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

ID PMID Title PublicationDate abstract
16802344 Differential survival of leukocyte subsets mediated by synovial, bone marrow, and skin fib 2006 Jul OBJECTIVE: Synovial fibroblasts share a number of phenotype markers with fibroblasts derived from bone marrow. In this study we investigated the role of matched fibroblasts obtained from 3 different sources (bone marrow, synovium, and skin) to test the hypothesis that synovial fibroblasts share similarities with bone marrow-derived fibroblasts in terms of their ability to support survival of T cells and neutrophils. METHODS: Matched synovial, bone marrow, and skin fibroblasts were established from 8 different patients with rheumatoid arthritis who were undergoing knee or hip surgery. Resting or activated fibroblasts were cocultured with either CD4 T cells or neutrophils, and the degree of leukocyte survival, apoptosis, and proliferation were measured. RESULTS: Fibroblasts derived from all 3 sites supported increased survival of CD4 T cells, mediated principally by interferon-beta. However, synovial and bone marrow fibroblasts shared an enhanced site-specific ability to maintain CD4 T cell survival in the absence of proliferation, an effect that was independent of fibroblast activation or proliferation but required direct T cell-fibroblast cell contact. In contrast, fibroblast-mediated neutrophil survival was less efficient, being independent of the site of origin of the fibroblast but dependent on prior fibroblast activation, and mediated solely by soluble factors, principally granulocyte-macrophage colony-stimulating factor. CONCLUSION: These results suggest an important functional role for fibroblasts in the differential accumulation of leukocyte subsets in a variety of tissue microenvironments. The findings also provide a potential explanation for site-specific differences in the pattern of T cell and neutrophil accumulation observed in chronic inflammatory diseases.
16165349 Inhibition of Tpl2 kinase and TNF-alpha production with 1,7-naphthyridine-3-carbonitriles: 2005 Dec 1 The synthesis and structure-activity studies of a series of 6-substituted-4-anilino-[1,7]-naphthyridine-3-carbonitriles as inhibitors of Tpl2 kinase are described. The early exploratory work described here may lead to the discovery of compounds with significant therapeutic potential for treating rheumatoid arthritis and other inflammatory diseases.
16079172 Patient reported outcomes in a trial of combination therapy with etanercept and methotrexa 2006 Mar OBJECTIVE: To compare patient reported measures of function, health related quality of life (QoL), and satisfaction with medication among patients with rheumatoid arthritis (RA) treated with methotrexate (MTX), etanercept, or both for up to 1 year. METHODS: In a 52 week, double blind, clinical trial, patients with active RA were randomised to receive etanercept 25 mg twice weekly, methotrexate up to 20 mg weekly, or combination therapy. The Health Assessment Questionnaire (HAQ) disability index, EuroQoL health status visual analogue scale (EQ-5D VAS), patient global assessment, and patient general health VAS were administered at baseline and weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52. Satisfaction with the medication was compared at 52 weeks. RESULTS: Of 682 enrolled patients, 522 completed 52 weeks of treatment. Mean improvement from baseline in HAQ score was 0.65, 0.70, and 1.0 for MTX, etanercept, and the combination, respectively. The mean percentage and absolute improvement in the HAQ was significantly higher (p<0.01) for combination therapy than for either of the monotherapies. Combination therapy produced significantly more rapid achievement of HAQ < or =0.5 sustained for 6 months than either of the monotherapies (p<0.01). Compared with patients receiving monotherapy, those receiving combination therapy achieved a significantly better (p<0.05) health state as measured by the EQ-5D VAS (mean (SD) 63.7 (3.2), 66.8 (3.2), 72.7 (3.1) for MTX, etanercept, and the combination, respectively). Results were similar for other assessments (p<0.01). Patients in combination and etanercept groups were significantly more likely (p<0.0001, p = 0.0009, respectively) to report satisfaction with the medication. CONCLUSIONS: Combination therapy with etanercept and methotrexate improved function, QoL, and satisfaction with the medication significantly more than monotherapy.
