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ID PMID Title PublicationDate abstract
16872482 Macrophage migration inhibitory factor: a mediator of matrix metalloproteinase-2 productio 2006 Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by destruction of bone and cartilage, which is mediated, in part, by synovial fibroblasts. Matrix metalloproteinases (MMPs) are a large family of proteolytic enzymes responsible for matrix degradation. Macrophage migration inhibitory factor (MIF) is a cytokine that induces the production of a large number of proinflammatory molecules and has an important role in the pathogenesis of RA by promoting inflammation and angiogenesis. In the present study, we determined the role of MIF in RA synovial fibroblast MMP production and the underlying signaling mechanisms. We found that MIF induces RA synovial fibroblast MMP-2 expression in a time-dependent and concentration-dependent manner. To elucidate the role of MIF in MMP-2 production, we produced zymosan-induced arthritis (ZIA) in MIF gene-deficient and wild-type mice. We found that MMP-2 protein levels were significantly decreased in MIF gene-deficient compared with wild-type mice joint homogenates. The expression of MMP-2 in ZIA was evaluated by immunohistochemistry (IHC). IHC revealed that MMP-2 is highly expressed in wild-type compared with MIF gene-deficient mice ZIA joints. Interestingly, synovial lining cells, endothelial cells, and sublining nonlymphoid mononuclear cells expressed MMP-2 in the ZIA synovium. Consistent with these results, in methylated BSA (mBSA) antigen-induced arthritis (AIA), a model of RA, enhanced MMP-2 expression was also observed in wild-type compared with MIF gene-deficient mice joints. To elucidate the signaling mechanisms in MIF-induced MMP-2 upregulation, RA synovial fibroblasts were stimulated with MIF in the presence of signaling inhibitors. We found that MIF-induced RA synovial fibroblast MMP-2 upregulation required the protein kinase C (PKC), c-jun N-terminal kinase (JNK), and Src signaling pathways. We studied the expression of MMP-2 in the presence of PKC isoform-specific inhibitors and found that the PKCdelta inhibitor rottlerin inhibits MIF-induced RA synovial fibroblast MMP-2 production. Consistent with these results, MIF induced phosphorylation of JNK, PKCdelta, and c-jun. These results indicate a potential novel role for MIF in tissue destruction in RA.
17890271 Poly(ADP-ribose) polymerase inhibition reduces tumor necrosis factor-induced inflammatory 2008 May OBJECTIVES: To investigate the effect of poly(ADP-ribose) polymerase (PARP) inhibition on the production of inflammatory mediators and proliferation in tumour necrosis factor (TNF)-stimulated fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA). METHODS: Cultured FLS from patients with RA were treated with two PARP inhibitors, 3,4-dihydro-5-[4-1(1-piperidinyl)buthoxy]-1(2H)-isoquinolinona (DPQ) or 4-amino-1,8-naphthalimida (ANI) before TNF stimulation. PARP-1 expression was also suppressed in RA FLS by small interfering RNA (siRNA) transfection. Expression and secretion of inflammatory mediators were analysed by quantitative polymerase chain reaction and by enzyme-linked immunosorbent assay, respectively. Proliferation of RA FLS was also determined. Mitogen-activated protein kinase (MAPK) activity was analysed by western blot assay and activator protein (AP)-1 and nuclear factor (NF)kappaB binding by electrophoretic mobility shift assay. RESULTS: We show, for the first time, that PARP inhibition either with specific inhibitors or by siRNA transfection significantly reduced TNF-induced cytokine and chemokine expression in FLS from patients with RA. PARP inhibitors also decreased TNF-induced RA FLS proliferation. PARP inhibition reduced TNF-induced JNK phosphorylation and AP-1 and NF kappaB binding activities were partially impaired by treatment with PARP inhibitors or by PARP-1 knockdown. CONCLUSION: PARP inhibition reduces the production of inflammatory mediators and the proliferation of RA FLS (in response to TNF), suggesting that PARP inhibitors could have therapeutic benefits in RA.
