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ID PMID Title PublicationDate abstract
15853748 Inflammatory mediators as potential therapeutic targets in the spine. 2005 Apr Inflammation plays a variable part in the pathogenesis of several spinal disorders. Ankylosing spondylitis is a chronic inflammatory arthropathy of the spine and rheumatoid arthritis, whilst affecting predominantly limb joints, also affects the cervical spine in a significant proportion of people. Inflammation is also involved in disorders such as disc herniation and sciatica, which have previously been thought of as being primarily mechanical or degenerative. Anti-inflammatory agents which have been shown to be effective elsewhere in the body are discussed in this review as possible therapeutic agents in the spine. As the inflammatory cascade and immunopathology of these conditions continue to be elucidated, it has become apparent that individual molecules may be potential targets for inactivation or down-regulation. Candidates include pro-inflammatory cytokines, such as TNF-alpha, cytokines, e.g. IL-1 and IL-15, or enzymes enhancing the inflammation pathway such as the cyclooxygenases. Hence treatments based on inactivation of these molecules by various mechanisms, including antibodies, receptor antagonists, enzyme inhibitors or gene therapy, are being introduced. However, the mode of action of a particular molecule can be complex and sometimes apparently contradictory. For example, TNF-alpha is known to play an important role in promoting inflammation by upregulating expression of cell adhesion molecules on endothelial cells and stimulating the production of reactive oxygen intermediates, nitric oxide and prostaglandins. However, it can also have an immunosuppressive and anti-inflammatory role after prolonged release. Therefore, although inhibitors of many of these molecules are now in clinical application and trials (many with promising results in rheumatoid arthritis), it is important to remain vigilant and monitor long-term outcomes particularly when these treatments are used in clinical syndromes with relatively poorly defined immunopathology such as spinal disorders.
16278286 Genome scan meta-analysis of rheumatoid arthritis. 2006 Feb OBJECTIVE: Genome scans for rheumatoid arthritis (RA) have yielded inconsistent results. The absence of replication of linkage might be due to lack of power of individual studies. We performed a genome scan meta-analysis of published data to increase statistical power and to assess evidence for linkage of RA across genome scan studies. METHODS: Four RA whole-genome scans containing 767 families with 964 sibling pairs were included for the genome scan meta-analysis (GSMA). The GSMA method was applied to pool the results obtained from four genome scans. For each study, 120 genomic bins of approximately 30 centimorgans were defined and ranked according to maximum evidence for linkage within each bin. Bin ranks were weighted and summed across all studies. The summed rank for each bin was assessed empirically for significance using permutation methods. RESULTS: A total of nine bins lay above the 95% confidence level (P=0.05) and four bins were above the 99% confidence level (P=0.01) in the RA GSMA, suggesting that these bins contain RA-linked loci: bins 6.2, 6.4, 8.1, 18.3, 12.3, 12.2, 1.5, 6.3 and 16.2. The strongest evidence for linkage occurred on chromosome 6p22.3-6p21.1 (bin 6.2), containing the HLA region (P(sumrnk)=0.0000008). CONCLUSION: This RA GSMA confirmed the evidence for HLA loci as the greatest susceptibility factor to RA and showed evidence for linkage at non-HLA loci, such as chromosomes 1p, 6, 8p, 12, 16 and 18q, across studies. These data may provide a basis to carry out targeted linkage and candidate gene studies, particularly in the regions.
15712005 [Multidisciplinary treatment rheumatoid arthritis. Statistical and clinical change in pain 2005 Feb INTRODUCTION: To date only few studies have been reported on the effect of multidisciplinary inpatient treatment on pain experience in patients with rheumatoid arthritis (RA). Aims of the present research were: to asses the development of different pain qualities at the beginning, at the end of treatment and at a follow-up three months later in a RA-patient sample as a whole, to determine statistically and clinically significant changes on individual base, and to study pain coping behaviors as predictive and pain-change associated variables. METHODS: Subjects were 66 patients with a diagnosis of RA. They were treated with non-steroidal antiphlogistic and disease modifying drugs as well as with physical therapy. Measurement instruments were the pain experience scale with 5 subtests, the four-dimensional questionnaire of pain behavior, the functional disability scale, and a joint-index. RESULTS: At follow-up the reduction was strongest in the quality of persistent pain experience (effect size d: 0.54). Among sensory components a marked reduction was found for the experience of thermal pain. A statistically and clinically reliable change was assessed in 18% of he RA-patients, further 26% indicated a statistical only change. 33% remained stable at a functional level of pain experience. 12% did not change a high level of pain, and 11% deteriorated. Change in the coping behaviors of avoidance and support were associated with success in pain reduction. CONCLUSION: In the assessment of patient improvement different qualities of pain experience should be taken into account. It was suggested that inpatient multidisciplinary treatment was beneficial with regard to pain reduction in nearly on half of the RA-patients. The coping behaviors of avoidance and social support deserve attention as pain change associated variables.