15976836 [Clinical experience with TNF-alpha inhibitors in rheumatoid arthritis]. 2005 Jun 16 BACKGROUND: Infliximab and etanercept, both tumour necrosis factor-alpha inhibitors, are proven to be effective in patients with rheumatoid arthritis in randomised controlled trials. MATERIAL AND METHODS: Patients with active rheumatoid arthritis were treated with infliximab (n = 29) or etanercept (n = 24) in clinical hospital practice. They were examined before and during treatment. All patients had tried at least one DMARD before. Details of disease activity were monitored by measuring tender and swollen joints, global and pain patient visual analogue scales, Disease Activity Index Score (DAS 28), the Modified Health Assessment Questionnaire, blood and urine samples, and adverse effects. The patients were monitored regularly for two years or until they stopped treatment. RESULTS: In the infliximab group we observed statistically significantly better values for all the registered variables after 6 weeks. At the other times of registration the variables were varying a lot; however, DAS 28 scores after baseline were all within the limits of moderate effect. In the etanercept group we observed statistically significantly better values for all the variables except for erythrocyte sedimentation rate after 6 weeks. At the other times of registration all the variables had significantly better values. Adverse effects were reported in 9 patients in the infliximab group and in 5 in the etanercept group, but no serious adverse effects were reported. 18 patients in the infliximab group (61%) and 10 in the etanercept group (42%) had stopped treatment within two years, either because of adverse effects or lack of effect. CONCLUSION: In this open study of patients with active rheumatoid arthritis, most experienced a rapid effect of infliximab, but a varying effect later on. In the etanercept group the patients experienced both a rapid and sustained effect among those who tolerated the medication. Compared to what several others have reported, a large number of patients stopped treatment; this may reflect limited experience.
15934099 Association between the PTPN22 gene and rheumatoid arthritis and juvenile idiopathic arthr 2005 Jun OBJECTIVE: The protein tyrosine phosphatase N22 (PTPN22) gene exhibits regulatory activities for both T cells and B cells. A missense single-nucleotide polymorphism (SNP) within this gene (rs2476601) has recently been associated with 4 autoimmune diseases: rheumatoid arthritis (RA), systemic lupus erythematosus, autoimmune thyroid disease, and type 1 diabetes mellitus, all of which are T cell-mediated and associated with the elaboration of autoantibody. The aim of this study was to investigate associations of the missense SNP of PTPN22 in a number of autoimmune diseases in the UK population, including RA, juvenile idiopathic arthritis (JIA), psoriasis, psoriatic arthritis (PsA), and multiple sclerosis (MS), some of which have not been examined previously. METHODS: The PTPN22 missense SNP was genotyped in 886 RA, 661 JIA, 279 psoriasis, 455 PsA, and 379 MS patients and in 595 healthy controls. Association with the PTPN22 SNP was analyzed by chi-square test as implemented in Stata software. RESULTS: There was a significant association between the PTPN22 SNP and RA (P = 1.8 x 10(-8)) and JIA (P = 0.0005). In contrast, no association with psoriasis, PsA, or MS was detected. CONCLUSION: We replicated the findings of a previous association with RA and identified a novel association with JIA. Together with previous data showing associations with other autoimmune diseases, our findings provide further evidence that the PTPN22 gene plays a role in the pathogenesis of a subgroup of autoimmune diseases.
16819695 Skin protection underneath the pneumatic tourniquet during total knee arthroplasty: a rand 2006 Jun BACKGROUND: The use of a pneumatic tourniquet to obtain a bloodless field during a total knee arthroplasty (TKA) allows the surgeon to work with greater technical precision in a safe, clear environment. Despite the benefits of surgical tourniquets and many advances in tourniquet equipment, their use is not without risk and complications may still occur. The primary aim of this study was to determine whether there are any differences between an elastic stockinette, cast padding, and no protective material at all regarding skin injuries after a primary TKA in a bloodless field using a pneumatic tourniquet. METHODS: 92 patients were randomized to 1 of 3 groups. In the first group, the limb underneath the pneumatic tourniquet was protected by a two-layer elastic stockinette (E). In the second group, it was protected by cast padding (C), and no protective material (N) was used in the third group. The presence of major skin injuries (blisters) was recorded when the tourniquet was removed after surgery. RESULTS: The two groups with skin protection had fewer skin injuries (p = 0.007). The elastic stockinette was significantly better than having no protective material and there was a trend towards better results in the elastic stockinette group than in the cast padding group. INTERPRETATIONS: Our findings indicate that protective material underneath the tourniquet cuff reduces the risk of skin injuries, i.e. blisters. An elastic stockinette appears to be best.
