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ID PMID Title PublicationDate abstract
20039432 Antibodies to several citrullinated antigens are enriched in the joints of rheumatoid arth 2010 Jan OBJECTIVE: High titers of specific anti-citrullinated protein antibodies (ACPAs) are frequently present in the serum of rheumatoid arthritis (RA) patients, but their presence in synovial fluid is less well characterized. The purpose of this study was to compare the levels of antibody to 4 well-defined citrullinated candidate RA autoantigens in serum and synovial fluid and to determine whether antibodies to one citrullinated antigen are dominant over another. Furthermore, we studied their relationships with mutated citrullinated vimentin (MCV), a newly identified RA-specific serum assay, and the classic cyclic citrullinated peptide (CCP) in the synovial fluid of well-defined HLA-DR groups. METHODS: Paired serum and synovial fluid samples from 290 RA patients and serum samples from 100 age- and sex-matched healthy controls were analyzed for the presence of anti-MCV and anti-CCP antibodies and for reactivity to citrullinated fibrinogen, alpha-enolase, type II collagen, and vimentin. A total of 219 of the 290 patients were genotyped for the HLA-DR shared epitope alleles. RESULTS: Significantly higher proportions of antibodies against all RA-associated citrullinated antigens were found in synovial fluid as compared with serum. This was also true for the MCV and CCP responses but not for non-RA-associated anti-tetanus toxoid antibodies. As expected, we found a high correlation between citrullinated vimentin and MCV responses. All synovial fluid ACPAs were predominantly associated with HLA-DRB1*04 alleles and were confined to the CCP+/MCV+ subset of patients. CONCLUSION: MCV and CCP positivity represent a similar subset of RA patients, whereas ACPAs with different fine specificities fall into subgroups of anti-CCP+/anti-MCV+ patients. The levels of all specific ACPAs were elevated in synovial fluid, suggesting that there is local antibody production and/or retention of ACPAs at the site of inflammation governed by RA-predisposing genes.
19714631 Outside-to-inside signaling through transmembrane tumor necrosis factor reverses pathologi 2009 Sep OBJECTIVE: Monocytes are a major source of proinflammatory cytokines in rheumatoid arthritis (RA), and inhibitors of monocytic cytokines are highly efficient agents for treatment of the disease. The aim of this study was to analyze the effects of a therapeutic anti-tumor necrosis factor alpha (anti-TNFalpha) antibody on monocytes from patients with RA and healthy control subjects. METHODS: Peripheral blood monocytes from patients with RA and healthy control subjects were incubated in the presence of anti-TNFalpha antibody or IgG. Annexin V staining, caspase activation, poly(ADP-ribose) polymerase cleavage, and DNA staining with propidium iodide were used to analyze apoptosis. The signaling events elicited in monocytes by infliximab were analyzed by Western blotting and electromobility shift assay. RESULTS: Peripheral blood monocytes from patients with RA were characterized by increased expression of transmembrane TNFalpha, spontaneous in vitro production of interleukin-1beta (IL-1beta), and a decreased rate of spontaneous ex vivo apoptosis. Incubation with infliximab induced significantly increased apoptosis in monocytes from patients with RA but not in monocytes from healthy control subjects. This apoptosis was triggered by reverse signaling of transmembrane TNF after ligation by infliximab and was independent of caspase activation. Instead, transmembrane TNF reverse signaling inhibited the constitutive NF-kappaB activation in RA monocytes, suppressed IL-1beta secretion, and normalized spontaneous in vitro apoptosis. This normalization was reversible by the addition of exogenous IL-1beta. CONCLUSION: This study demonstrates that outside-to-inside signaling through transmembrane TNF after ligation by infliximab inhibits constitutive NF-kappaB activation and suppresses spontaneous IL-1beta production by monocytes from patients with RA. Besides the induction of monocyte apoptosis, this inhibition could also contribute to the therapeutic effects observed during treatment with TNFalpha inhibitors.
