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ID PMID Title PublicationDate abstract
18390587 Glucocorticoid treatment inhibits annexin-1 expression in rheumatoid arthritis CD4+ T cell 2008 May OBJECTIVE: Annexin-1 (Anx-A1) has been recently shown to play a key role in T-cell activation and to be highly expressed in T cells from RA patients. Here, we investigated the effects of glucocorticoids (GCs) on Anx-A1 expression in T cells in vitro and in vivo. METHODS: To evaluate the effects of dexamethasone (Dex) on Anx-A1 expression, human peripheral blood T cells were incubated with Dex and then analysed by real-time PCR and western blotting. Similar experiments were carried out in vivo by measuring Anx-A1 levels in T cells from patients with RA before and after administration of steroids. RESULTS: Incubation of T cells with Dex decreased Anx-A1 levels in a time-dependent fashion and almost abolished its expression after 12 h. Stimulation of T cells pre-incubated with Dex for 12 h with anti-CD3/CD28 led to significant reduction of IL-2 production. Addition of human recombinant Anx-A1 to Dex-treated cells reversed the inhibitory effects of the steroids on anti-CD3/CD28-induced IL-2 production. Treatment of RA patients with steroid decreased Anx-A1 expression in T cells. CONCLUSIONS: GCs suppress Anx-A1 expression in T cells in vitro and in vivo. These results provide evidence for a novel pathway by which steroids regulate the adaptive immune response and suggest that Anx-A1 may represent a target for the treatment of autoimmune diseases.
17540745 A comparison of survival of moulded monoblock and modular tibial components of 751 AGC tot 2007 May We evaluated the survival of moulded monoblock and modular tibial components of the AGC total knee replacement in patients with rheumatoid arthritis. Between 1985 and 1995, 751 knees with this diagnosis were replaced at our institution. A total of 256 tibial components were of the moulded design and 495 of the modular design. The mean follow-up of the moulded subgroup was 9.6 years (0.5 to 14.7), and that of the modular group 7.0 years (0.1 to 14.7). The groups differed significantly from each other in Larsen grade, cementing of components and patellar resurfacing, but no statistically significant difference between the survival of the components was found (Log rank test, p = 0.91). The cumulative success rate of the moulded group was 96.8% (95% confidence interval 93.6% to 98.4%) at five years and 94.4% (95% confidence interval 90.4% to 96.7%) at ten years, and of the modular group 96.2% (95% confidence interval 94% to 97.6%) and 93.6% (95% confidence interval 89.7% to 96%), respectively. Revision was required in 37 total knee replacements, the main causes were infection, pain, loosening of the tibial component and patellar problems. Survival rates for both components were satisfactory.
17330244 Interleukin-4 regulates proteoglycan-induced arthritis by specifically suppressing the inn 2007 Mar OBJECTIVE: Interleukin-4 (IL-4) is an antiinflammatory cytokine that inhibits the onset and severity of proteoglycan-induced arthritis (PGIA). To distinguish the role of IL-4 in the innate immune response versus the adaptive immune response, we generated mice with a specific deletion of the IL-4 receptor alpha-chain (IL-4Ralpha) in macrophages and neutrophils. METHODS: To obtain mice in which IL-4Ralpha is deleted in macrophages and neutrophils, we intercrossed mice carrying a loxP-flanked (floxed) IL-4Ralpha allele and Cre recombinase expressed under control of the regulatory region for the lysozyme M gene (LysM(cre) mice) with conditional IL-4Ralpha(flox/flox) mice and then mated them to complete IL-4Ralpha(-/-) mice to obtain hemizygous LysM(cre)IL-4Ralpha(flox/-) mice. LysM(cre)-negative IL-4Ralpha(flox/-) mice (IL-4Ralpha(flox/-) mice) were used as control mice. PGIA was induced by immunization with human PG in adjuvant. The onset, incidence, and severity of arthritis were monitored over time. Levels of proinflammatory cytokines were measured in the sera of PG-immunized mice, and cytokine and chemokine transcripts were measured in joints. RESULTS: The severity of PGIA was exacerbated in IL-4Ralpha(-/-) and LysM(cre)IL-4Ralpha(flox/-) mice in comparison with control (IL-4Ralpha(flox/-)) mice. The increase in arthritis susceptibility in IL-4Ralpha(-/-) and LysM(cre)IL-4Ralpha(flox/-) mice correlated with elevated serum levels of the proinflammatory cytokines IL-1beta and IL-6 and with elevated cytokine (IL-1beta and IL-6) and chemokine (macrophage inflammatory protein 1alpha [MIP-1alpha] and MIP-2) transcripts from joints. However, arthritis susceptibility did not correlate with IL-2 or interferon-gamma (IFNgamma) concentrations or with PG-specific antibody IgG2a isotype, since levels of IL-2, IFNgamma, or PG-specific antibody IgG2a isotype in control (IL-4Ralpha(flox/-)) and LysM(cre)IL-4Ralpha(flox/-) mice were reduced in comparison with those in IL-4Ralpha(-/-) mice. CONCLUSION: These findings indicate that IL-4 functions as a major antiinflammatory cytokine in PGIA by governing the activity of macrophages/neutrophils and less so by controlling T cell activity and autoantibody isotype expression.