17068699 Femoral head diameter affects the revision rate in total hip arthroplasty: an analysis of 2006 Oct BACKGROUND: In a previous study concerning 1,660 ScanHip THAs that were followed for up to 12 years, the cumulative revision rate was not found to be dependent on whether a 22-mm or a 32-mm head size had been used. We have re-examined these patients to see whether a longer follow-up time (9-21 years) would disclose an effect of head size on the revision rate. PATIENTS AND METHODS: We analyzed the cumulative revision rate for 1,720 Scan Hip arthroplasties with either 22-mm or 32-mm femoral heads. The patients were followed for 9-21 years. RESULTS: Arthroplasties with 32-mm head had 2.8-times higher cumulative revision rate than those with a 22-mm head. Older age reduced the risk of revision while male sex increased the risk. INTERPRETATION: We found that head size affects revision risk, but that even in a reasonably large material a long follow-up time is required to disclose the effects of head size--and thus wear--on survival.
16167387 Simplified search strategies were effective in identifying clinical trials of pharmaceutic 2005 Sep BACKGROUND AND OBJECTIVES: Assess the efficacy of simplified search strategies and identify the best electronic bibliographic database for clinical trials in the field of musculoskeletal disorders and pain. METHODS: Clinical trials within selected reviews from the Cochrane Back, Musculoskeletal, and PaPaS Review Groups were searched using MEDLINE, EMBASE, CINAHL, and CENTRAL to identify which database included the highest percentage of trials. Simplified search strategies for each review were devised and compared to the original, more complex strategy for sensitivity, specificity and precision. RESULTS: Individually, MEDLINE, and EMBASE included 90 and 89% of the relevant studies respectively, and 94% when combined. CENTRAL contained 87% and CINAHL 31%. Generally, simplified search strategies (two to four lines) had higher specificity than the original strategies (approximately 27 lines). Sensitivity was also high, but varied according to intervention. Super simple search strategies (one to two lines) proved as sensitive, but were slightly less specific, depending on the intervention. Both simple and super simple search strategies were often more precise than the original. CONCLUSION: Simplified search strategies are an effective, efficient way to search for clinical trials. They work best when the intervention is a pharmaceutical or a well-defined physical treatment. Their sensitivity, however, is not adequate for conducting systematic reviews.
16406555 The combined effects of anti-TNFalpha antibody and IL-1 receptor antagonist in human rheum 2005 Dec 21 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.
16187511 The unstable metacarpophalangeal joint in rheumatoid arthritis: anatomy, pathomechanics, a 2005 Aug The metacarpophalangeal (MCP) joints bestow important strength to the longitudinal and transverse arch systems of the hand. In addition, these joints guide active movements of the fingers in 2 degrees of freedom, while allowing sufficient laxity for passive accessory motions. Both stability and mobility functions are attained in the healthy hand by a complex interaction among the muscles and the joints' periarticular connective tissues. Rheumatoid arthritis (RA) often causes destruction of the MCP joints' connective tissues, which leads to weakness of the tissues and an imbalance of active and passive forces, and subsequently, instability, pain, and deformity. The 2 most common deformities of the MCP joints associated with RA and instability are palmar subluxation and ulnar "drift." Therapists and physicians often collaborate to treat these conditions through a combination of surgical and nonsurgical interventions. Two of the more conservative nonsurgical interventions typically involve a combination of splinting and education on joint protection. Additional nonsurgical treatment may include the judicious use of exercise and methods for relieving pain and reducing inflammation. Surgical intervention is often indicated when the more conservative treatments fail to arrest the progression of the pain or deformity. Regardless of the specific approach, effective intervention for instability of the MCP joint requires that the clinician possess a sound knowledge of the anatomy and the pathomechanical influences that predispose or cause the instability. This clinical commentary is intended to provide this information, as well as offer treatment guidelines based on our clinical experience. Whenever possible, research will be cited to support clinical interventions. This paper is especially geared to the therapist who may not currently specialize in the treatment of instability of the MCP joint but may require basic information on this important topic.
