of RA in a large female cohort. METHODS: We studied female reproductive and hormonal risk factors for RA in a cohort of 121,700 women enrolled in the longitudinal Nurses' Health Study. The diagnosis of incident RA (between 1976 and 2002) in 674 women was confirmed by a connective tissue disease screening questionnaire and blinded medical record review for American College of Rheumatology criteria. Sixty percent of the patients with RA were rheumatoid factor positive. The relationship between potential risk factors, including age, age at menarche, parity, age at first birth, total lifetime history of breast-feeding, use of OCs, and irregular menstrual cycles and the multivariate-adjusted risk of RA was estimated using Cox proportional hazards models. RESULTS: Using a multivariate model that adjusted for age, body mass index, smoking, parity, and other hormonal factors, we observed a strong trend for decreasing risk of RA with increasing duration of breast-feeding (P for trend = 0.001). For women who breast-fed (compared with parous women who did not breast-feed), the risk ratios (RRs) and 95% confidence intervals (95% CIs) were as follows: breast-feeding for < or =3 total months, RR 1.0 (95% confidence interval [95% CI] 0.8-1.2); for 4-11 total months, RR 0.9 (95% CI 0.7-1.1); for 12-23 total months, RR 0.8 (95% CI 0.6-1.0); and for > or =24 total months, RR 0.5 (95% CI 0.3-0.8). Very irregular menstrual cycles were associated with an increased risk of RA (RR 1.4, 95% CI 1.0-2.0). Age at menarche < or =10 years was associated with an increased risk of seropositive RA (RR 1.6, 95% CI 1.1-2.4) but not significantly associated with risk of RA. Parity, total number of children, age at first birth, and OC use were not associated with an increased risk of RA in this cohort. CONCLUSION: In this large cohort, breast-feeding for >12 months was inversely related to the development of RA. This apparent effect was dose-dependent, with a significant trend toward lower risk with longer duration of breast-feeding. Irregular menstrual cycles and earlier age at menarche increased the risk of RA. Other reproductive hormonal factors were not associated with RA risk.
12017855 [Ultrasound diagnosis of hand and finger joints. Changes in arthritis]. 2002 Mar Arthritis of the hand and finger joints is seen with unspecific and specific signs, as known from the hip and knee joints. The examination has to be done with special applicators (small sized with 7-13 MHz). Especially signs such as erosions and surrounding synovitis ensure the diagnosis of rheumatoid arthritis.
14558084 Galectin 3 and its binding protein in rheumatoid arthritis. 2003 Oct OBJECTIVE: To characterize the expression pattern and role of galectin 3 and galectin 3 binding protein (G3BP) in rheumatoid arthritis (RA), in comparison with galectin 1, and to explore whether soluble galectin 3 and G3BP, investigated in serum, synovial fluid, or cell culture supernatant, are associated with disease. METHODS: Synovial tissues from patients with RA or osteoarthritis (OA), as well as from healthy controls, were analyzed for galectins 1 and 3 and G3BP by in situ hybridization and immunohistochemistry. Levels of galectin 3 and G3BP in serum and synovial fluid from patients with RA and OA and controls, as well as in cell culture supernatants, were determined by enzyme-linked immunosorbent assay (ELISA). In vitro, the intracellular expression of galectin 3 in RA and OA synovial fibroblasts after modulation with tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), and anti-CD40 monoclonal antibodies was measured by flow cytometry. RESULTS: In RA, galectin 3 messenger RNA and protein stained throughout the synovial membrane, whereas G3BP was particularly expressed at sites of bone destruction. In contrast, the expression of galectin 1 was not uniform in different RA specimens, and was never found at sites of invasion. In OA and normal synovial tissues, only a small number of cells were positive for galectins and/or G3BP. Galectin 3 was elevated in RA sera and synovial fluids, whereas G3BP was increased in RA synovial fluids only. In RA, serum galectin 3 correlated with C-reactive protein levels, whereas G3BP was associated with joint destruction and/or synovial cell activation as measured by the levels of cartilage oligomeric matrix protein. In vitro, RA synovial fibroblasts showed an increased release of galectin 3 into culture medium, as measured by ELISA, but decreased secretion of G3BP. In RA synovial fibroblasts with low basal expression of galectin 3, TNFalpha increased its intracellular level in a dose-dependent manner. In contrast, IL-1beta or anti-CD40 monoclonal antibodies showed no effect. CONCLUSION: Our data indicate that galectin 3 and G3BP are not only involved in inflammation, but also contribute to the activation of synovial fibroblasts. The intracellular accumulation of galectin 3 can be enhanced by TNFalpha. Thus, galectin 3 and G3BP represent novel markers of disease activity in RA.
