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1.
Marotte H Pallot-Prades B Grange L Gaudin P Alexandre C Miossec P 《Arthritis research & therapy》2007,9(3):R61
The goal of the present study was to record changes in bone mineral density (BMD) and markers of bone turnover in patients
with rheumatoid arthritis (RA) who were treated with methotrexate combined (or not combined) with infliximab. Included were
90 patients with RA who required anti-TNF-α therapy with infliximab because of persistent active disease despite treatment
with methotrexate. The historical control group included 99 patients with RA who were treated with methotrexate at a time
when anti-TNF-α treatment was not yet available. Lumbar and femoral neck BMD was measured using dual energy X-ray absorptiometry
at baseline and 1 year later. Osteocalcin, C-terminal cross-linked telopeptide of type I collagen, parathyroid hormone and
25-hydroxycholecalciferol were measured in plasma at baseline and 1 year later. At 1 year BMD had decreased in the control
group at spine (P < 0.01) and femoral neck (P < 0.001). In contrast, BMD at spine and femoral neck did not change after 1 year of infliximab treatment. At the same time
point, no change in bone remodelling markers was observed. No association was observed between clinical response and changes
in BMD, indicating that even those who did not respond clinically did not lose bone over a 1-year period. These data confirm
the BMD decrease observed in RA patients treated with methotrexate alone. This bone loss was prevented by infliximab therapy.
Importantly, this beneficial effect was also observed in apparent nonresponders. 相似文献
2.
3.
Changes in gene expression during pegylated interferon and ribavirin therapy of chronic hepatitis C virus distinguish responders from nonresponders to antiviral therapy
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Taylor MW Tsukahara T Brodsky L Schaley J Sanda C Stephens MJ McClintick JN Edenberg HJ Li L Tavis JE Howell C Belle SH 《Journal of virology》2007,81(7):3391-3401
Treating chronic hepatitis C virus (HCV) infection using pegylated alpha interferon and ribavirin leads to sustained clearance of virus and clinical improvement in approximately 50% of patients. Response rates are lower among patients with genotype 1 than with genotypes 2 and 3 and among African-American (AA) patients compared to Caucasian (CA) patients. Using DNA microarrays, gene expression was assessed for a group of 33 African-American and 36 Caucasian American patients with chronic HCV genotype 1 infection during the first 28 days of treatment. Results were examined with respect to treatment responses and to race. Patients showed a response to treatment at the gene expression level in RNA isolated from peripheral blood mononuclear cells irrespective of degree of decrease in HCV RNA levels. However, gene expression responses were relatively blunted in patients with poor viral response (<1.5 log(10)-IU/ml decrease at 28 days) compared to those in patients with a marked (>3.5 log(10)-IU/ml decrease) or intermediate (1.5 to 3.5 log(10)-IU/ml decrease) response. The number of genes that were up- or down-regulated by pegylated interferon and ribavirin treatment was fewer in patients with a poor response than in those with an intermediate or marked viral response. However AA patients had a stronger interferon response than CA patients in general. The induced levels of known interferon-stimulated genes such as the 2'5'-oligoadenylate synthetase, MX1, IRF-7, and toll-like receptor TLR-7 genes was lower in poor-response patients than in marked- or intermediate-response patients. Thus, the relative lack of viral response to interferon therapy of hepatitis C virus infection is associated with blunted interferon cell signaling. No specific regulatory gene could be identified as responsible for this global blunting or the racial differences. 相似文献
4.
《Clinical Immunology Newsletter》1990,10(10):143-148
The treatment of RA is generally empirical. While there are many effective agents available, there are no agents that are curative. Progressive disease is frequently seen even in patients who are responsive to current therapies. Newer, more effective therapies are needed. The most promising area for new treatments appears to be specific biologic approaches with monoclonal antibodies or stimulants or inhibitors of lymphocytokines. 相似文献
5.