18395773 Risk factors associated with different stages of atherosclerosis in Colombian patients wit 2008 Oct OBJECTIVES: Rheumatoid arthritis (RA) is associated with an increased prevalence of cardiovascular disease (CVD). Since atherosclerosis development is a gradual process of damage inside the artery wall, and the phenotype-genotype correlation of complex diseases may vary depending on ethnicity, we sought to investigate the influence of clinical features, routine inflammatory markers, and the genetic component of RA on different stages of atherosclerosis in northwestern Colombian patients with RA. METHODS: A group of 140 patients with RA were enrolled in this study. All patients underwent a noninvasive evaluation of endothelial function by flow-mediated vasodilation (FMV) and an assessment of carotid intima-media thickness (IMT) by high-resolution B-mode ultrasonography. The patients were classified into 3 categories: endothelial dysfunction (FMV <5%), increased IMT (0.91-1.29 mm), and plaque (IMT >1.30 mm). The risk of being in each category was assessed by investigating traditional and nontraditional cardiovascular risk factors. For each stage of atherosclerosis development, we searched for nontraditional risk factors that were significantly associated with the stage after adjusting for traditional risk factors and current age. RESULTS: Rheumatoid factor seropositivity was significantly associated with endothelial dysfunction (adjusted odds ratio, AOR = 3.0). A duration of RA >10 years (AOR = 29.0) and being a carrier of an HLA-DRB1 shared epitope allele (AOR = 4.8) were associated with atherosclerotic plaque. No association of extra-articular manifestations, anticyclic citrullinated peptide (anti-CCP3) antibodies, and tumor necrosis factor -308 polymorphism with CVD was found. CONCLUSIONS: Our results reveal the presence of RA-related risk factors for CVD which act independently of traditional risk factors. These factors can be used by clinicians to predict CVD in RA patients, and this data should assist in the development of public health policies in our population for the improvement of patient outcomes.
18606650 Increased frequency of EBV-specific effector memory CD8+ T cells correlates with higher vi 2008 Jul 15 EBV is a candidate trigger of rheumatoid arthritis (RA). We determined both EBV-specific T cell and B cell responses and cell-associated EBV DNA copies in patients with RA and demographically matched healthy virus carriers. Patients with RA showed increased and broadened IgG responses to lytic and latent EBV-encoded Ags and 7-fold higher levels of EBV copy numbers in circulating blood cells. Additionally, patients with RA exhibited substantial expansions of CD8(+) T cells specific for pooled EBV Ags expressed during both B cell transformation and productive viral replication and the frequency of CD8(+) T cells specific for these Ags correlated with cellular EBV copy numbers. In contrast, CD4(+) T cell responses to EBV and T cell responses to human CMV Ags were unchanged, altogether arguing against a defective control of latent EBV infection in RA. Our data show that the regulation of EBV infection is perturbed in RA and suggest that increased EBV-specific effector T cell and Ab responses are driven by an elevated EBV load in RA.
16220229 Systematic review of a marine nutriceutical supplement in clinical trials for arthritis: t 2006 May BACKGROUND: Nutritional supplements, such as Seatone, which contain freeze-dried tissue from the New Zealand green-lipped mussel Perna canaliculus, are sold in many countries to relieve arthritic symptoms and to aid in the regeneration of arthritic and injured joints. METHODS: Searches for all published controlled trials on the clinical effectiveness of green-lipped mussel, as a nutritional supplement with potential health benefits for arthritis, were carried out from four independent databases. No language restrictions were imposed, and the review was undertaken from extracted data and was assessed critically according to predefined criteria by the authors. RESULTS: Reports of clinical studies, using freeze-dried mussel powder, show mixed outcome measures and are not conclusive, with only two of five randomized controlled trials attesting benefits for rheumatoid and osteoarthritis patients. Similarly, animal studies have likewise yielded mixed findings. In both these cases possibly due to the lack of stabilization of the omega-3 polyunsaturated fatty acids, now known to be the basis of anti-inflammatory activity. CONCLUSION: There is little consistent and compelling evidence, to date, in the therapeutic use of freeze-dried green-lipped mussel powder products for rheumatoid or osteoarthritis treatment, particularly in comparison to other cheaper alternative nutriceutical supplements of proven efficacy. However, further investigations are necessary to determine whether green-lipped mussel supplements, such as Seatone, are therapeutic options in the management of arthritis.