17154104 [Rheumatoid arthritis and osteoporosis: trends in their treatments]. 2006 Dec Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic synovitis and bone damages, which consist of joint destruction and systemic osteoporosis. During the pathological process, pro-inflammatory cytokines such as TNF-alpha are largely produced from inflamed synovium and cause activation of osteoclasts deviated from bone remodeling cycle, resulting in joint destruction. On the other side, systemic osteoporosis, mainly caused by glucocorticoid (GC) is often complicated in RA, in which GC decreases number of osteoblasts, reduces synthesis of bone matrix proteins from them and enhances bone resorption, resulting in impairment of bone remodeling. Thus, joint destruction and systemic osteoporosis are brought about by different mechanisms. However, recent treatment strategies have improved managements of RA-related joint destruction as well as GC-induced osteoporosis. Treatments using biologics including infliximab and etanercept, effective for treating RA disease activity, also reduce joint destruction. Also, bisphosphonate is well known to be effective for not only treatment but also prevention of GC-induced osteoporosis. Thus, it is a clinical trend that physicians treat joint destruction as an inflammatory disease and osteoporosis as a metabolic disease.
17130265 Mycophenolate mofetil treatment improves hypertension in patients with psoriasis and rheum 2006 Dec Evidence that was obtained in several experimental models and in strains of hypertensive rats indicates that infiltration of inflammatory cells and oxidative stress in the kidney play a role in the induction and maintenance of hypertension. Similar evidence is lacking in human hypertension, at least in part, because immunosuppressive treatment is unjustified in patients with hypertension. For addressing this issue, patients who were prescribed by their private physicians mycophenolate mofetil (MMF) for the treatment of psoriasis or rheumatoid arthritis and had, in addition, grade I essential hypertension and normal renal function were studied. Eight patients were studied before MMF was started, during MMF treatment, and 1 mo after MMF treatment had been discontinued. Other treatments and diet were unchanged in the three phases of the study. MMF therapy was associated with a significant reduction in systolic, diastolic, and mean BP. Urinary excretion of TNF-alpha was reduced progressively by MMF treatment and increased after MMF was discontinued. Reduction of urinary malondialdehyde, TNF-alpha, and RANTES excretion during MMF administration did not reach statistical significance but had a direct positive correlation with the BP levels. These data are consistent with the hypothesis that renal immune cell infiltration and oxidative stress play a role in human hypertension.
15701693 The induction of matrix metalloproteinase and cytokine expression in synovial fibroblasts 2005 Feb 22 Rheumatoid arthritis is a chronic inflammatory disease characterized by destruction of cartilage and bone that is mediated by synovial fibroblasts. To determine the mechanisms by which these cells are activated to produce matrix metalloproteinases (MMPs), the effects of microparticles were investigated. Microparticles are small membrane-bound vesicles whose release from immune cells is increased during activation and apoptosis. Because microparticles occur abundantly in the synovial fluid in rheumatoid arthritis, they could represent novel stimulatory agents. Microparticles derived from T cells and monocytes strongly induced the synthesis of MMP-1, MMP-3, MMP-9, and MMP-13 in fibroblasts. The induction was time-dependent, with effects primarily observed after 36 h; under these conditions, MMP-2, MMP-14, and tissue inhibitor of MMP-1 (TIMP-1), TIMP-2, and TIMP-3 were not induced. Microparticles also increased the synthesis of inflammatory mediators including IL-6, IL-8, monocyte chemoattractant protein 1 (MCP-1), and MCP-2. In Ikappa-B-transfected synovial fibroblasts, MMPs were less inducible by microparticles compared with wild-type fibroblasts. Blocking of TNFalpha and IL-1beta with antibodies against TNFalpha and with IL-1 receptor antagonist did not abrogate stimulation by microparticles. These data provide evidence for a novel mechanism by which vesicles derived from activated or apoptotic immune cells can promote the destructive activity of synovial fibroblasts in rheumatoid arthritis.