Ablin JN Boguslavski V Aloush V Elkayam O Paran D Caspi D George J 《Life sciences》2006,79(25):2364-2369
Rheumatoid arthritis (RA) is associated with increased cardiovascular morbidity and mortality, which may be attenuated by anti-inflammatory treatment. Endothelial progenitor cells (EPCs) have the ability to differentiate into mature endothelium and have a potentially reparative role protecting against ischemia and atherosclerosis. OBJECTIVE: To investigate the effect of treatment with infliximab on the number and functional capacity of endothelial progenitor cells (EPCs) in patients with RA, as a possible mechanism for reducing cardiovascular morbidity in this disorder. METHODS: Patients: Active seropositive RA patients (N = 14) considered candidates for starting infliximab treatment, were recruited. Assessment, based on DAS-28, was performed before treatment and 14 days later. Peripheral blood mononuclear cells were isolated and EPC numbers evaluated by the colony-forming unit (CFU) method. Endothelial phenotyping of CFU was performed by immunofluorescence employing antibodies to Tie-2 VEGF-receptor 2, and CD31. EPC Functional properties were evaluated by fibronectin adherance. RESULTS: A significant 33.4% increase (p < 0.001) in EPC levels was observed after infliximab. A 60% increase was noted in the EPC differentiation scale, (p < 0.002) while a 37.6% increase was observed in mean EPC adhesion (p < 0.001). These changes were associated with a 17.5% decrease in the DAS-28 (p < 0.0001). A significant correlation was observed between the clinical response, reflected by changes in DAS-28 and the degree of increase in EPC CFUs. CONCLUSION: A single dose of infliximab improved the number and functional properties of EPCs, in parallel with an early clinical effect, suggesting a possible mechanism by which anti-inflammatory treatment may reduce cardiovascular risk in RA patients. 相似文献
6.
Fasciola hepatica: host responders and nonresponders to parasite glutathione S-transferase. 总被引:1,自引:0,他引:1
Fasciola hepatica glutathione S-transferase (FhGST) was isolated from adult worms by glutathione agarose affinity chromatography. SDS-PAGE shows three proteins of M(r) ranging from 29-27.8 kDa. Western immunoblot analyses using SDS-PAGE separated adult worm extracts and probed with a rabbit anti-FhGST antiserum reveal two bands in the same M(r) range. Mice and rabbits immunized with purified FhGST develop copious amounts of anti-FhGST antibodies. Moreover, antisera to F. hepatica adult worms and excretion-secretion products also react with FhGST. Cross-reactivity with schistosomes is evidenced in the reactivity with FhGST of anti-Schistosoma mansoni adult worm antisera and, to a lesser extent, antisera to S. mansoni-soluble egg antigens. The time of appearance of anti-FhGST antibodies in different species of animals infected with F. hepatica was determined. Sheep and a New Zealand white rabbit developed anti-FhGST antibodies detectable by ELISA as early as 2 weeks postexposure with F. hepatica. However, neither mice nor calves infected with F. hepatica developed antibodies to FhGST through the 5-10 weeks of infection tested. But mice infected with S. mansoni developed anti-FhGST cross-reacting antibodies by 6 weeks of infection. Calves immunized with a Fasciola/Schistosoma cross-reactive, cross-protective antigen complex in which a 12,000-kDa protein (Fh12) has been shown to contain immunoprophylactic activity, also developed antibodies to FhGST. Since FhGST is a novel potential vaccine, its protection-inducing capability in a multivalent vaccine combined with Fh12 clearly warrants study. In summary, it appears that hosts with fascioliasis are either responders to FhGST (rabbits, sheep) or nonresponders (mice, cattle), offering interesting models for studying the immune response. 相似文献
7.
Sacre SM Andreakos E Taylor P Feldmann M Foxwell BM 《Expert reviews in molecular medicine》2005,7(16):1-20
In an attempt to combat the pain and damage generated by rheumatoid arthritis (ra), new drugs are being developed to target molecular aspects of the disease process. Recently, a major development has been the use of biologicals (antibodies and soluble receptors) that neutralise the activity of tumour necrosis factor alpha (TNF-alpha) and interleukin 1 (IL-1), both of which are involved in disease progression. An increase in our understanding of cell and molecular biology has resulted in the identification and investigation of potential new targets, and also the refinement and improvement of current therapeutic modalities. This review describes therapies that are approved, in clinical trials or under pre-clinical investigation at the laboratory level, particularly focusing on cytokines, although other therapeutic targets of interest are mentioned. 相似文献
8.
The combined effects of anti-TNFalpha antibody and IL-1 receptor antagonist in human rheumatoid arthritis synovial membrane 总被引:1,自引:0,他引:1
TNFalpha and IL-1 are the pivotal cytokines involved in rheumatoid arthritis (RA). More recently, the biological therapy targeting TNFalpha or IL-1 has been impressively effective for many RA patients, however, it remains insufficient in some patients. In the present study, we examined the combined effects of two agents against TNFalpha and IL-1 in human RA synovial membrane. Synovial explants (an ex vivo model) and synovial fibroblasts (an in vitro model) were prepared from 11 RA patients, and then anti-TNFalpha antibody (Anti-TNFalpha) and IL-1 receptor antagonist (IL-1Ra), either alone or in combination, were added to the synovial explants and fibroblasts. IL-6 and MMP-3 production were measured after incubation. As a result, their production significantly decreased by the combination of agents compared with the control group in both the synovial explants and fibroblasts. The efficacy of this combination was also observed for IL-6 production compared with each agent alone in the synovial explants, and for IL-6 and MMP-3 production compared with each agent alone in the synovial fibroblasts. Therefore, the combination of Anti-TNFalpha and IL-1Ra appears more beneficial in synovial membrane, particularly when compared with a single agent alone. 相似文献
9.