16401811 Medicare coverage of tumor necrosis factor alpha inhibitors as an influence on physicians' 2006 Jan 9 BACKGROUND: Rheumatoid arthritis is a chronic debilitating disease that affects 1% of the population. Tumor necrosis factor alpha inhibitors, such as etanercept and infliximab, have revolutionized the treatment of rheumatoid arthritis by averting disability but at great financial expense, generally borne by third-party payors. Prior to implementation of the Medicare Modernization Act, Medicare reimbursed for the infusion drug infliximab but not for the self-injectable drug etanercept. To determine the impact of this differential Medicare drug coverage on physicians' prescribing behavior in clinical practice, we analyzed patterns of prescribing etanercept and infliximab for patients with rheumatoid arthritis who had public insurance compared with those who had private insurance. METHODS: We conducted an observational cohort study of 1663 patients with rheumatoid arthritis newly prescribed etanercept or infliximab after enrollment in the National Databank for Rheumatic Diseases. Univariate and multivariable analyses of patient demographic and disease characteristics were conducted to characterize predictors of the biologic drug prescribed. RESULTS: Treatment groups who received etanercept and infliximab differed in 6 of 8 demographic variables and in 8 of 10 disease variables. However, stratification by type of insurance reduced many of these differences. In multivariable analyses, type of insurance plan and demographic factors were strong predictors of differential prescribing of etanercept compared with prescribing of infliximab, whereas disease characteristics generally were not. Patients with public insurance were 30% more likely to receive infliximab than those who were privately insured (P<.001). CONCLUSIONS: Public insurance predicted prescription of infliximab, reflecting preferential Medicare reimbursement for infusion drugs. Financial considerations are influential in physicians' prescription decisions. Differential drug coverage has an impact on patient care and health care costs because it influences physicians' prescribing behavior.
16979149 Anti-cyclic citrullinated peptide (CCP) antibodies in patients with long-standing rheumato 2006 Oct OBJECTIVES: To evaluate frequency of anti-cyclic citrullinated peptide antibodies (anti-CCP) in long-standing rheumatoid arthritis (LsRA) patients and their relationship with extra-articular manifestations of rheumatoid arthritis (RA), in addition to comparing frequency of anti-CCP antibodies in early RA (ERA) and LsRA group. DESIGN AND METHODS: One hundred and fifteen consecutive RA patients were included in the study as having LsRA because their disease duration was longer than 3 years. Thirty-nine consecutive patients with RA were included in the study as having ERA (<3 years). Also, 64 individuals were included in the study as healthy controls to verify the specificity and sensitivity of anti-CCP antibodies. Anti-CCP antibody and rheumatoid factor (RF) were evaluated with enzyme-linked immunosorbent assay kits and standard nephelometry methods, respectively. Extra-articular manifestations were diagnosed by relevant criteria. RESULTS: The total number of patients with extra-articular manifestations was found to be 45 (39%). No significant difference was found between LsRA group and ERA group in terms of extra-articular manifestations. There were no differences between both groups regarding the number of patients with positive anti-CCP antibodies and the levels of anti-CCP antibodies. In LsRA group, there was a positive correlation between erosion and disease duration (r=0.24, p<0.01), between erosion and RF (r=0.29, p<0.002), and between erosion and anti-CCP antibody (r=0.21, p<0.02). Positive correlations between RF and anti-CCP antibody (r=0.32, p<0.0001), as well as between subcutaneous nodule and lung involvement (r=0.24, p<0.008), were found in the LsRA group. However, no positive correlation could be found between anti-CCP antibody positivity and extra-articular organ involvement, either cumulatively or separately. CONCLUSIONS: Although anti-CCP antibodies are associated with the severity of the disease and erosion, they do not seem to have much linkage with extra-articular manifestations of RA.