16436036 Anti-TNF-alpha agents in the treatment of psoriatic arthritis. 2006 Feb Psoriatic arthritis (PsA) is a potentially debilitating disease that may affect small and large peripheral joints, entheses and the axial skeleton. The different clinical manifestations of PsA have been accounted for by various proposals of subdividing the patients into different subgroups. According to the predominant clinical symptoms, most patients can be classified as belonging to the spectrum of spondyloarthritides (SpA) or rheumatoid arthritis (RA). The conventional therapeutic approach comprises non-steroidal anti-inflammatory drugs, systemic and intra-articular corticosteroids, and disease-modifying antirheumatic drugs such as sulfasalazine, methotrexate, ciclosporin and leflunomide. Similar to RA, recent trials in PsA have shown excellent results with the tumour necrosis factor (TNF) blockers etanercept, infliximab and adalimumab, which have positive effects not only on joints, but also on the skin when affected by psoriasis, quality of life, function and slowing of disease progress, as evidenced radiologically. Anti-TNF therapy has been generally safe in clinical trials of PsA. Taken together, there has been definite recent progress in the treatment of PsA, especially for severely affected patients.
15634812 Quadriceps tendon rupture after total knee arthroplasty. Prevalence, complications, and ou 2005 Jan BACKGROUND: There is relatively little information about quadriceps tendon tears after total knee arthroplasty. The purpose of this study was to determine the prevalence of this condition and the outcomes of patients who had a tear of the quadriceps tendon after a total knee arthroplasty. METHODS: From a cohort of 23,800 primary total knee arthroplasties, we identified twenty-four patients who had a rupture of the quadriceps tendon postoperatively. Ten additional patients had the total knee arthroplasty done elsewhere and were referred for care after sustaining a tear of the quadriceps tendon. Thus, the study group consisted of thirty-four patients, and all had at least two years of follow-up. Eleven patients had a complete tear, and twenty-three had a partial tear. RESULTS: The prevalence of a quadriceps tendon tear after total knee arthroplasty was 0.1% (twenty-four of 23,800). Seven patients with a partial tear were treated nonoperatively, and all had a satisfactory outcome. One patient with a complete tear was treated nonoperatively and had an unsatisfactory result. Of the ten patients treated operatively after a complete tear, four subsequently had rerupture of the repaired tendon and four had a satisfactory outcome. Of the sixteen patients with a partial tear treated operatively, only one had rerupture and twelve had a satisfactory outcome. Complications occurred in eleven of the twenty-six patients managed operatively. CONCLUSIONS: The prevalence of complications was high, and the outcomes were poor for seven of the eleven patients who had a complete quadriceps tendon tear after total knee arthroplasty. Patients who sustained a partial tear and were treated nonoperatively had no complications and had uniformly good outcomes.