16892137 [Therapeutic effect and impact on cytokine production by methotrexate in rheumatoid arthri 2006 Aug 18 OBJECTIVE: To examine the clinical benefit and impact on cytokine production by methotrexate in rheumatoid arthritis. METHODS: Thirty patients with RA were treated with oral methotrexate (mean, 15 mg per week) as monotherapy for 24 weeks. Clinical assessment using the American College of Rheumatology (ACR) criteria for improvement was performed at baseline and at the end of 2, 4, 8, 12 and 24 weeks. The pro-inflammation cytokine TNF-alpha, INF-gamma,IL-1beta, IL-6 and anti-inflammation cytokine IL-10 were measured in RA sera at baseline and after 24 weeks of therapy. RESULTS: There was remarkable improvement in disease activity following the MTX treatment. At the end of 24 weeks, the percent age of ACR20 was 70% (21/30), ACR50 30% (9/30) and ACR70 10% (3/30). The levels of IL-6 (46.83+/-35.81 vs. 20.92+/-17.98, P=0.001), TNF-alpha (162.52+/-107.63 vs. 18.32+/-14.36, P=0.026) and INF-gamma (67.79+/-43.76 vs. 35.78+/-27.51, P=0.004) were significantly higher than those of the health control at baseline, respectively. The levels of TNF-alpha (123.36+/-89.61,P=0.018), INF-gamma (41.53+/-13.49, P=0.015), IL-1beta (7.47+/-7.33, P=0.026), IL-6 (26.01+/-25.64, P=0.025) were significantly decreased after treatment with methotrexate. In contrast, IL-10 was remarkably increased (71.76+/-41.01, P=0.02). CONCLUSION: Methotrexate is effective in patients with rheumatoid arthritis. It can suppress the symptoms and joint damage. In addition, methotrexate treatment decreases the levels of pro-inflammatory cytokine, and increases the level of anti-inflammatory cytokine.
16906378 Development of interstitial pneumonia in a rheumatoid arthritis patient treated with infli 2006 Infliximab, an anti-tumor necrosis factor (TNF)-alpha antibody, was introduced to a 66-year-old woman with methotrexate (MTX)-resistant rheumatoid arthritis (RA). Although the TNF-blocking therapy was successful, she developed noninfectious interstitial pneumonia (IP) after a second infusion of infliximab. In most cases reported previously, infliximab-associated noninfectious IP occurred after a second or third infusion of infliximab, and this type of IP was more fatal in comparison with cases associated with MTX treatment alone. Keeping a sharp lookout on IP development during this period is crucial to the success of infliximab treatment. After MTX discontinuation and steroid pulse therapy, our patient made a dramatic recovery from IP.
16685139 Outcome and treatment of bucillamine-induced nephropathy. 2006 BACKGROUND: Bucillamine (BCL), a treatment for rheumatoid arthritis, occasionally causes proteinuria. Renal specimens are reported to show segmental granular deposition of immunoglobulin G, associated with membranous nephropathy. Long-term course and optimal treatment have remained unknown, and were investigated here. METHODS: We examined clinical records of 400 patients treated with BCL for rheumatoid arthritis, at our hospital from 1998 to 2003, finding 17 with proteinuria and biopsy-proven BCL-induced nephropathy. RESULTS: In all 17 patients, proteinuria resolved without loss of renal function between 3 and 85 months after discontinuing BCL (14.1 +/- 3.4). The only factor influencing time to remission was pathologic stage of membranous nephropathy (stage I vs. stage II or III: 11.5 +/- 4.8 vs. 21.6 +/- 3.3 months; p = 0.02). Maximal proteinuria, total amount of BCL, BCL exposure time, and use of prednisolone or other immunosuppressant agents did not significantly influence time until remission. CONCLUSION: The most important therapeutic step in treating BCL-induced nephropathy is to discontinue BCL. Prednisolone or other immunosuppressant agents might not be effective.