19039998 [Relationship between HLA-DR4/1 subtypes and T cell response to influenza virus hemaggluti 2008 Jul 15 OBJECTIVE: To investigate the relationship between HLA-DR4/1 subtypes and T cell response to influenza virus hemagglutinin (HA) as well as anti-HA308-317 antibodies in rheumatoid arthritis (RA). METHODS: The peripheral blood mononuclear cells (PBMCs) from 70 RA patients were cultured with HA308-317 for 5 days. T cell proliferative responses to HA308-317 were evaluated by [3H] thymidine incorporation assay. ELISA was used to detect the antibodies to HA308-317. HLA-DR4/1 subtypes were analyzed by PCR with sequence-specific primers. RESULTS: Twenty-seven of the 70 RA patients (38.6%) were positive for HLA-DR4/1 subtypes and 43 patients (61.4%) were negative for HLA-DR4/1 subtypes. In the HLA-DR4/1 positive group, T cell proliferative response to HA308-317 was observed in 17 (62.9%) RA patients and anti-HA308-317 antibodies were present in 15 RA patients (55.6%). In the HLA-DR4/1 negative group, T cell proliferative response to HA308-317 was observed in 10 (23.3%) patients and anti-HA308-317 antibodies were present in 25 (58.1% ) patients. T cell proliferative response to HA308-317 in the HLA-DR4/1 positive group was higher than in the negative group (P<0.01). However, there was no significant difference in production of antibodies to HA308-317 between the HLA-DR4/1 positive and negative groups (P>0.05). CONCLUSION: There is a relationship between HLA-DR4/1 subtypes and T cell response to HA308-317. Antibodies to HA308-317 are not associated with HLA-DR4/1 phenotype. HA308-317 peptide may be involved in the pathogenesis of RA through activating HLA-DR4/1 specific T cells.
18025202 The rheumatoid arthritis-associated autoantigen hnRNP-A2 (RA33) is a major stimulator of a 2007 Dec 1 A single intradermal injection of the mineral oil pristane in susceptible DA.1F rats induces erosive arthritis closely mimicking rheumatoid arthritis (RA). Pristane-induced arthritis (PIA) is driven by autoreactive T cells but no autoantigen has been identified to date. We therefore analyzed B and T cell responses to autoantigens potentially involved in the pathogenesis of RA, including IgG, citrullinated proteins, stress proteins, glucose-6-phosphate isomerase, and heterogeneous nuclear ribonucleoprotein (hnRNP)-A2 (RA33). IgG and IgM autoantibodies to hnRNP-A2 were detectable in sera of pristane-primed DA.1F rats already 1 wk before disease onset, reached maximum levels during the acute phase, and correlated with arthritis severity. Apart from rheumatoid factor, autoantibodies to other Ags were not observed. CD4(+) lymph node cells isolated 10 days after pristane injection produced IFN-gamma but not IL-4 in response to stimulation with hnRNP-A2, whereas none of the other candidate Ags elicited cytokine secretion. Surprisingly, hnRNP-A2 also stimulated lymph node cells of naive animals to produce inflammatory cytokines in a MyD88-dependent manner. Furthermore, hnRNP-A2 was highly overexpressed in the joints of rats injected with pristane. Overexpression coincided with the appearance of anti-RA33 Abs and preceded the onset of clinical symptoms of PIA by several days. Taken together, these data suggest hnRNP-A2 to be among the primary inducers of autoimmunity in PIA. Therefore, this Ag might play a pivotal role in the pathogenesis of PIA and possibly also human RA.