15642766 Depletion of endothelial progenitor cells in the peripheral blood of patients with rheumat 2005 Jan 18 BACKGROUND: Rheumatoid arthritis (RA) is characterized by increased cardiovascular morbidity and mortality that cannot be explained solely by traditional cardiovascular risk factors. Cardiovascular morbidity is related to disease activity and can be normalized by effective therapy. Because the quantity of endothelial progenitor cells (EPCs) in the peripheral blood is correlated inversely with cardiovascular risk, we studied whether such abnormalities could also be observed in patients with RA. METHODS AND RESULTS: EPCs were determined in 52 RA patients and in 16 healthy referents (HRs) by fluorescence-activated cell-sorting (FACS) analysis. Patients were divided into groups characterized by active disease (n=36) and low disease activity (n=16). Cells that were positive by flow cytometry for CD34/KDR/AC133 within the lymphocyte population were characterized as EPCs. Furthermore, in subgroups of patients, circulating EPCs were also quantified by a colony-forming unit (CFU) and a circulating angiogenic cell (CAC) assay. EPCs were significantly decreased in RA patients suffering from active disease compared with those from HRs, as measured by FACS analysis (0.026+/-0.002% versus 0.045+/-0.008%, respectively, P<0.05), CFU assay (mean of 5+/-2 versus 18+/-5 CFU/well in HRs, P<0.05), and CAC assay (mean of 7+/-2 versus 52+/-16 positive cells/high-power field, P<0.005). In contrast, the frequency of circulating EPCs from patients with low disease activity was comparable to that of healthy individuals (0.052+/-0.006% by FACS analysis), CFU assay (10+/-5 CFU/well), and CAC assay (mean of 25+/-5 positive cells). Moreover, EPC quantities in peripheral blood were correlated inversely with disease activity as assessed by the disease activity score (r=-0.38, P<0.01). CONCLUSIONS: Our observations indicate that active RA is associated with a depletion of circulating EPCs. This might be one of several factors contributing to the increased cardiovascular risk in RA.
17405193 The early history of hand surgery in the Philippines and highlights in my experience at th 2006 Several years ago, while attending a Philippines Orthopaedic Association (PDA) Annual Convention, held at the Westin Philippine Plaza Hotel, Manila in December, I had the opportunity to meet with Professor Yoshikazu Ikuta, a well-known microsurgery and hand surgeon from Japan and one of the foreign guest speakers. I had been invited to work with him at the Armed Forces of the Philippines (AFP) Medical Center on the case of a high ranking general of the AFP, with a hand contracture disability problem. The case was referred to him by Dr. Evaristo Sanchez, Chief of Orthopaedics and the Commanding General of the AFP Medical Center. He had been pre-scheduled for surgery the next day, a Sunday morning, the day before Prof. Ikuta was due to return to Japan. After a brief examination and evaluation of the generals affected hand, in the operating room with Prof. Ikuta, just before he was placed under general anaesthesia, we performed the operation together. The operation did not involve microsurgery. The procedures done were multiple combined Bunnell-Zancolli pulley advancements and MP-joint volar capsulorraphies plus flexor tendon releases in the volar forearm, which although quite extensive, were only palliative, to minimise and improve on the contracture deformities, in preparation for a final re-evaluation for possible later, more definitive tendon transfers for hand function. However, I never received any further information regarding the results of our surgery. Recently, I have been honoured and invited again by Prof. Ikuta, presently the Editor-in-Chief of the Hand Surgery Journal (Asian Volume), this time to write the history of hand surgery in the Philippines and add to it, "Highlights in my experience at the National Orthopaedic Hospital, Mandaluyong, and the Our Lady of Lourdes Hospital, Manila", the last portion of which is on paralytic disabilities of the Hand. I am deeply grateful to Prof. Ikuta for giving me this honour and opportunity to present the total experience, favourable and unfavourable, of a hand surgeon from a developing country, like the Philippines. Furthermore, this would afford me also, the chance to be able to make known to readers of this now prestigious journal, the philosophical thoughts which led me to unwittingly originate or come up with and develop a few of my own "Long Tendon Rerouting Procedures" which may possibly and hopefully merit as this author's title contribution to surgery of the hands.
16641042 Drug survival and reasons for discontinuation of intramuscular methotrexate: a study of 21 2006 Mar OBJECTIVES: To assess the drug survival and reasons for discontinuation of intramuscular methotrexate (imMTX) in rheumatological patients who had switched to imMTX from oral methotrexate (oMTX). METHODS: Data from 212 consecutive patients who switched from oMTX to imMTX therapy at our outpatient clinic between April 1997 and January 2004 were collected retrospectively through survey of case records. Data included reason for discontinuation of oMTX, disease activity parameters, duration of imMTX therapy, and, in patients who withdrew, the reason for discontinuation of imMTX. RESULTS: The main reasons for switching from oMTX to imMTX were lack of efficacy (66%) and adverse events (28%). After 6 months, 114 patients (54%) were still receiving imMTX therapy, and their median serum C-reactive protein (CRP) and the percentage of patients who had received glucocorticoids during the previous 6 weeks had decreased (p<0.001). The median survival of imMTX therapy was 7.5 months (interquartile range 3-17). Twenty per cent of the patients received imMTX for more than 24 months. Of the 212 patients, 41% and 9% stopped imMTX therapy because of lack of efficacy and adverse events, respectively. Of the patients who had stopped oMTX because of adverse events, 22% also withdrew from imMTX because of adverse events. CONCLUSION: Half of the patients benefited from switching from oral to intramuscular methotrexate for at least 6 months, but only a minority adhered to the treatment for years. Lack of efficacy was the most frequent reason for discontinuation, while adverse events were rare.