Patty Zwollo Eva Ehrlich-Kautzky Stephen J. Scharf Aftab A. Ansari Henry A. Erlich David G. Marsh 《Immunogenetics》1991,33(2):141-151
We investigated the molecular basis for the striking association between HLA-DR2,Dw2 and human immune responsiveness to the Ambrosia artemisiifolia (short ragweed) pollen allergen Amb a V by sequencing the second exons of the DRB and DQBI genes of 17 selected ragweed-allergic Caucasoid subjects. We also studied the DQA1 allelic polymorphic regions (APRs) in these patients by dot-blotting using sequence-specific oligonucleotides (SSOs). The deduced amino acid sequences of the respective class II and polypeptides were compared, with particular emphasis on residues in the APRs that are implicated in antigen binding. No evidence for new HLA-DRB or DQB sequences unique to Amb a V responders were found on sequencing seven Dw2+ subjects. This suggests that the presence of a particular Dw2-associated class II molecule usually provides a necessary, but not always sufficient condition for responsiveness to Amb a V. The HLA phenotypes of three subjects suggest that they possess novel recombinant haplotypes containing either DRB1
*
1501 and DRB5
*
0101 (Dr2.2-associated) or DQB1
*
0602 (DQ1.2-associated) sequences. In these subjects, responsiveness to Amb a V was associated with the DR2.2 but not the DQ1.2 sequences, suggesting that DRI or DRV class II molecules are involved in antigen presentation. We investigated whether there may be shared HLA-D-encoded responder sequences present in all responders, including some exceptional DR2–
Amb a V responders. The 13 subjects producing antibody (Ab) responses to Amb a V [either from natural exposure and/or after ragweed immunotherapy (Rx)] possessed DRB1
*
1501, 1601, 1602, 0103, 0402, 0404, 0801 or 1101 sequences, which share the majority of their aa residues in the APRs 2–4. Some of these shared residues might be important for the binding of a common Amb a V agretope prior to presentation of the class II Amb a V complex to the T-cell receptor (Tcr). An alternative postulate is that the recognition of two different Amb a V agretopes may be determined by the I polypeptides of molecules having the DR2 and DQw3 specificities. 相似文献
10.
Lars Erik Kristensen Tore Saxne Jan-?ke Nilsson Pierre Geborek 《Arthritis research & therapy》2007,8(6):R174
The objective of this work is to compare the adherence to therapy of patients receiving etanercept and infliximab during first
tumour necrosis factor (TNF)-blocking treatment course in rheumatoid arthritis. Special emphasis is placed on potential predictors
for treatment termination and the impact of concomitant methotrexate (MTX) or other disease-modifying antirheumatic drugs
(DMARDs). Patients (n = 1,161) with active rheumatoid arthritis, not responding to at least two DMARDs including MTX starting etanercept or infliximab
therapy for the first time, were included in a structured clinical follow-up protocol. Information on diagnosis, disease duration,
previous and ongoing DMARDs, treatment start and termination, as well as cause of withdrawal was prospectively collected during
the period of March 1999 through December 2004. Patients were divided into six groups according to TNF-blocking drugs and
concomitant DMARDs. Five-year level (one-year) of adherence to therapy was 36% (69%) for patients receiving infliximab in
combination with MTX compared with 65% (89%) for patients treated with etanercept and MTX (p < 0.001). Cox regression models showed that the risk for premature treatment termination of patients treated with infliximab
was threefold higher than for etanercept (p < 0.001). Also, the regression analysis showed that patients receiving concomitant MTX had better treatment continuation
than patients treated solely with TNF blockers (p < 0.001). Moreover, patients receiving concomitant MTX had superior drug survival than patients receiving other concomitant
DMARDs (p < 0.010). The superior effect of MTX was associated primarily with fewer treatment terminations because of adverse events.
In addition, the study identifies low C-reactive protein level, high age, elevated health assessment questionnaire score,
and higher previous number of DMARDs as predictors of premature treatment termination. In summary, treatment with etanercept
has higher adherence to therapy than treatment with infliximab. Concomitant MTX is associated with improved treatment continuation
of biologics when compared with both TNF blockers as monotherapy and TNF blockers combined with other DMARDs. 相似文献
11.