19627955 Exploratory analysis of the relationships between aerobic capacity and self-reported fatig 2009 Jul OBJECTIVE: To determine if self-reported levels of physical activity and fatigue are related to peak oxygen uptake (VO(2peak)) and whether these relationships differ among the patient groups (rheumatoid arthritis [RA], polymyositis [PM], and chronic fatigue syndrome [CFS]). DESIGN: Correlational investigation. SETTING: Two ambulatory research clinics at the National Institutes of Health, Clinical Center, Bethesda, MD. PARTICIPANTS: There were 9 patients with PM, 10 with RA, and 10 with CFS. All patients met case criteria for their respective diagnoses. METHODS/MAIN OUTCOME MEASUREMENTS: VO(2peak) during bicycle ergometry and self-reported fatigability, fatigue, and physical activity. VO(2peak) was used as the criterion measurement of physiological fatigue with which the self-reported variables were compared. RESULTS: The Pearson r revealed that self-reported physical activity correlated with VO(2peak) (r = 61, P = .01). However, fatigability and fatigue did not correlate with VO(2peak). Linear regression analysis was performed to assess the effects of diagnosis group, self-reported activity level or fatigue, and their interaction. A trend in the data showed a distinctive relationship between fatigue/fatigability within the 3 groups. In addition, when controlling for group status, self-reported activity predicted aerobic capacity as measured by VO(2peak). CONCLUSIONS: This study confirms that patients with chronic, but stable RA, PM, or CFS are fatigued and have significantly decreased aerobic capacity. Self-reports of physical activity predicted VO(2peak), and may be used as an indicator of activity-based aerobic capacity. Self-reports of fatigue, however, did not correlate with VO(2peak) and hence are assessing something other than an index of aerobic capacity, and provide additional information about patients' perceptions, which will require further investigation.
20085177 Traditional herbal medicines (Kampo) for patients with rheumatoid arthritis receiving conc 2010 Jan OBJECTIVE: To assess the clinical effectiveness and safety of traditional herbal medicines (THM: Kampo) used in combination with oral methotrexate (MTX) in order to control the disease activity of rheumatoid arthritis (RA) in patients whose disease remains active despite treatment with MTX. METHODS: Patients (n=13; male:female = l:12) with RA who achieved only a suboptimal response to MTX therapy (> or =6 mg/week and > or =6 months) were enrolled in this assessment. All patients were treated with Keishinieppiittokaryojutsubu (KER; decoction) according to the traditional diagnostic system. Every 3 months, joint symptoms were examined, and routine blood analysis and general serological tests including anticyclic citrullinated peptide antibody (aCCP) were performed, and then we calculated the disease activity score of 28 joints (DAS28). RESULTS: One patient withdrew from the study after 4 weeks and discontinued consultations with our department for unknown reasons. Five (41.7%) of the twelve patients were defined as responders, and seven patients (58.3%) were classified as nonresponders based on DAS28-CRP findings. On comparison between responders and nonresponders, there was no significant difference with regard to age or disease duration and the dosages of concomitant prednisolone at baseline. KER responders had lower levels of aCCP at baseline than nonresponders (mean +/- standard deviation: 329.2 +/- 113.9 U/mL vs 623.8 +/- 242.8 U/mL, respectively) (P = .046, Mann-Whitney test). Furthermore, responders to KER showed a significant decrease in the serum levels of aCCP. The annual cost for KER treatment is much less than that for other new drugs. CONCLUSION: In patients whose active RA persists despite treatment with MTX, KER in combination with MTX is safe and well tolerated and provides clinical and economic benefits. Furthermore, pretreatment serum levels of aCCP are a useful predictor of a good response to KER treatment, and a decrease in serum levels of aCCP may be an adjunctive indicator in predicting the efficacy of this kind oftreatment.