17645792 Identification of an altered peptide ligand based on the endogenously presented, rheumatoi 2007 We sought to identify an altered peptide ligand (APL) based on the endogenously expressed synovial auto-epitope of human cartilage glycoprotein-39 (HC gp-39) for modulation of cognate, HLA-DR4-restricted T cells. For this purpose we employed a panel of well-characterized T cell hybridomas generated from HC gp-39-immunized HLA-DR4 transgenic mice. The hybridomas all respond to the HC gp-39(263-275) epitope when bound to HLA-DR4(B1*0401) but differ in their fine specificities. First, the major histocompatibility complex (MHC) and T-cell receptor (TCR) contact residues were identified by analysis of single site substituted analogue peptides for HLA-DR4 binding and cognate T cell recognition using both T hybridomas and polyclonal T cells from peptide-immunized HLA-DR4 transgenic mice. Analysis of single site substituted APL by cognate T cells led to identification of Phe265 as the dominant MHC anchor. The amino acids Ala268, Ser269, Glu271 and Thr272 constituted the major TCR contact residues, as substitution at these positions did not affect HLA-DR4(B1*0401) binding but abrogated T cell responses. A structural model for visualisation of TCR recognition was derived. Second, a set of non-classical APLs, modified at the MHC key anchor position but with unaltered TCR contacts, was developed. When these APLs were analysed, a partial TCR agonist was identified and found to modulate the HC gp-39(263-275)-specific, pro-inflammatory response in HLA-DR4 transgenic mice. We identified a non-classical APL by modification of the p1 MHC anchor in a synovial auto-epitope. This APL may qualify for rheumatoid arthritis immunotherapy.
18794853 Common variants at CD40 and other loci confer risk of rheumatoid arthritis. 2008 Oct To identify rheumatoid arthritis risk loci in European populations, we conducted a meta-analysis of two published genome-wide association (GWA) studies totaling 3,393 cases and 12,462 controls. We genotyped 31 top-ranked SNPs not previously associated with rheumatoid arthritis in an independent replication of 3,929 autoantibody-positive rheumatoid arthritis cases and 5,807 matched controls from eight separate collections. We identified a common variant at the CD40 gene locus (rs4810485, P = 0.0032 replication, P = 8.2 x 10(-9) overall, OR = 0.87). Along with other associations near TRAF1 (refs. 2,3) and TNFAIP3 (refs. 4,5), this implies a central role for the CD40 signaling pathway in rheumatoid arthritis pathogenesis. We also identified association at the CCL21 gene locus (rs2812378, P = 0.00097 replication, P = 2.8 x 10(-7) overall), a gene involved in lymphocyte trafficking. Finally, we identified evidence of association at four additional gene loci: MMEL1-TNFRSF14 (rs3890745, P = 0.0035 replication, P = 1.1 x 10(-7) overall), CDK6 (rs42041, P = 0.010 replication, P = 4.0 x 10(-6) overall), PRKCQ (rs4750316, P = 0.0078 replication, P = 4.4 x 10(-6) overall), and KIF5A-PIP4K2C (rs1678542, P = 0.0026 replication, P = 8.8 x 10(-8) overall).