16447223 Prevention of spontaneous arthritis by inhibiting homeostatic expansion of autoreactive CD 2006 Feb OBJECTIVE: K/BxN-transgenic mice are a model of autoimmune arthritis, similar to rheumatoid arthritis. This study was undertaken to determine whether inhibition of lymphopenia-provoked homeostatic expansion can prevent spontaneous development of disease in the K/BxN model. METHODS: To inhibit homeostatic expansion of autoreactive T cells, K/BxN mice with disease in the preclinical stage were adoptively transferred with CD4+ T cells purified from nontransgenic BxN or Thy1.1+ BxN mice. To observe the profile of proliferation of CD4+ T cells derived from the hosts, carboxyfluorescein diacetate succinimidyl ester-labeled autologous CD4+ T cells were cotransferred to K/BxN mice together with BxN CD4+ T cells. Disease onset and progression were scored, and the dynamics and phenotypes of recipient CD4+ T cells were determined by flow cytometry, before and after cell infusion. RESULTS: During the preclinical phase of disease, K/BxN mice exhibited CD4+ T lymphopenia, which was followed by a compensatory expansion of these cells during the early clinical phase. The majority of CD4+ T cells acquired a memory phenotype (CD44(high),CD62L(low),CD25-), which is a hallmark of homeostatically expanding cells. Importantly, K/BxN mice subjected to syngeneic T cell transfer did not develop symptoms of arthritis and also possessed fewer transgenic T cell receptor-encoded Vbeta6+,CD4+ T cells. This effect was associated with decreased proliferation of recipient-derived CD4+ T cells but not with the function of CD25+ T regulatory cells present in donor cells. CONCLUSION: These results provide the first evidence that lymphopenia-associated homeostatic proliferation of autoreactive CD4+ T cells potentiates autoimmune arthritis, and that inhibition of this process protects mice from the development of this pathologic condition.
16639488 [Migraine in SLE: role of antiphospholipid antibodies and Raynaud's phenomenon]. 2006 Jan OBJECTIVES: To determine the role of antiphospholipid antibodies (aPL) and of Raynaud's phenomenon (RP) in the development of migraine in patients with systemic lupus erythematosus (SLE). METHODS: 50 unselected SLE patients and 20 rheumatoid arthritis (RA) controls underwent an interview to define the presence of migraine according to the guidelines of the International Headache Society (1988). Serological tests for aPL were performed in all patients. SLE patients were divided according to positivity for RP and/or aPL into 4 subsets: R-/aPL-, R-/aPL+, R+/aPL- and R+/aPL+. Data were analysed using Fisher's exact test, Chi-square test and U Mann-Whitney test. RESULTS: SLE and RA patients were similar for demographic and clinical features; aPL positivity was found in a greater proportion of SLE patients versus RA controls (68% vs 25%, p=0.0036). 31 of the 50 lupic patients (62%) and 7 of the 20 RA controls (35%) suffered from migraine (OR=3, CI:1-8.9). Among SLE and RA patients, migraine was associated with aPL positivity (p=0.027 and p=0.019). Analysing the combined effect of aPL and RP on migraine, in R+/aPL+ patients we detected an higher frequency of migraine (85.7%) with respect to the patients negative for these two features (27%, p=0.0051, OR=16, CI:2.2-118) and to the patients positive only for aPL (65%, p=0.0031, OR=6.2, CI:1.2-32). CONCLUSIONS: Migraine in SLE and RA associates with aPL positivity. The simultaneous presence of RP increases by 2,5 times the probability of having migraine, suggesting that cerebral vasospasm might be more common in patients with peripheral vasospasm, given the presence of aPL.
16927048 Fracture risk associated with use of nonsteroidal anti-inflammatory drugs, acetylsalicylic 2006 Aug We studied the effects of various nonmorphine pain medications as well as rheumatoid arthritis and osteoarthritis on fracture risk in a nationwide case-control study. Cases were all subjects with any fracture sustained during the year 2000 (n = 124,655) in Denmark. For each case, three controls (n = 373,962) matched on age and gender were randomly drawn from the background population. The primary exposure variables were use of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), or acetylsalicylic acid (ASA). Adjustments were made for several confounders. The effect of dose was examined by stratifying for cumulated dose (defined daily dose, DDD). For acetaminophen, a small increase in overall fracture risk was observed with use within the last year (odds ratio [OR] = 1.45, 95% confidence interval [CI] 1.41-1.49). For ASA, no increase in overall fracture risk was present with recent use. Significant heterogeneity was present for the NSAIDs; e.g., ibuprofen was associated with an increased overall fracture risk (OR = 2.09, 95% CI 2.00-2.18 for <20 DDD), while celecoxib was not (OR = 0.76, 95% CI 0.51-1.13 for <20 DDD, 2P < 0.01 for comparison). Osteoarthritis was associated with a decreased risk of any fracture if the diagnosis had been made more than 1 year ago (OR = 0.70, 95% CI 0.67-0.72). Rheumatoid arthritis was associated with an increase in overall fracture risk if the diagnosis had been made within the last year (OR = 1.86, 95% CI 1.68-2.07). Weak analgesics may be associated with fracture risk in a varying way. The effects in most cases were small. Falls may be one reason for the increase in fracture risk with some NSAIDs.