18409539 [Case of rheumatoid meningitis: findings on diffusion-weighted image versus FLAIR image]. 2008 Mar We report a 63-year-old man with rheumatoid meningitis. At 47-years-old, he developed rheumatoid vasculitis causing arthralgia and skin ulcer. Although the patient had been treated with prednisolone and cyclosporine A, headache and recurrent focal seizures of the right upper limb and generalized seizures developed. Brain magnetic resonance imaging showed high signal intensity lesions on FLAIR MRI and associated abnormal enhancement of the leptomeninges. Part of the lesions also showed patchy high signal intensity on diffusion-weighted imaging (DWI). This features may be useful for differentiating rheumatoid meningitis from subdural empyema, because the extent of the lesions on DWI matches the lesion on FLAIR imaging in patients with subdural empyema. Cerebrospinal fluid analysis revealed monocytic pleocytosis and negative findings for infection or malignancy. After intravenous administration of methylprednisolone (1,000 mg/day for 3 days), the patient showed improvements in headache, cerebrospinal fluid findings and abnormal hyperintensity on DWI. Rheumatoid meningitis is an extremely rare neurological manifestation, but careful attention should be paid even in the inactive stage of rheumatoid arthritis. This disease tends to present with unilateral supratentorial lesions. In this case, serial diffusion-weighted and FLAIR MRI was useful for following the leptomeningeal lesions.
16355402 A two-step procedure for constructing confidence intervals of trait loci with application 2006 Jan Preliminary genome screens are usually succeeded by fine mapping analyses focusing on the regions that signal linkage. It is advantageous to reduce the size of the regions where follow-up studies are performed, since this will help better tackle, among other things, the multiplicity adjustment issue associated with them. We describe a two-step approach that uses a confidence set inference procedure as a tool for intermediate mapping (between preliminary genome screening and fine mapping) to further localize disease loci. Apart from the usual Hardy-Weiberg and linkage equilibrium assumptions, the only other assumption of the proposed approach is that each region of interest houses at most one of the disease-contributing loci. Through a simulation study with several two-locus disease models, we demonstrate that our method can isolate the position of trait loci with high accuracy. Application of this two-step procedure to the data from the Arthritis Research Campaign National Repository also led to highly encouraging results. The method not only successfully localized a well-characterized trait contributing locus on chromosome 6, but also placed its position to narrower regions when compared to their LOD support interval counterparts based on the same data.
18762862 Response of early active rheumatoid arthritis to tumor necrosis factor inhibitors: evaluat 2009 Inflammatory changes (synovitis and bone marrow edema) and destructive changes (bone erosion) were evaluated by magnetic resonance imaging (MRI) in patients with rheumatoid arthritis (RA), and their relations with disease activity were assessed during treatment with tumor necrosis factor (TNF) inhibitors. Ten patients with early active RA underwent MRI at 0 and 16 weeks of TNF-inhibitor treatment. The carpal bones of the dominant hand were evaluated by the outcome measures in rheumatology clinical trials MRI score for RA. After 16 weeks, the mean disease activity score (DAS 28) decreased significantly from 5.54 to 2.70, while the number of tender joints, number of swollen joints, and inflammatory parameters were also significantly improved. The mean synovitis and marrow edema scores determined by MRI showed a significant decrease from 6.1 to 2.2 and 12.8 to 6.2, respectively, while the annual bone-erosion progression score decreased from 12.6 to 2.0. Although synovitis persisted in some patients, imaging remission was achieved in two patients. In conclusion, TNF-inhibitor therapy achieved an early decrease of disease activity and MRI revealed amelioration of joint destruction. The MRI score for RA is useful for assessing the early response to TNF inhibitors.