20236522 Development of a self-administered early inflammatory arthritis detection tool. 2010 Mar 17 BACKGROUND: Barriers to care limit the potential benefits of pharmacological intervention for inflammatory arthritis. A self-administered questionnaire for early inflammatory arthritis (EIA) detection may complement contemporary triage interventions to further reduce delays to rheumatologic care. The objective of this study was to develop a self-administered EIA detection tool for implementation in pre-primary care settings. METHODS: A core set of dimensions and constructs for EIA detection were systematically derived from the literature and augmented by investigative team arbitration. Identified constructs were formulated into lay language questions suitable for self-administration. A three-round Delphi consensus panel of EIA experts and stakeholders evaluated the relevance of each question to EIA detection and suggested additional items. Questions accepted by less than 70% of respondents in rounds one or two were eliminated. In round three, questions accepted by at least 80% of the panel were selected for the tool. RESULTS: Of 584 citations identified, data were extracted from 47 eligible articles. Upon arbitration of the literature synthesis, 30 constructs encompassing 13 dimensions were formulated into lay language questions and posed to the Delphi panel. A total of 181 EIA experts and stakeholders participated on the Delphi panel: round one, 60; round two, 59; and, round three, 169; 48 participated in all three rounds. The panel evaluated the 30 questions derived from the literature synthesis, suggested five additional items, and eliminated a total of 24. The eleven-question instrument developed captured dimensions of articular pain, swelling, and stiffness, distribution of joint involvement, function, and diagnostic and family history. CONCLUSIONS: An eleven-question, EIA detection tool suitable for self-administration was developed to screen subjects with six to 52 weeks of musculoskeletal complaints. Psychometric and performance property testing of the tool is ongoing.
19565514 Induction of CCL13 expression in synovial fibroblasts highlights a significant role of onc 2009 Jul OBJECTIVE: To investigate the molecular mechanisms of CCL13/monocyte chemoattractant protein 4 (MCP-4) chemokine expression through proinflammatory cytokines in different primary human fibroblasts and the contribution of CCL13 to monocyte migration. METHODS: Using RNase protection assays and enzyme-linked immunosorbent assays, we quantified the expression of CCL13 compared with that of CCL2/MCP-1 in primary human fibroblasts. Boyden chamber assays were performed to determine the importance of CCL13 for migration of primary monocytes. Pharmacologic inhibitors as well as small interfering RNA knockdown approaches were used to investigate the signaling pathways regulating CCL13 expression. RESULTS: The interleukin-6 (IL-6)-type cytokine oncostatin M (OSM) was a powerful inducer of CCL13 expression in primary synovial fibroblasts from patients with rheumatoid arthritis (RA) as well as those from healthy control subjects but not in other types of fibroblasts. Neither IL-6 nor tumor necrosis factor alpha could stimulate the expression of CCL13 in synovial fibroblasts; IL-1beta was a very weak inducer. Synovial fibroblasts from patients with RA constitutively produced low amounts of CCL13, which was partially dependent on constitutive production of OSM. By investigating the underlying molecular mechanism, we identified STAT-5, ERK-1/2, and p38 as critical factors involved in OSM-dependent transcription and messenger RNA stabilization of CCL13. CONCLUSION: In contrast to other prominent cytokines involved in the pathogenesis of RA, OSM can strongly up-regulate the expression of CCL13, a chemokine recently identified in the synovial fluid of patients with RA. Despite potent OSM-induced signal transduction in all types of fibroblasts analyzed, only synovial fibroblasts secreted CCL13, which might be indicative of tissue-specific imprinting of different fibroblasts during development.
19808146 Pattern and predictors of the initiation of biologic agents for the treatment of rheumatoi 2009 Aug OBJECTIVE: The aim of this study was to identify factors associated with the initiation of biologic agents for the treatment of rheumatoid arthritis (RA) in a large US observational cohort. METHODS: Semiannual patient-reported data in the ARAMIS (Arthritis, Rheumatism and Aging Medical Information System) data bank from January 1998 to January 2006 were analyzed retrospectively using pooled logistic regression (with adjustment for center-level and temporal effects) to identify patient-, disease-, and treatment-related characteristics associated with the initiation of biologics for the treatment of RA. RESULTS: The analysis included 1545 patients from 7 US centers. By 2006, 41.4% of 679 patients remaining in the sample had received biologics. Initiation of biologics was significantly associated with greater disability in the previous 6-month period (per 1-unit increase in Health Assessment Questionnaire score: odds ratio [OR] = 1.45; 95% CI, 1.22-1.72; P < 0.01) and treatment in the previous period with steroids (OR = 2.24; 95% CI, 1.76-2.85; P < 0.01) or nonbiologic disease-modifying antirheumatic drugs (OR = 2.43; 95% CI, 1.71-3.46; P < 0.01). Two sociodemographic factors were significant predictors of decreased use of biologics: older age (per 10 years: OR = 0.74; 95% CI, 0.660.82; P < 0.01) and lower annual income (per $10,000 reduction: OR = 0.95; 95% CI, 0.91-1.00; P = 0.04). There were no significant differences with respect to sex, race, employment status, comorbidity, previous NSAID use, or treatment center. CONCLUSIONS: Disease- and treatment-related factors were significant predictors of the initiation of biologics for RA. Independent of these factors, however, biologics were less often used in patients who were older and those with lower incomes. Use of biologics increased steadily over the period studied.