15593319 Modeling the 5-year cost effectiveness of treatment strategies including tumor necrosis fa 2004 Dec 15 OBJECTIVE: To determine the cost effectiveness of treatment strategies for rheumatoid arthritis patients satisfying the indication for tumor necrosis factor (TNF)-blocking treatment. METHODS: A Markov model study was performed. The following treatment strategies were considered: 1) usual treatment; 2) treatment with leflunomide, in the case of nonresponse after 3 months, switch to usual treatment; 3) TNF-blocking treatment, in the case of nonresponse after 3 months, switch to usual treatment; 4) treatment with leflunomide, in the case of nonresponse, switch to TNF-blocking treatment, in the case of nonresponse to TNF-blocking treatment, switch to usual treatment; 5) TNF-blocking treatment, in the case of nonresponse, switch to leflunomide treatment, in the case of nonresponse to leflunomide, switch to usual treatment. Expected patient-years in the different Markov states, costs, and quality-adjusted life years (QALYs) were compared between the treatment strategies; incremental cost-effectiveness ratios (ICERs) were calculated. RESULTS: Over the 5-year period, the expected effect on disease activity and QALYs was better for treatment strategies that included TNF-blocking treatment than for the other treatment strategies. The greater effectiveness of these treatment strategies reduced medical and nonmedical costs compared with usual treatment by about 16% and 33%, respectively, omitting the costs of medication. When the costs of medication were included, the costs of strategies that started with TNF-blocking treatment were higher than those of the other treatment strategies. Treatment strategy 4 had the most favorable ICER of the treatment strategies that included TNF-blocking treatment: 163,556/QALY compared with usual treatment. CONCLUSION: Among strategies that include TNF-blocking agents, one starting with leflunomide and, in the case of nonresponse, switching to TNF-blocking treatment probably results in the most favorable ratio between incremental costs and effects.
12115181 FLICE-inhibitory protein expression in synovial fibroblasts and at sites of cartilage and 2002 Jun OBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by a hyperplastic synovial tissue, inflammatory infiltrates, and a progressive destruction of cartilage and bone. FLICE-inhibitory protein (FLIP) prevents the association of caspase 8 with FADD and thus exerts an antiapoptotic effect through inhibition of Fas-mediated apoptosis. We undertook this study to examine the expression of FLIP in RA, osteoarthritic (OA), and normal synovial tissues. METHODS: We investigated the expression of FLIP (long form) in 5 RA, 2 OA, and 2 normal synovial tissue samples. A 393-bp fragment was amplified from complementary DNA obtained from cultured RA synovial fibroblasts (RASF) by reverse transcription-polymerase chain reaction (RT-PCR). Using in situ hybridization, the expression of FLIP messenger RNA (mRNA) in paraffin-embedded synovial tissue sections was investigated semiquantitatively by analyzing the lining layer, the sublining, and sites of invasion. Immunohistochemistry with anti-CD68 antibodies was performed on serial tissue sections to further characterize the cell types expressing FLIP. In addition, quantitative expression of FLIP was measured by real-time PCR. RESULTS: RT-PCR revealed the expression of FLIP mRNA in all RA and OA samples tested. Using in situ hybridization in synovial tissue, FLIP was detected in all 5 RA samples and in 1 of 2 OA samples, but in neither of the 2 normal control samples. In RA, FLIP expression could be found in both the lining and sublining layers; most importantly, it could also be identified at sites of cartilage invasion and bone destruction. Moreover, quantitative PCR analysis showed 50% higher FLIP expression in RASF than in OASF. CONCLUSION: The expression of antiapoptotic FLIP in RA synovial tissue and in synovial fibroblasts suggests the idea of a novel pathway in RA that potentially extends the lifespan of cartilage- and bone-degrading synovial cells, thus contributing to the progression of joint destruction.
11756959 Acral localized acquired cutis laxa associated with rheumatoid arthritis. 2002 Jan We report the first case of the acral localization of the acquired form of cutis laxa associated with severe rheumatoid arthritis. The skin laxity was preceded by episodes of itching and swelling of the hands and feet. Histopathology showed that the elastic fibers were lost in the areas of cutis laxa and decreased in adjacent skin. The pathogenetic relationship with rheumatoid arthritis or the intake of related drugs is discussed.
12440967 Targeting anticomplement agents. 2002 Nov Biological targeting is normally thought of as a process of specific direction of one molecule (the agent) to another (the target) in vivo. However, an addressive approach in which the agent is concentrated, first within the vasculature and then at a disease site containing one or more targets, may be more suitable for delivering therapeutic quantities of certain drugs. This approach has been applied to complement regulatory molecules expressed in recombinant soluble forms and attached post-translationally to highly soluble synthetic peptide derivatives comprising two addressin units, one with affinity for the membrane bilayer interior and the other for phospholipid headgroups. This combination conferred affinity for outer cell membranes in general, and areas of translocated acidic phospholipid in particular. Large increases in potency in cell-based antihaemolytic assays accompanied modification and were shown to be associated with membrane binding. Modified agents co-localized with glycosylphosphatidyl- inositol-anchored proteins in lipid rafts on cell membranes. One agent, a modified fragment of human complement receptor-1 (APT070), has been prepared on a large scale and has been shown to be an active anti-inflammatory agent when administered locally and systemically in animal models of vascular shock, rheumatoid arthritis and transplantation reperfusion injury. APT070 has been shown to be well tolerated in human subjects when given intravenously and is currently under study in rheumatoid arthritis patients to explore the therapeutic potential of localized complement inhibition in the synovial space.