18799084 Osteoarthritis and rheumatoid arthritis pannus have similar qualitative metabolic characte 2008 Jul OBJECTIVE: Pannus in osteoarthritis (OA) has only recently been characterized. Little is known, however, regarding the behavior of OA pannus in vitro compared to rheumatoid arthritis (RA) pannus. The purpose of our study was to compare OA with RA pannus. METHODS: Pannus and synovial tissue co-cultures from 5 patients with OA and 5 patients with RA obtained during arthroplasty were studied. Pannus was defined as the microscopic invasive granulation tissue covering the articular surface. Tissues were cultured for 7 days and stained with Alcian Blue technique. Interleukin-1beta (IL-1beta), IL-8, IL-10, IL-12, tumor necrosis factor-alpha (TNF-alpha), and interferon gamma (IFN-gamma) were also determined in supernatants by ELISA. Cartilage oligomeric matrix protein (COMP), type II collagen, TNF-alpha, IL-10 and Ki-67 expression were also detected by immunohistochemistry. RESULTS: All patients had vascular or fibrous pannus. Synovial proliferation, inflammatory infiltrates and a decrease of extracellular matrix proteins were observed in all tissue samples. Chondrocyte proliferation was lower in OA than RA cartilage. OA synovial tissue expressed lower levels of proteoglycans than RA synoyium. Type II collagen levels were lower in OA than in RA cartilage. Significantly higher levels of IL-1beta were found in the supernatants of RA pannus compared to OA pannus (p<0.05). High but similar levels of TNF-alpha, IL-8 and TIMP-1 were detected in OA and RA pannus supernatants. IL-10, IL-12 and IFN-gamma were undetectable. CONCLUSION: RA and OA pannus had similar pro-inflammatory and anti-inflammatory cytokine profile expression. OA cartilage, synovial tissue and pannus had lower production of proteoglycans, type II collagen and IL-1beta. It remains to be elucidated why OA pannus invades the cartilage surface but does not cause the marginal erosions typically seen in RA.
18065500 The FCRL3 -169T>C polymorphism is associated with rheumatoid arthritis and shows suggestiv 2008 Sep BACKGROUND AND OBJECTIVES: The Fc receptor-like 3 (FCRL3) gene -169T>C single nucleotide polymorphism (SNP) has been reported to be associated with several autoimmune diseases (AIDs) in Japanese populations. However, association results in other populations have been conflicting. Therefore, we investigated this SNP in a Scandinavian panel of AIDs. METHODS: We genotyped patients with rheumatoid arthritis (RA; n = 708), juvenile idiopathic arthritis (JIA; n = 524), systemic lupus erythaematosus (SLE; n = 166), ulcerative colitis (UC; n = 335), primary sclerosing cholangitis (PSC; n = 365), Crohn disease (CD; n = 149), a healthy control group (n = 1030) and 425 trio families with type 1 diabetes (T1D). Statistical analysis consisted of case-control and family-based association tests. RESULTS: RA was associated with the C allele (odds ratio (OR) = 1.16, 95% CI 1.01 to 1.33) and the CC genotype (OR = 1.30, 95% CI 1.01 to 1.67) of the FCRL3 -169T>C SNP in our material. Suggestive evidence for association was also found for JIA (CC genotype: OR = 1.30, 95% CI 0.99 to 1.70), and clinical subgroup analysis indicated that this was connected to the polyarticular subgroup. No significant association was found with SLE, UC, CD, PSC or T1D. In patients with RA, we found no significant interaction between the FCRL3 -169T>C and PTPN22 1858C>T SNPs, nor between the FCRL3 -169CC genotype and IgM-rheumatoid factor or anti-cyclic citrullinated peptide titre levels. CONCLUSION: We found an association between the FCRL3 -169T>C SNP and RA, and suggestive evidence for involvement with JIA, in a Norwegian population. These findings lend support for a role for this SNP in RA across ethnically diverse populations, and warrant follow-up studies in JIA.