20510234 Innate immunity and rheumatoid arthritis. 2010 May Innate immunity, with macrophages playing a central role, is critically important in the pathogenesis of RA. Although environmental insults such as smoking have been implicated in the initiation of rheumatoid arthritis (RA) in patients who express the shared epitope, the understanding of the role of innate immunity in the pathogenesis of this disease is also expanding. As the understanding continues to expand, enticing targets for new therapeutic interventions continue to be identified. This article focuses on cells of myelomonocytic origin, their receptors, and factors that interact with them.
19741008 Investigating the viability of genetic screening/testing for RA susceptibility using combi 2009 Nov OBJECTIVE: Five loci-the shared epitope (SE) of HLA--DRB1, the PTPN22 gene, a locus on 6q23, the STAT4 gene and a locus mapping to the TRAF1/C5 genetic region--have now been unequivocally confirmed as conferring susceptibility to RA. The largest single effect is conferred by SE. We hypothesized that combinations of susceptibility alleles may increase risk over and above that of any individual locus alone. METHODS: We analysed data from 4238 RA cases and 1811 controls, for which genotypes were available at all five loci. RESULTS: Statistical analysis identified eight high-risk combinations conferring an odds ratio >6 compared with carriage of no susceptibility variants and, interestingly, 10% population controls carried a combination conferring high risk. All high-risk combinations included SE, and all but one contained PTPN22. Statistical modelling showed that a model containing only these two loci could achieve comparable sensitivity and specificity to a model including all five. Furthermore, replacing SE (which requires full subtyping at the HLA-DRB1 gene) with DRB1*1/4/10 carriage resulted in little further loss of information (correlation coefficient between models = 0.93). CONCLUSIONS: This represents the first exploration of the viability of population screening for RA and identifies several high-risk genetic combinations. However, given the population incidence of RA, genetic screening based on these loci alone is neither sufficiently sensitive nor specific at the current time.
20358362 An observational study of glucocorticoid-induced osteoporosis prophylaxis in a national co 2011 Jan We applied regression techniques to a large cohort of patients to understand why certain patients are prescribed medications to prevent glucocorticoid-induced osteoporosis (GIO). Rates of prescriptions to prevent osteoporosis were low. The presence of drugs and disorders associated with osteoporosis and gastrointestinal conditions actually are associated with a decreased likelihood of receiving osteoporosis-preventing medications. INTRODUCTION: To understand why some patients are prescribed medications to prevent GIO while other patients are not, we examined whether there is an association among osteoporosis-inducing medical conditions or medications and prescriptions for osteoporosis prophylaxis in a large cohort of rheumatoid arthritis patients on chronic glucocorticoids. METHODS: Department of Veterans' Affairs national administrative databases were used to construct a cohort (n = 9,605) and provide the data for this study. Multivariate logistic regression was performed to determine medical conditions and medications associated with dispensing of GIO-preventive medications, controlling for sociodemographic variables, comorbidities, glucocorticoid dosage, prior fractures, and rheumatoid arthritis severity. A subanalysis examined predictors of early GIO prevention. RESULTS: Subjects were more likely to receive GIO prophylaxis if they were older, African American, treated with multiple antirheumatic disease-modifying drugs, or received greater glucocorticoid exposure. The prescription of certain drug classes (loop diuretics and anticonvulsants) and conditions (malignancy, renal insufficiency, alcohol abuse, and hepatic disease) were associated with lower likelihood of GIO prophylaxis, despite putative links between these agents/conditions and osteoporosis. The presence of gastrointestinal disorders dramatically decreased likelihood of GIO prophylaxis. Few characteristics predicted the dispensing of GIO-preventing medications within 7 days of the initial glucocorticoid start date. CONCLUSIONS: Rates of prescriptions to prevent osteoporosis in a cohort of older men with rheumatoid arthritis on chronic glucocorticoids were low. Gastrointestinal disorders and drugs and disorders potentially linked to osteoporosis are associated with diminished odds of being prescribed GIO-preventing medications.