18462498 Genetic polymorphisms in PTPN22, PADI-4, and CTLA-4 and risk for rheumatoid arthritis in t 2008 INTRODUCTION: PTPN22, PADI-4, and CTLA-4 have been associated with risk for rheumatoid arthritis (RA). We investigated whether polymorphisms in these genes were associated with RA in Caucasian women included in two large prospective cohorts, adjusting for confounding factors and testing for interactions with smoking. METHODS: We studied RA risk associated with PTPN22 (rs2476601), PADI-4 (rs2240340), and CTLA-4 (rs3087243) in the Nurses' Health Study (NHS) and NHSII. Participants in NHS were aged 30 to 55 years at entry in 1976; those in NHSII were aged 25 to 42 years at entry in 1989. We confirmed incident RA cases through to 2002 in NHS and to 2003 in NHSII by questionnaire and medical record review. We excluded reports not confirmed as RA. In a nested case-control design involving participants for whom there were samples for genetic analyses (45% of NHS and 25% of NHSII), each incident RA case was matched to a participant without RA by year of birth, menopausal status, and postmenopausal hormone use. Genotyping was performed using Taqman single nucleotide polymorphism allelic discrimination on the ABI 7900 HT (Applied Biosystems, 850 Lincoln Centre Drive, Foster City, CA 94404 USA) with published primers. Human leukocyte antigen shared epitope (HLA-SE) genotyping was performed at high resolution. We employed conditional logistic regression analyses, adjusting for smoking and reproductive factors. We tested for additive and multiplicative interactions between each genotype and smoking. RESULTS: A total of 437 incident RA cases were matched to healthy female control individuals. Mean (+/- standard deviation) age at RA diagnosis was 55 (+/- 10), 57% of RA cases were rheumatoid factor (RF) positive, and 31% had radiographic erosions at diagnosis. PTPN22 was associated with increased RA risk (pooled odds ratio in multivariable dominant model = 1.46, 95% confidence interval [CI] = 1.02 to 2.08). The risk was stronger for RF-positive than for RF-negative RA. A significant multiplicative interaction between PTPN22 and smoking for more than 10 pack-years was observed (P = 0.04). CTLA-4 and PADI-4 genotypes were not associated with RA risk in the pooled results (pooled odds ratios in multivariable dominant models: 1.27 [95% CI = 0.88 to 1.84] for CTLA-4 and 1.04 [95% CI = 0.77 to 1.40] for PADI-4). No gene-gene interaction was observed between PTPN22 and HLA-SE. CONCLUSION: After adjusting for smoking and reproductive factors, PTPN22 was associated with RA risk among Caucasian women in these cohorts. We found both additive and multiplicative interactions between PTPN22 and heavy cigarette smoking.
19028128 Regulatory T cells (Treg) in rheumatoid arthritis. 2009 Jan Modulation of the T-cell response depends chiefly on regulatory T cells (Treg), which express CD4 and CD25. Some Treg cells are present naturally, whereas others are induced in response to antigens. The immunomodulating effects of Treg cells are mediated by membrane molecules (e.g., CTLA4, GITR, and OX40) and cytokines. IL-35 seems to be a crucial mediator, although IL-10 and TGFbeta are also important. The role for Treg cells in rheumatoid arthritis (RA) has been established in both patients and animal models. Treg function is deficient in RA, whereas Treg counts vary. Treg counts increase in patients who are responding to TNFalpha antagonist therapy. Among current hypotheses, Treg expansion or transfer may hold promise for the treatment of RA.
19180723 Effect of an intensive hand exercise programme in patients with rheumatoid arthritis. 2008 Sep The aim of this study was to test the effect of an intensive hand exercise programme in patients with rheumatoid arthritis (RA). Designed as a clinical controlled trial, the first 30 participants received a conservative exercise programme (CEP), while the next 30 received an intensive exercise programme (IEP). Outcomes were assessed at baseline, and after 2 and 14 weeks. Hand strength, measured as grip strength and pinch strength, was the primary outcome variable. Secondary outcomes were joint mobility, hand pain, and functional ability. After two weeks, there were significant differences between the groups in favour of the IEP in pinch strength in the dominant hand (p = 0.01), as well as grip and pinch strength in the non-dominant hand (p = 0.04 and 0.05, respectively). After 14 weeks, there was a significant difference between the two groups in grip strength in the non-dominant hand (p = 0.04), again in favour of the IEP. There was a trend towards increased pain in the CEP group and towards decreased pain in the IEP group, with significant differences between the groups in several measures of pain after 2 and 14 weeks. However, there were few significant differences between the two groups regarding joint mobility and functional ability. The results indicate that, compared with a traditional programme, an intensive hand exercise programme is well tolerated and more effective in improving hand function in patients with RA.