16622721 Adrenocorticotropic hormone and dehydroepiandrosterone sulfate levels of rheumatoid arthri 2006 To assess adrenal function with respect to the presence or absence of steroid therapy, we investigated differences in the blood levels of adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone sulfate (DHEAS) in relation to steroid (prednisolone) administration in 123 patients with rheumatoid arthritis (RA). Levels of ACTH and DHEAS were significantly lower in the steroid-treated group than in the non-treated group (ACTH: 11.79 pg/ml vs 27.92 pg/ml) (DHEAS: 418.12 ng/ml vs 883.91 ng/ml) (P<0.0001). We observed no steroid dose-related differences in ACTH levels. However, DHEAS levels showed a slight decrease at a prednisolone dose of 2.5 mg/day, with a significant decrease being observed at a dose of 5 mg/day when statistical adjustments were made for age and sex (P<0.0001). At doses of 7.5 mg/day or greater, DHEAS levels were significantly lower than those for 5 mg/day (P<0.0006). These results suggest that low-dose prednisolone reduces adrenal function in patients with RA. We recommend that doses of prednisolone should be limited to 5 mg/day or less in consideration of adrenal function when treating RA patients. The measurement of ACTH and DHEAS may be useful for evaluating adrenal function in patients with RA.
18847311 The evolution of biomarkers in rheumatoid arthritis: from clinical research to clinical ca 2008 Nov BACKGROUND: Treatment efficacy in rheumatoid arthritis (RA) has been measured by clinical response, gross radiological results and some biochemical markers. With the new biologic treatments, markers for disease development, progress, severity and therapy response have evolved. OBJECTIVES: This review focuses on a selection of current markers and the need for better markers for determining RA treatment susceptibility and success. METHODS: A review of the literature was conducted and expert opinions expressed. RESULTS/CONCLUSION: Current biomarkers mainly focus on disease activity and severity. Biomarkers for treatment response and susceptibility that help clinicians make initial treatment decisions are lacking or insufficient, yet required for optimal control of RA. A combination of biomarkers is necessary to classify a complex immune disease, such as RA.
16870092 Treatment continuation rate in relation to efficacy and toxicity in long-term therapy with 2006 May OBJECTIVE: To evaluate the effectiveness of disease-modifying antirheumatic drugs, namely, methotrexate (MTX), sulfasalazine (SSZ) and bucillamine (BUC) at low-doses (4, 6 or 8 mg MTX, 500 or 1,000 mg SSZ, and 100 or 200 mg BUC) in 1,358 patients with a follow-up of at least 12 months and more than 120 months. METHODS: Clinical assessments were based on the number of painful joints (NPJ) and that of swollen joints (NSJ), CRP level, erythrocyte sedimentation rate, rheumatoid factor level and morning stiffness before and after treatment. Results were evaluated on the basis of the duration of treatment for each drug with inefficacy or inadequate efficacy as one endpoint for discontinuation and adverse drug reactions (ADRs) as the other in single agent and combination therapy. The incidence and nature of ADRs in single and combination treatment are described. RESULTS: The effects of MTX, SSZ and BUC on clinical parameters were monitored over the first three months, and in particular, NPJs and NSJs were found to decrease significantly during single agent MTX or BUC treatment over 108 months. CRP levels remained significantly improved for more than 120 months with MTX. In the single and combination long-term treatments, continuation rate with inefficacy or inadequate efficacy as the end point achieved for each of the treatments were 83.1% for MTX, 76.0% for BUC, 68.5% for SSZ, and in the case of the combination treatments, these rates were 83.3% for MTX + BUC and 71.0% for MTX+SSZ. Continuation rates using ADRs as the end point were 88% for SSZ, 79.6% for BUC and 79.4% for MTX. The incidences of ADRs for the various treatments were: MTX 22.2%, SSZ 11.0%, BUC 20.6%, MTX + BUC 30.0% and MTX + SSZ 31.2%. CONCLUSION: MTX showed the highest efficacy even though it was administrated at a low dose (6-8 mg), as a single agent or in combination with other treatment. However, in combination treatments, the continuous duration of treatment ending in ADRs as the end point were lower than those in single treatments with MTX, SSZ and BUC.