16435580 Artemether: a new therapeutic strategy in experimental rheumatoid arthritis. 2005 The current research was designed to determine the effect of artemether in treatment of experimental rheumatoid arthritis. Collagen-induced arthritis was induced in Lewis rats. The intramusculary administration of artemether (ART) and intraperitoneally injection of methotrexate (MTX) were started on day 25 postimmunization and continued until final assessment on day 35. During this period, clinical examination was taken intermittently. The anticollagen type II antibody (CII Ab) and nitric oxide synthesis were measured. The paws and kness were then removed for histopathology and radiography assay. The biocompatibility of ART and MTX were assessed using fibrosarcoma cell line. Data showed that i.m. injection of ART to arthritic rats induced a significant reduction in paw edema. This beneficial effect was associated with a significant decrease in anti-CII antibody response compared with untreated rats. Histopathological assessment showed a reduced inflammatory cell infiltrate in joints of treated rats; tissue edema, and bone erosion in the paws were markedly reduced following ART therapy. Furthermore, our radiography results paralleled our histological findings. Cytotoxicity analysis of ART showed greater tolerability compared with MTX. Treatment with ART significantly diminished NO formation in treated rats compared with nontreated controls. Our data shed light on the therapeutic efficacy of artemether in experimental rheumatoid arthritis compared with a choice drug (methotrexate), and it may be offered as a second-line drug in treatment of rheumatoid arthritis.
16539821 Rituximab in refractory autoimmune diseases: Brazilian experience with 29 patients (2002-2 2006 Jan OBJECTIVE: Rituximab, a monoclonal antibody against B-lymphocytes that express CD 20, is already available for the treatment of non-Hodgkin's lymphoma. Due to the increased relevance of B-cell regulation in the pathogenesis of autoimmune diseases, rituximab is being used in the treatment of patients whose condition is refractory to conventional therapy. METHODS: We retrospectively evaluated the short-term efficacy and tolerance of rituximab in patients with various autoimmune diseases who were treated at the Hospital Israelita Albert Einstein in the city of Sao Paulo. RESULTS: During the period 2002-2004, 29 patients with various autoimmune diseases were treated with rituximab 375 mg/m2 for 4 consecutive weeks, or two doses of 1 g 2 weeks apart. We observed remarkable short-term results in all cases, except for one patient with thrombocytopenic purpura. Of note, we describe the results in two patients with diseases not previously treated with rituximab (hypergammaglobulinemic purpura of Waldenstrom and eosinophilic fasciitis with hypergammaglobulinemia). Treatment was well tolerated, with no unexpected adverse events. We also observed a marked reduction in steroid dosage. CONCLUSION: Rituximab seems to be safe and effective in the treatment of patients with a variety of autoimmune diseases that are refractory to other modalities of treatment.
16793840 Imaging and serum analysis of immune complex formation of radiolabelled infliximab and ant 2007 Feb BACKGROUND: Many patients with rheumatoid arthritis are currently successfully treated with infliximab (anti-tumour necrosis factor); however, about 30% of the patients do not respond to infliximab. One of the postulated hypotheses of not responding is the fast clearance of infliximab due to the development of infliximab-anti-infliximab complexes. OBJECTIVE: To investigate the in vivo mechanism of not responding and the role of human anti-chimeric antibodies (HACAs) by using radiolabelled infliximab. METHODS: Two responding and two non-responding patients with rheumatoid arthritis, infused with radiolabelled infliximab, were investigated by both imaging and serum analysis. RESULTS: Images showed predominant presence of infliximab in blood up to 24 h, with a trend of faster blood clearance and of higher liver/spleen uptake in a non-responding patient. Clinically inflamed joints showed uptake of the drug. The HACA level in the non-responders was high (1641 and 1008 U/ml), but low or not detectable in responders. Sucrose gradients of serum showed antibody complexes in both non-responders. Various sizes of antibody complexes, including very large ones, were observed in a non-responder who developed a serious infusion reaction. CONCLUSION: Formation of infliximab-anti-infliximab complexes were found in non-responders due to the presence of large amounts of HACA. This finding, supported by both imaging and serum analysis data, may explain failure of infliximab treatment.