16934964 The metabolic syndrome, omega-3 fatty acids and inflammatory processes in relation to schi 2006 Oct Although schizophrenia is normally regarded as a brain disease, there is clear evidence that schizophrenia is strongly associated with a variety of physical conditions. These include an increased rate of the metabolic syndrome and its physical complications including diabetes and coronary heart disease, and a reduced rate of rheumatoid arthritis. It is argued that these associations may point to a commonality of some aetiological factors. Evidence implicating omega-3 fatty acids in all of these disorders is presented. The associations may derive either from genetic or from environmental factors, including nutrition. Further investigation of these associations may give important clues regarding the aetiology of schizophrenia.
18466681 Safety and efficacy of T-614 in the treatment of patients with active rheumatoid arthritis 2008 Apr 5 BACKGROUND: A novel anti-rheumatic drug, T-614, has been shown to have an anti-inflammatory effect and to improve abnormal immunological findings in rheumatoid arthritis (RA). To assess the safety and efficacy of T-614 versus placebo in patients with active RA we conducted a 24-week clinical study in 280 Chinese patients. METHODS: In a multicenter, randomized, double blind, placebo controlled study, 280 patients were randomly assigned to receive placebo (n = 95) or T-614 at 50 mg (n = 93) or 25 mg (n = 92) daily. Active disease was defined by 4 of the following 5 criteria: >or= 5 tender joints, >or= 3 swollen joints, morning stiffness lasting for >or= 60 minutes, and Westergren erythrocyte sedimentation rate (ESR) >or= 28 mm/h, the assessment of pain at the rest by patient as moderate or severe. Clinical and laboratory parameters were analyzed at baseline, 2, 4, 6, 12, 18 and 24 weeks. The primary efficacy variable at week 24 was the American College of Rheumatology (ACR) response rate using the intent-to-treat population. RESULTS: The ACR response rate was significantly higher in the T-614 treatment group compared with the placebo group within 8 weeks after the initiation of treatment. After 24 weeks, the 25 mg/d and 50 mg/d dosage groups and the placebo group showed 39.13%, 61.29% and 24.21% in ACR20 and 23.91%, 31.18% and 7.37% in ACR50, respectively. A time-response in ACR response was observed, with clear superiority for the 25 mg/d and 50 mg/d dosage groups compared to placebo (P < 0.0001), and the 50 mg/d dose compared to the 25 mg/d dose (P < 0.05) when using the ACR response analyses after 24 weeks. ESR and c-reactive protein (CRP) were significantly different in the treatment groups after 24 weeks. The incidence of adverse events (AEs) was not significantly higher with T-614 than with placebo, but upper abdominal discomfort, leucopenia, elevated serum alanine aminotransferase (sALT), skin rash and/or pruritus were more common in the 50 mg and 25 mg dosage groups. CONCLUSION: T-614, a new slow-acting drug, is effective in treatment of rheumatoid arthritis and is well tolerated.
18087673 Replication of reported genetic associations of PADI4, FCRL3, SLC22A4 and RUNX1 genes with 2008 We conducted population-based association tests for the four selected SNPs (rs2240340/padi4_94, rs7528684/fcrl3_3, rs3792876/slc2F2 and rs2268277/runx1) previously reported to be associated with rheumatoid arthritis (RA). The study population consisted of 950 unrelated Japanese subjects with RA and 507 controls, none of whom had previously been tested for these variants. Only the SNP rs2240340/padi4_94 was modestly associated with RA [allele odds ratio (OR) 1.22, 95% confidence interval (CI) 1.04-1.43, P=0.012]. The most significant association effect was found for genotype contrast between minor and major allele homozygotes (OR 1.53, 95% CI 1.10-2.12, P=0.010). No other SNPs showed a statistically significant association with RA in our population. Meta-analysis of published studies and our new data confirmed a highly significant association between PADI4 gene SNPs and increased risk of RA in East Asian populations (allele fixed-effects summary OR 1.31, 95% CI 1.22-1.41, P<0.0001). We found some evidence for an association of either rs7528684/fcrl3_3 or rs3792876/slc2F2 with RA; however, because the magnitudes of effects were apparently much weaker than those reported in the initial positive reports, and there were substantial levels of inter-study OR heterogeneity, we concluded that additional studies are needed to fully understand the present results.