The objective of this work is to compare the adherence to therapy of patients receiving etanercept and infliximab during first tumour necrosis factor (TNF)-blocking treatment course in rheumatoid arthritis. Special emphasis is placed on potential predictors for treatment termination and the impact of concomitant methotrexate (MTX) or other disease-modifying antirheumatic drugs (DMARDs). Patients (n = 1,161) with active rheumatoid arthritis, not responding to at least two DMARDs including MTX starting etanercept or infliximab therapy for the first time, were included in a structured clinical follow-up protocol. Information on diagnosis, disease duration, previous and ongoing DMARDs, treatment start and termination, as well as cause of withdrawal was prospectively collected during the period of March 1999 through December 2004. Patients were divided into six groups according to TNF-blocking drugs and concomitant DMARDs. Five-year level (one-year) of adherence to therapy was 36% (69%) for patients receiving infliximab in combination with MTX compared with 65% (89%) for patients treated with etanercept and MTX (p < 0.001). Cox regression models showed that the risk for premature treatment termination of patients treated with infliximab was threefold higher than for etanercept (p < 0.001). Also, the regression analysis showed that patients receiving concomitant MTX had better treatment continuation than patients treated solely with TNF blockers (p < 0.001). Moreover, patients receiving concomitant MTX had superior drug survival than patients receiving other concomitant DMARDs (p < 0.010). The superior effect of MTX was associated primarily with fewer treatment terminations because of adverse events. In addition, the study identifies low C-reactive protein level, high age, elevated health assessment questionnaire score, and higher previous number of DMARDs as predictors of premature treatment termination. In summary, treatment with etanercept has higher adherence to therapy than treatment with infliximab. Concomitant MTX is associated with improved treatment continuation of biologics when compared with both TNF blockers as monotherapy and TNF blockers combined with other DMARDs. 相似文献
12.
Elizabeth A Martin Wayne T Nicholson John H Eisenach Nisha Charkoudian Michael J Joyner 《Journal of applied physiology》2006,101(6):1678-1684
We previously demonstrated a bimodal distribution of vasodilator responsiveness to adenosine (Ado) infusion in human subjects, despite similar responses to exercise between subgroups [subjects responsive to Ado infusion (Ado responders) and subjects with blunted vasodilator responses to Ado infusion (Ado nonresponders]). (Martin EA, Nicholson WT, Eisenach JH, Charkoudian N, and Joyner MJ. J Appl Physiol 101: 492-499, 2006). A component of this difference was attributed to a larger nitric oxide component of Ado-mediated vasodilation in responders. However, there may also be differences in Ado receptors between these subgroups. We hypothesized that Ado receptor antagonism would reduce vasodilator responsiveness to Ado and exercise only in Ado responders. To test this hypothesis, we compared forearm vasodilation induced by intra-arterial infusion of three doses of Ado to vasodilation during three workloads of forearm handgrip exercise before and after Ado receptor antagonism with aminophylline (Aph) in 19 subjects. In Ado responders, the change in forearm vascular conductance above baseline for the low, medium, and high doses of Ado, respectively, was 93 +/- 16, 140 +/- 14, 194 +/- 18 before Aph and 27 +/- 12, 71 +/- 19, and 134 +/- 34 ml.min(-1).100 mmHg(-1) after Aph (P < 0.05 for low and medium dose before vs. after Aph). For nonresponders, these values were 30 +/- 5, 39 +/- 6, and 78 +/- 9 ml.min(-1).100 mmHg(-1) before Aph (P < 0.05 vs. responders), with no difference after Aph (P > 0.05). We found that Ado receptor blockade significantly inhibited exercise hyperemia only at high workloads in both responders and nonresponders (P < 0.05 before vs. after Aph). We conclude that there may be reduced Ado receptor responsiveness or sensitivity in nonresponders. Furthermore, Ado may play a limited role exercise hyperemia in both subgroups. 相似文献
13.
14.