16802340 Increased case fatality rates following a first acute cardiovascular event in patients wit 2006 Jul OBJECTIVE: Among patients with rheumatoid arthritis (RA), cardiovascular mortality is increased compared with the rate among unaffected peers. In this study, 30-day mortality rates following a first acute cardiovascular event (myocardial infarction or stroke) were compared between RA patients and the general population. METHODS: All cases of a first acute cardiovascular event between July 1, 2001 and November 30, 2003 in Victoria, Australia were identified from hospital discharge data. Individuals were classified as having RA when an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) or an International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Australian Modification code for RA was recorded at the index admission or during the previous 5 years. Thirty-day mortality rates were determined from linkage to the state death registry. RESULTS: A total of 29,924 patients experienced a first cardiovascular event during the study period, 359 (1.2%) of whom had RA. Thirty-day cardiovascular mortality was 17.6% in RA patients versus 10.8% in non-RA patients. In fully adjusted models, the odds ratio (OR) for cardiovascular death in RA patients following a first acute cardiovascular event was 1.6 (95% confidence interval [95% CI] 1.2-2.2). Analysis of index event subgroups revealed that this increased case fatality rate in patients with RA was accounted for almost entirely by excess deaths following myocardial infarction. The adjusted ORs for cardiovascular death in RA after myocardial infarction and stroke were 1.9 (95% CI 1.3-2.7) and 1.2 (95% CI 0.7-2.0), respectively. CONCLUSION: RA patients have a substantially increased risk of 30-day case fatality following myocardial infarction, but not stroke, compared with non-RA patients. This higher case fatality rate is likely to contribute to the observed overall excess of cardiovascular deaths in RA populations.
16439435 Safety analyses of adalimumab (HUMIRA) in global clinical trials and US postmarketing surv 2006 Jul OBJECTIVE: To assess the safety of adalimumab in global clinical trials and postmarketing surveillance among patients with rheumatoid arthritis (RA). METHODS: Safety data for adalimumab treated patients from randomised controlled trials, open label extensions, and two phase IIIb open label trials were analysed. In addition, postmarketing spontaneous reports of adverse events in the United States were collected following Food and Drug Administration approval of adalimumab on 31 December 2002. RESULTS: As of 15 April 2005, the RA clinical trial safety database analysed covered 10,050 patients, representing 12,506 patient-years (PYs) of adalimumab exposure. The rate of serious infections, 5.1/100 PYs, was comparable to that reported on 31 August 2002 (4.9/100 PYs), and to published reports of RA populations naive to anti-tumour necrosis factor (TNF) therapy. Following implementation of tuberculosis (TB) screening in clinical trials, the rate of TB decreased. There were 34 cases of TB as of this analysis (0.27/100 PYs). The standardised incidence ratio for lymphoma was 3.19 (95% CI 1.78 to 5.26), consistent with the observed increased incidence in the general RA population. As of 30 June 2005, there were an estimated 78 522 PYs of exposure to adalimumab in the US postmarketing period. Seventeen TB cases were spontaneously reported (0.02/100 PYs) from the US. Rates of other postmarketing events of interest, such as congestive heart failure, systemic lupus erythematosus, opportunistic infections, blood dyscrasias, lymphomas, and demyelinating disease, support observations from clinical trials. CONCLUSION: Analyses of these data demonstrate that long term adalimumab treatment is generally safe and well tolerated in patients with RA.