18077428 Protective effect of noninherited maternal HLA-DR antigens on rheumatoid arthritis develop 2007 Dec 11 Rheumatoid arthritis (RA) is a complex genetic disorder in which the HLA-region contributes most to the genetic risk. HLA-DRB1-molecules containing the amino acid sequence DERAA (i.e., HLA-DRB1*0103, *0402, *1102, *1103, *1301, *1302, and *1304) are associated with protection from RA. It has been proposed that not only inherited but also noninherited HLA-antigens from the mother (NIMA) can influence RA-susceptibility. Up to now, no protective NIMAs were described. Here, we studied whether DERAA-containing HLA-DRB1-alleles as NIMA are associated with a protective effect. One hundred seventy-nine families were studied, 88 from the Netherlands and 91 from the United Kingdom. The frequency of DERAA-containing HLA-DRB1-alleles of the Dutch mothers (16.1%), but not of the fathers (26.2%), was lower compared with the general Dutch population (29.3%; P = 0.02). This was replicated in the English set of patients and controls (P = 0.01). Further, of all families, 45 contained at least one DERAA-negative child with RA and at least one DERAA-positive parent. The odds for the DERAA-negative RA patients of having a DERAA-positive mother was significantly lower compared with having a DERAA-positive father (OR 0.25; P = 0.003). These data show a protective NIMA-effect in a human autoimmune disease and indicate that a DERAA-positive mother can transfer protection against RA to her DERAA-negative child.
17322150 Pharmacokinetics and safety of golimumab, a fully human anti-TNF-alpha monoclonal antibody 2007 Mar Golimumab is a fully human antitumor necrosis factor alpha (TNF-alpha) monoclonal antibody that is being developed for intravenous and subcutaneous administration. To assess the pharmacokinetics and safety of the intravenous formulation of golimumab, 36 adult subjects with rheumatoid arthritis were randomly assigned to receive a single infusion of placebo or golimumab (0.1, 0.3, 1, 3, 6, or 10 mg/kg). Serum concentrations of golimumab were determined using a validated enzyme-linked immunosorbent assay method. In addition to the noncompartmental analysis and compartmental modeling, a population pharmacokinetics analysis using NONMEM was also conducted. Both the maximum serum concentration and the area under the serum concentrationtime curve appeared to increase in a dose-proportional manner. The median half-life ranged from 7 to 20 days. A 2-compartment population pharmacokinetic model adequately described the pharmacokinetics of golimumab. The following pharmacokinetic parameters (typical value [% coefficient of variation]) were estimated from the population pharmacokinetic model: clearance (CL: 0.40 [10.1%] L/d), volume of distribution in the central compartment (V(c): 3.07 [6.4%] L), intercompartmental clearance (Q: 0.42 [15.5%] L/d), and volume of distribution in the peripheral compartment (V(p): 3.68 [11.8%] L). Interindividual variability of the pharmacokinetic parameters was quantified for CL (44.3%), V(c) (25.5%), Q (44.6%), and V(p) (44.6%). Residual variability was estimated to be 15.0%. Body weight was found to be an important covariate on V(c). Golimumab was generally well tolerated. The pharmacokinetics of golimumab appeared to be linear over the dose range evaluated in this study.