16980213 Diversity of regulatory T cells to control arthritis. 2006 Oct During follow-up of the suppressive functions of CD4+ T helper (Th) 2 cells in recent years, the suppressive capacities of newly recognised CD4+ Th cells with more widespread suppressive potential have been extensively investigated. These Th cells, collectively termed regulatory T cells, are characterised by the secretion of specific cytokines, such as interleukin (IL)-10 (Tr1 Th cells), transforming growth factor (TGF)beta (Th3 cells) or the constitutive expression of CD25 (naturally occurring T regulatory cells, nTregs). The balance of these regulatory T cells with pro-inflammatory effector T cells, such as Th1 (interferon (IFN)gamma secreting), Th17 (IL-17 secreting) and CD25- Th cells, has been shown to be of pivotal importance for the development and persistence of autoimmune diseases. The high potential of regulatory T cells (in particular nTregs), to efficiently suppress several arthritic responses both in humans and in animal models of arthritis, make them therapeutic targets of interest in arthritic conditions such as rheumatoid arthritis.
16322085 Trends in disease modifying antirheumatic drug prescription in early rheumatoid arthritis 2006 Aug OBJECTIVE: To characterise temporal trends and factors associated with the prescription of disease modifying antirheumatic drugs (DMARDs) at the initial consultation in early rheumatoid arthritis (RA). METHODS: Data from 2584 patients with early RA at 19 hospitals were extracted from the Swedish Rheumatoid Arthritis Register for the period 1997-2001. Disease characteristics and DMARD prescription at first consultation with the rheumatologist were investigated using cross tabulation and logistic regression. RESULTS: DMARD prescriptions, particularly for methotrexate, increased from 1997 to 2001 independently of patient characteristics. Stratification by hospital type showed that patients in district hospitals were less likely to be prescribed DMARDs than those in university hospitals (adjusted odds ratio (OR) = 0.53 (95% confidence interval (CI) 0.40 to 0.69), p<0.001), independently of confounding factors. Association of the DAS28 with the likelihood of DMARD prescription was greater among patients attending district hospitals (OR = 1.65 (1.34 to 2.02), p<0.001) than those at university hospitals (OR = 1.23 (1.07 to 1.41), p = 0.003) and county hospitals (OR = 1.34 (1.01 to 1.63), p = 0.003). Interaction testing indicated that the difference was significant (p = 0.007). CONCLUSIONS: Temporal trends in DMARD prescription indicate an increasingly aggressive approach to disease management among Swedish rheumatologists. However, the association of hospital type with DMARD prescription suggests that the adoption of research findings in clinical care varies considerably.
17981914 Vaccination against influenza in patients with rheumatoid arthritis: the effect of rituxim 2008 Jul OBJECTIVE: To assess the effect of rituximab on the efficacy and safety of influenza virus vaccine in patients with rheumatoid arthritis (RA). METHODS: The study group comprised patients with RA treated with conventional disease-modifying drugs with or without rituximab. Split-virion inactivated vaccine containing 15 microg haemagglutinin/dose of B/Shanghai/361/02 (SHAN), A/New Caledonian/20/99 (NC) (H1N1) and A/California/7/04 (CAL) (H3N2) was used. Disease activity was assessed by the number of tender and swollen joints, duration of morning stiffness and evaluation of pain on the day of vaccination and 4 weeks later. CD19-positive cell levels were assessed in rituximab-treated patients. Haemagglutination inhibition (HI) antibodies were tested and response was defined as a greater than fourfold rise 4 weeks after vaccination or seroconversion in patients with a non-protective baseline level of antibodies (<1/40). Geometric mean titres (GMT) were calculated in all subjects. RESULTS: The participants were divided into three groups: RA (n = 29, aged 64 (12) years), rituximab-treated RA (n = 14, aged 53 (15) years) and healthy controls (n = 21, aged 58 (15) years). All baseline protective levels of HI antibodies and GMT were similar. Four weeks after vaccination, there was a significant increase in GMT for NC and CAL antigens in all subjects, but not for the SHAN antigen in the rituximab group. In rituximab-treated patients, the percentage of responders was low for all three antigens tested, achieving statistical significance for the CAL antigen. Measures of disease activity remained unchanged. CONCLUSION: Influenza virus vaccine generated a humoral response in all study patients with RA and controls. Although the response was significantly lower among rituximab-treated patients, treatment with rituximab does not preclude administration of vaccination against influenza.