16360554 An investigation of clinical studies suggests those with multiple objectives should have a 2006 Jan BACKGROUND AND OBJECTIVES: Many clinical studies have more than one objective, either formally or informally, but this is not usually taken into account in the determination of the sample size. We investigated the overall power of a study, that is, the probability that all the objectives will be met. METHODS: We calculated the overall power in the case that the study has two primary outcome variables and in the case that one outcome variable is evaluated on two subsets, in particular, the Per Protocol group and the Intention to Treat group. RESULTS: A power of 80% for each of the two end points leads to poor power for the end points combined. However, a power of 90% preserves better the overall power. The power of the Per Protocol analysis can be higher or lower than the power of the Intention to Treat analysis. CONCLUSION: Power should be calculated for all end points combined, and it should be at least 90% for each primary end point. If the sample size for the intention-to-treat analysis is determined by adding a percentage of "nonevaluable subjects" to the sample size required for the per protocol analysis, then this may lead to an underpowered study.
16431349 Developing the concept of adoptive cellular gene therapy of rheumatoid arthritis. 2006 Feb Progressive destruction of articular cartilage and bone is the pivotal problem of rheumatoid arthritis (RA). Joint destruction is the cause of severe disability and determines the long-term outcome of disease. Conventional therapy does not control this destructive process sufficiently and the anti-rheumatic drugs available today can cause severe systemic adverse effects. Local application of chondroprotective and osteoprotective agents by means of gene therapy would be an attractive alternative to conventional therapy of RA and could provide long-term expression of the therapeutic agents and minimize systemic adverse effects. For this purpose, we have developed the concept of adoptive cellular gene therapy. This treatment strategy is based on using genetically engineered cells that home specifically to sites of autoimmune inflammation and thus allow local delivery of therapeutic gene products. Ex vivo transduction of these cells avoids systemic exposure of the host to the transgene-encoding vector and thus adds to the safety of this approach. In this article of the CIS Spring School in Autoimmune Diseases 2005 proceedings, we review our work on developing the strategy of adoptive cellular gene therapy and summarize recent advances in the evaluation of therapeutic effects and the identification of novel therapeutic targets.
16980409 Aberrant MHC class II expression in mouse joints leads to arthritis with extraarticular ma 2006 Sep 26 Genetic susceptibility to rheumatoid arthritis (RA) is associated with certain MHC class II molecules. To clarify the role of these determinants in RA, we generated the D1CC transgenic mouse that expressed genes involved in antigen processing and presentation by the MHC class II pathway in joints. The class II transactivator, which was transcribed from the rat collagen type II promoter and enhancer, directed the expression of these genes. In D1CC mice congenic for the H-2(q) (DBA/1) background, small amounts of bovine collagen type II in adjuvant induced reproducibly an inflammatory arthritis resembling RA. Importantly, these stimuli had no effect in DBA/1 mice. Eighty-nine percent of D1CC mice developed chronic disease with joint swelling, redness, and heat in association with synovial proliferation as well as pannus formation and mononuclear infiltration of synovial membranes. Granulomatous lesions resembling rheumatoid nodules and interstitial pneumonitis also were observed. As in patients with RA, anticyclic citrullinated peptide antibodies were detected during the inflammatory stage. Finally, joints in D1CC mice displayed juxtaarticular demineralization, severe joint space narrowing, and erosions, which led to ankylosis, but without the appearance of osteophytes. Thus, aberrant expression of MHC class II in joints facilitates the development of severe erosive inflammatory polyarthritis, which is very similar to RA.