17314215 Anti-malarial agent artesunate inhibits TNF-alpha-induced production of proinflammatory cy 2007 Jun OBJECTIVES: Recent studies indicate that the anti-malarial agent artemisinin and its derivatives may exert an anti-inflammatory effect. In this study, we explored the effect of artesunate, an artemisinin derivative, on tumour necrosis factor (TNF)-alpha-induced production of interleukins, IL-1beta, IL-6 and IL-8, in human rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS), and further investigated the signal mechanism by which this compound modulates those cytokines' production. METHODS: RA FLS obtained from patients with active RA were stimulated with TNF-alpha and incubated with artesunate, and IL-1beta, IL-6 and IL-8 production was measured by ELISA. DNA-binding activity and nuclear translocation of nuclear factor kappa B (NF-kappaB) were measured by a sensitive multi-well colourimetric assay and confocal fluorescence microscopy, respectively. Signal transduction proteins expression was measured by western blot. RESULTS: Artesunate decreased the secretion of IL-1beta, IL-6 and IL-8 from TNF-alpha-stimulated RA FLS in a dose-dependent manner. Artesunate also prevented TNF-alpha-induced nuclear NF-kappaB translocation, DNA-binding activity and gene transcriptional activity, as well as phosphorylation and degradation of IkappaBalpha, but phosphorylation of p38 mitogen-activated protein kinase, extracellular signal-regulated kinase and c-Jun N-terminal kinase were unaffected. The production of IL-1beta, IL-6 and IL-8 induced by TNF-alpha was decreased by pyrrolidine dithiocarbamate (PDTC), a chemical inhibitor of NF-kappaB. These observations suggest that artesunate inhibits production of IL-1beta, IL-6 and IL-8 through inhibition of NF-kappaB signalling pathway. We also showed that artesunate prevented Akt phosphorylation. TNF-alpha-induced production of IL-1beta, IL-6 and IL-8 was hampered by treatment with the phosphatidylinositol 3 (PI3) kinase inhibitor LY294002, suggesting that inhibition of Akt activation might inhibit IL-1beta, IL-6 and IL-8 production induced by TNF-alpha. CONCLUSIONS: Our results indicate that artesunate exerts an anti-inflammatory effect in RA FLS and provide the evidence that artesunate may have therapeutic potential for RA.
16673131 Anemia in rheumatoid arthritis: high prevalence of iron-deficiency anemia in Indian patien 2006 Oct Anemia in rheumatoid arthritis (RA) is multi-factorial. We studied the prevalence and type of anemia and its correlation with disease variables in RA patients. Among patients with RA anemia was defined as hemoglobin
17938929 Telomerase activity in connective tissue diseases: elevated in rheumatoid arthritis, but m 2008 Apr Telomerase is a reverse transcriptase enzyme contributing to the maintenance of the telomeric structure by adding telomere repeat sequences to chromosomal ends, thus compensating for its shortening. Telomerase activity which is common in cancers and human germ line tissue, may also be increased, although to a lesser extent, in systemic autoimmune diseases. We aimed to evaluate telomerase activity in a group of Turkish patients with various connective tissue diseases. In this cross sectional study, 19 patients with systemic sclerosis (SSc), 15 with systemic lupus erythematosus (SLE), 10 with rheumatoid arthritis (RA) and 14 with primary Sjögren's syndrome (pSjS) were studied. As the control group, 29 healthy subjects were also included. Human telomerase-specific reverse transcriptase (hTERT) was measured in peripheral blood lymphocytes, using online real-time reverse-transcriptase polymerase chain reaction (PCR). We also investigated if hTERT values in each patient group were correlated with clinical parameters and disease activity. Highest hTERT values were observed in RA group (21.24 +/- 28.54), followed by SLE (13.38 +/- 26.05) and pSjS (11.73 +/- 10.59) groups. Only hTERT values in RA group was significantly higher than the healthy control group (7.62 +/- 4.21) (p < 0.05). Interestingly, hTERT values in SSc were very low (2.09 +/- 3.18), even less than the healthy control group. In consistent with previous studies, telomerase activity was increased in SLE and RA. Very low telomerase activity in SSc group was rather surprising. Since existing telomerase data in SSc was limited and telomere shortening was previously reported in SSc, our finding of low telomerase activity in SSc group deserves relevant discussion and further studies.
18484699 A new disease activity index for rheumatoid arthritis: Mean Overall Index for Rheumatoid A 2008 Aug OBJECTIVE: To develop a continuous composite index of disease activity for rheumatoid arthritis (RA) based on the 7 American College of Rheumatology (ACR) core data set of disease activity measures: Mean Overall Index for Rheumatoid Arthritis (MOI-RA). METHODS: The MOI-RA is the mean of standardized values of tender and swollen joint counts (28, 42, or 66/68 joint counts), physical function (Health Assessment Questionnaire 0-3), patient's and physician's assessments of global health and patient's assessment of pain (visual analog scale 0-100 mm) and erythrocyte sedimentation rate (1-100). All the 7 components were standardized (0-100), and the mean of standardized values was calculated. The range of MOI-RA is 0-100; higher values indicate poorer outcomes. The validity and measurement properties of MOI-RA were analyzed in 169 patients in the Finnish RA Combination therapy trial. RESULTS: The mean MOI-RA28 decreased from 38.5 to 13.3 [standardized response mean (SRM) = 1.8, effect size (ES) = 1.9] from baseline to 6 months, compared to Disease Activity Score (DAS) 28, which decreased from 5.55 to 2.77 (SRM = 2.0, ES = 2.8). Correlation between MOI-RA28 and DAS28 was 0.90. When compared to the ACR response categories (20/50/ACR remission), changes in MOI-RA versions (using 28/42/66 joints) were similar. The reproducibility of MOI-RA with different joint counts was 0.97. A simulation in which 15% of the component values of MOI-RA were randomly omitted indicated an intraclass correlation coefficient of 0.98 between incomplete and complete data. CONCLUSION: MOI-RA is a simple and feasible index based on the ACR core data set of disease activity measures for assessment of disease activity and treatment response in RA trials and clinical settings.