Mahdi Zavvar Sara Assadiasl Narjes Soleimanifar Fatemeh Dadgar Pakdel Kamal Abdolmohammadi Yousef Fatahi Mohsen Abdolmaleki Hamed Baghdadi Lobat Tayebi Mohammad H. Nicknam 《Journal of cellular physiology》2019,234(10):16913-16924
Significant advances have been achieved in recent years to ameliorate rheumatoid arthritis (RA) in animal models using gene therapy approaches rather than biological treatments. Although biological agents serve as antirheumatic drugs with suppressing proinflammatory cytokine activities, they are usually accompanied by systemic immune suppression resulting from continuous or high systemic dose injections of biological agents. Therefore, gene transfer approaches have opened an interesting perspective to deliver one or multiple genes in a target-specific or inducible manner for the sustained intra-articular expression of therapeutic products. Accordingly, many studies have focused on gene transferring methods in animal models by using one of the available approaches. In this study, the important strategies used to select effective genes for RA gene therapy have been outlined. Given the work done in this field, the future looks bright for gene therapy as a new method in the clinical treatment of autoimmune diseases such as RA, and by ongoing efforts in this field, we hope to achieve feasible, safe, and effective treatment methods. 相似文献
15.
Feldmann M 《Nature reviews. Immunology》2002,2(5):364-371
The aetiology of systemic, autoimmune, chronic inflammatory diseases--such as rheumatoid arthritis--is not known, and their pathogenesis is complex and multifactorial. However, progress in the characterization of intercellular mediators--proteins that are now known as cytokines--has led to the realization that one cytokine, tumour-necrosis factor (TNF; previously known as TNF-alpha), has an important role in the pathogenesis of rheumatoid arthritis. This discovery heralded a new era of targeted and highly effective therapeutics for rheumatoid arthritis and, subsequently, other chronic inflammatory diseases. 相似文献
16.
《Life sciences》1993,53(12):PL195-PL200
Following a single dose of nicotine, (NIC, 1 mg/kg s.c.), 60% of tested rats revealed significant anticociception as measured by the tail-flick (TF) test, and were classified as responders, with those in which TF latencies did not change, nonresponders. The following experiments were carried out one week later. In nonresponders, pretreatment with ethylenediaminetetraacetic acid (EDTA, 250 μM/kg s.c. four times every 15 min) followed by 1 mg NIC, produced significant analgesia in 50% of rats, to the same magnitude as did nicotene alone (1 mg) in responders. The other 50% of rats which failed to respond to EDTA pretreatment, all revealed similar analgesia following the higher dose of NIC (1.5 mg/kg s.c.), with similar side effects, as generally observed in responders. In responders, pretreatment with CaCl2 (1.5 mM/kg s.c.) completely abolished NIC (1 mg/kg s.c.) - induced analgesia in all rats. Our data provide stronger evidence and a further verification that EDTA potentiates, whereas CaCl2 completely abolishes, nicotene-induced analgesia in rats; supporting our hypothesis of the involvement of calcium ions in this effect. 相似文献
17.
B-lymphocyte depletion therapy in rheumatoid arthritis and other autoimmune disorders 总被引:11,自引:0,他引:11
B-lymphocyte depletion therapy is being explored in a wide range of autoimmune disorders. In many, there is early evidence for efficacy, and immunosuppression has not been a major problem. The mechanism of action is unclear, but appears to be consistent with the lowering of autoantibody levels, where relevant antibodies are quantifiable. An interesting finding is the persistence of clinical improvement for periods of 1 year or more after B-lymphocyte return, which supports the concept that stochastic generation of rare pathogenic B-lymphocyte subsets may be a rate-limiting step in pathogenesis. 相似文献
18.
U Frick G Frick S Preussner H Konrad P Nowotny M Keysser G Bast 《Folia haematologica (Leipzig, Germany : 1928)》1976,103(5):715-718
In 12 patients with chronic rheumatoid arthritis the immunoglobulins IgG, IgA and IgM were determined according to Mancini and the fibrinolytic split products according to Nilehn before and after a gold treatment of 3 to 6 months. The IgG values were always increased and even after the treatment there was only little regression. The fibrinolytic split products found in 5 cases speak in favour of an enhanced intravasal coagulation, which increased still further after the gold therapy. In spite of clinical improvement the immunological processes and latent actions of coagulation seem to pass almost undiminished. 相似文献
19.
Maria J Leandro 《Arthritis research & therapy》2009,11(5):128-2
The efficacy of B-cell depletion therapy in rheumatoid arthritis (RA) has led to a renewed interest in B cells and their products
and the role they play in the pathogenesis of the disease. Agents blocking tumour necrosis factor (TNF) are also very effective
in the treatment of RA. It has long been known that the use of anti-TNF therapy can be associated with development of anti-nuclear
and anti-double-stranded DNA antibodies and, more rarely, a lupus-like syndrome. Recently, studies have been published investigating
further possible effects of anti-TNF agents on B cells and whether these could contribute to their effectiveness in RA. 相似文献