16308341 Long term efficacy and safety of adalimumab plus methotrexate in patients with rheumatoid 2006 Jun OBJECTIVE: To evaluate the efficacy and safety of adalimumab plus methotrexate (MTX) given for up to 4 years in patients with active, longstanding rheumatoid arthritis. METHODS: Patients responding inadequately to MTX were entered into a 24 week, controlled study (ARMADA) with adalimumab plus MTX or placebo plus MTX, and some were enrolled in a subsequent open label extension. The efficacy and safety of treatment were evaluated. Additional analyses were made for those patients whose corticosteroid and/or MTX dosages were adjusted during the extension. RESULTS: Of 271 patients in the original ARMADA trial, 262 received at least one dose of adalimumab and were evaluated. At the time of analysis, 162/262 (62%) patients had remained in the study and received treatment for a mean of 3.4 years. Withdrawals were for lack of efficacy (8%), adverse events (12%), and other reasons (18%). In 147 patients who completed 4 years' treatment, efficacy achieved at 6 months was maintained. At 4 years, 78%, 57%, and 31% had achieved ACR20/50/70; 43% achieved clinical remission (DAS28 <2.6); and 22% had no physical function abnormalities (HAQ = 0). Results were similar for 196 patients who received treatment for 2-4 years. Efficacy was maintained in many patients when dosages were decreased (corticosteroids (51/81 (63%) patients), MTX (92/217 (42%)), or both (25/217 (12%))). Serious adverse events were comparable during open label treatment and the controlled phase. Serious infections occurring during open label treatment and the blinded period were similar (2.03 v 2.30 events per 100 patient-years, respectively). CONCLUSIONS: Adalimumab plus MTX sustained clinical response and remission in patients with RA during 4 years. The safety profile during the first 6 months was similar to that after 4 years' follow up. Reduction of corticosteroid and/or MTX dosages did not adversely affect long term efficacy.
16684367 Local treatment with the selective IkappaB kinase beta inhibitor NEMO-binding domain pepti 2006 Nuclear factor (NF)-kappaB is a key regulator of synovial inflammation. We investigated the effect of local NF-kappaB inhibition in rat adjuvant arthritis (AA), using the specific IkappaB kinase (IKK)-beta blocking NF-kappaB essential modulator-binding domain (NBD) peptide. The effects of the NBD peptide on human fibroblast-like synoviocytes (FLS) and macrophages, as well as rheumatoid arthritis (RA) whole-tissue biopsies, were also evaluated. First, we investigated the effects of the NBD peptide on RA FLS in vitro. Subsequently, NBD peptides were administered intra-articularly into the right ankle joint of rats at the onset of disease. The severity of arthritis was monitored over time, rats were sacrificed on day 20, and tissue specimens were collected for routine histology and x-rays of the ankle joints. Human macrophages or RA synovial tissues were cultured ex vivo in the presence or absence of NBD peptides, and cytokine production was measured in the supernatant by enzyme-linked immunosorbent assay. The NBD peptide blocked interleukin (IL)-1-beta-induced IkappaB alpha phosphorylation and IL-6 production in RA FLS. Intra-articular injection of the NBD peptide led to significantly reduced severity of arthritis (p < 0.0001) and reduced radiological damage (p = 0.04). This was associated with decreased synovial cellularity and reduced expression of tumor necrosis factor (TNF)-alpha and IL-1-beta in the synovium. Incubation of human macrophages with NBD peptides resulted in 50% inhibition of IL-1-beta-induced TNF-alpha production in the supernatant (p < 0.01). In addition, the NBD peptide decreased TNF-alpha-induced IL-6 production by human RA synovial tissue biopsies by approximately 42% (p < 0.01). Specific NF-kappaB blockade using a small peptide inhibitor of IKK-beta has anti-inflammatory effects in AA and human RA synovial tissue as well as in two important cell types in the pathogenesis of RA: macrophages and FLS. These results indicate that IKK-beta-targeted NF-kappaB blockade using the NBD peptide could offer a new approach for the local treatment of arthritis.