15987473 Regeneration of the immunoglobulin heavy-chain repertoire after transient B-cell depletion 2005 B-cell depletive therapies have beneficial effects in patients suffering from rheumatoid arthritis. Nevertheless, the role of B cells in the pathogenesis of the disease is not clear. In particular, it is not known how the regeneration of the B-cell repertoire takes place. Two patients with active rheumatoid arthritis were treated with rituximab, and the rearranged immunoglobulin heavy-chain genes (Ig-VH) were analysed to follow the B-cell regeneration. Patient A was treated with two courses of rituximab, and B-cell regeneration was followed over 27 months by analysing more than 680 Ig-VH sequences. Peripheral B-cell depletion lasted 7 months and 10 months, respectively, and each time was accompanied by a clinical improvement. Patient B received one treatment course. B-cell depletion lasted 5 months and was accompanied by a good clinical response. B cells regenerated well in both patients, and the repopulated B-cell repertoire was characterised by a polyclonal and diverse use of Ig-VH genes, as expected in adult individuals. During the early phase of B-cell regeneration we observed the expansion and recirculation of a highly mutated B-cell population. These cells expressed very different Ig-VH genes. They were class-switched and could be detected for a short period only. Patient A was followed long term, whereby some characteristic changes in the VH2 family as well as in specific mini-genes like VH3-23, VH 4-34 or VH 1-69 were observed. In addition, rituximab therapy resulted in the loss of clonal B cells for the whole period. Our data show that therapeutic transient B-cell depletion by anti-CD20 antibodies results in the regeneration of a diverse and polyclonal heavy-chain repertoire. During the early phase of B-cell regeneration, highly mutated B cells recirculate for a short time period in both the patients analysed. The longitudinal observation of a single patient up to 27 months shows subtle intraindividual changes, which may indicate repertoire modulation.
15647772 Regulated and constitutive expression of anti-inflammatory cytokines by nontransforming he 2005 Mar Herpesviral saimiri-(HVS) mediated expression of bovine growth hormone was one of the first applications of an episomal viral vector for gene therapy. Meanwhile, the long-term persistence of HVS vectors has been confirmed in a broad spectrum of infectable target cells in vitro and in vivo. Regulated gene expression is useful for many applications of gene therapy. Therefore, we inserted the Mifepristone-antiprogestin-inducible expression system (GeneSwitchtrade mark) into HVS viral vectors to regulate the combined expression of anti-inflammatory cytokines, IL-10 and IL-1RA. Constitutive CMV-promoter/enhancer-driven and Mifepristone-inducible cytokine expression was compared in the viral context in transduced primary human fibroblasts and rheumatoid arthritis (RA) fibroblast-like cells (RASF). Long-term persistence of vector genomes was shown for both construct types. Constitutive expression was efficient and more rapid in onset than in the inducible system, in which the selective induction of interleukin expression along with low background levels was obtained by Mifepristone concentrations that were more than 1000-fold below those required for endogenous Progesterone antagonism. Furthermore, transgene expression corresponded to vector doses. Global patterns of cytokine secretion were not significantly changed due to viral transduction, indicating a rather inert behavior of the viral vector itself. In an attempt to emulate the inflammatory cytokine-enriched environment in rheumatoid arthritic joints, the function of the vectors could be demonstrated in vitro by the successful blockade of IL-1beta-stimulated matrix-metalloproteinase (MMP)-3 expression from RASF cells. Evaluation of this system in future studies, in suitable long-term SCID models of RA or in non-human primate models, will exploit the possible in vivo benefits of nontransforming HVS vectors in gene therapy.
15989779 [The study on the relationship between the tumor-like proliferation of synoviocytes and th 2005 Jul AIM: To investigate the mechanism of the tumor-like proliferation of synoviocytes in adjuvant arthritis (AA) rats. METHODS: Wistar rats were randomly divided into 2 groups, AA group and control group. Freund's complete adjuvant was injected into AA group rats to induce adjuvant arthritis. The knee synovial tissues of the rats were taken and synoviocytes were separated and cultured in vitro. The proliferation of cultured synoviocytes was measured by MTT colorimetry. Meanwhile, the mRNAs of C-myc and ODC genes in synovial tissues of the rats were detected by semi-quantitative RT-PCR. RESULTS: (1)Synoviocytes of AA rats proliferated more markedly than those of control rats (P<0.01), and exhibited a tumor-like proliferation. (2)The mRNAs of C-myc and ODC genes were obviously higher in synovial tissues of AA rats than those of control rats. CONCLUSION: The tumor-like proliferation of synoviocytes from AA rat joint might be related to the increased mRNAs of C-myc and ODC genes.