18463945 Efficacy of low-dose tacrolimus added to methotrexate in patients with rheumatoid arthriti 2008 The aim of this study was to assess if low-dose tacrolimus is efficacious for the treatment of rheumatoid arthritis (RA) when combined with methotrexate (MTX). The clinical courses of 32 RA patients who received tacrolimus plus MTX were analyzed retrospectively. Disease activity and clinical response were evaluated by DAS28 (disease activity score of 28 joints) and EULAR (European League Against Rheumatism) response criteria. Tacrolimus was started at 1 mg/day in five patients, 1.5 mg/day in 24 patients, and three mg/day in 3 patients. At six months, tacrolimus was continued at 1-2 mg/day in 27 of 32 patients, but was discontinued in five cases who showed no or inadequate response. Of the 32 patients, 47% were evaluated as having a moderate or good response at one month of tacrolimus therapy, and 72% at six months. No serious adverse events were observed. Our results suggest that the addition of tacrolimus at low dose to MTX for the treatment of patients with moderately active RA appears to be highly efficacious. Further studies are required for the appropriate use of this expensive immunosuppressant in the treatment of RA.
18414783 A case of rheumatoid arthritis complicated by demyelination in both cerebral cortex and sp 2008 Tumor necrosis factor (TNF) antagonists, including etanercept, have been approved for the treatment of rheumatoid arthritis (RA). These agents are not free of adverse events like other antirheumatic agents. Several important adverse events in CNS lesions have been reported. In this paper, we report on one patient with RA that had complications from a demyelinating disorder during TNF-blockade therapy using etanercept at 24 months after initial administration. A 66-year-old Japanese woman was diagnosed with RA in 1959. She received various disease-modifying antirheumatic drugs (DMARDs), but all of these agents were ineffective. She was administered etanercept in June 2005, and stayed well. Twenty-four months after the initial administration of etanercept, she developed palsy of bilateral upper extremities and gait disturbance subacutely, and was then admitted to our institute in August 2007. MRI of her spinal cord revealed a high-intensity lesion from the third through to the seventh cervical (C3-C7) levels. Additionally, T2-weighted MRI images showed disseminated high-intensity lesions in the white matter of brain. She was suspected of having a demyelinating disorder based on these MRI findings. There was no significant finding that pointed to another neurological disorder. High-dose corticosteroid therapy was conducted and was effective for her.
18287875 Antitumor necrosis factor-alpha therapy and potential cancer inhibition. 2008 Apr Tumor necrosis factor-alpha (TNF-alpha) has been implicated in the pathogenesis of cancer, mainly in the context of chronic inflammation. Recent publications, however, have reported an increased risk of lymphoma in rheumatoid arthritis patients treated with immunomodulatory TNF-alpha blockers. To assess the role of TNF-alpha in neoplasia, a review of TNF-alpha effects on experimental and human cancer and the influence of anti-TNF-alpha therapy on cancer development was conducted. TNF-alpha produces a variety of cellular responses which, with sustained increased levels of activity, could either facilitate or inhibit tumorigenesis. In experimental models, most evidence supports the potential enhancement of neoplasia by TNF-alpha. The increased frequency of lymphoma that has been reported in patients with rheumatoid arthritis treated with anti-TNF-alpha therapy may reflect the severity of the disease, which could be associated with greater TNF-alpha activity. Skin cancer is also reported to be increased in some studies. Other findings, to the contrary, suggest that TNF-alpha inhibition could impede tumorigenesis. It is concluded that the presently available data do not permit a robust conclusion on the potential effects of anti-TNF-alpha therapy on the risk of human neoplasia, but reduction in neoplasia seems probable. Further investigation of this important topic is clearly warranted.