19394280 T cell large granular lymphocyte leukemia associated with rheumatoid arthritis and neutrop 2009 Aug T cell large granular lymphocyte leukemia (T-LGL) is a disease characterized by clonal expansion of cytotoxic T cells (CTLs). It generally follows an indolent course and is notable for an association with chronic inflammation, neutropenia and rheumatoid arthritis (RA). We present herein a case of a patient with rheumatoid arthritis (RA), neutropenia, large granular lymphocytosis, and an expanded clonal population of peripheral blood CD3(+)CD8(+)TCRalphabeta CTLs, consistent with the diagnosis of T-LGL. T-LGL is part of a spectrum of large granular lymphocytic (LGL) disorders, which includes the more common indolent variety of this disease (as illustrated by the case herein), an aggressive but rare form of this leukemia, natural killer (NK) cell LGL leukemia, Felty's syndrome (FS), and chronic large granular lymphocytosis. T-LGL appears to be a relatively rare disease, but the true prevalence is not known. FS occurs in less than 1% of patients with RA and is typically defined by the triad of destructive arthritis, neutropenia, and variable splenomegaly. A subset of patients with FS will demonstrate polyclonal expansion of LGLs, implying a relationship between proliferation of LGLs and the mechanisms of neutropenia. Thus, T-LGL leukemia and FS with LGL expansion in the setting of RA is classically distinguished by the clonality of the CTL population, with monoclonality in T-LGL and polyclonality in FS. Despite this difference, T-LGL and FS are often similar in their clinical and biological behavior. Both may respond to immunosuppressive therapy, and pursue a smoldering course typical of a chronic inflammatory disease.
20141484 The interleukin-1 family gene polymorphisms in Korean patients with rheumatoid arthritis. 2010 May OBJECTIVE: The interleukin (IL)-1 family and its related family members are primary inflammatory cytokines. The aim of this study was to assess the possible association between nine IL-1 family gene polymorphisms and rheumatoid arthritis (RA). METHODS: To investigate the genetic association between IL-1 family gene polymorphisms and the risk of RA in a Korean population, 69 single nucleotide polymorphisms (SNPs) of the nine IL-1 family gene regions were selected. A total of 806 subjects (498 controls and 308 RA patients) were included in the study. The genotypes of the selected SNPs in the IL-1 family genes were determined using Illumina Sentrix Array Matrix chips. SNP Stats, Haploview, and SNP Analyzer, and Helixtree programs were used for the analysis of the genetic data. RESULTS: We observed statistically significant associations between the SNPs of IL1F10 and IL1RN among the IL-1 family genes in the RA patients and the control population. When the patients were divided into two groups according to the parameters of disease activity, including C-reactive protein (CRP) level (> or = 0.5 or < 0.5 mg/dL), the erythrocyte sedimentation rate (ESR) (> or = 30 or < 30 mm/h), and parameters of severity, including rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP), and bone erosion (positive or not), we found significant associations between the parameters, including CRP, ESR, and bone erosion, and SNPs of the IL-1 family genes in RA. CONCLUSION: This study suggests that IL-1 family gene (IL1F10 and IL1RN) polymorphisms may play an important role in the susceptibility to developing RA.
19548124 Efficacy and safety of anti-tumour necrosis factor in elderly patients with rheumatoid art 2010 Apr This study aims to compare the efficacy and safety of anti-TNF agents in elderly (aged >or=65 years) and younger patients (aged 18-65 years) with active RA. The study involved 1,114 RA patients treated with anti-TNF drugs and followed-up for >6 months by LORHEN group, who were divided into two cohorts on the basis of their age (311 aged >or=65 and 803 aged <65 years) in order to evaluate 3-year outcomes and treatment discontinuations. Drug effectiveness was assessed by disease activity (DAS28 and EULAR response), functional status (HAQ) and serological parameters (ESR) at baseline and during anti-TNFalpha therapy; safety was evaluated on the basis of drug discontinuation rates. At baseline, the elderly patients showed greater disease activity (DAS28, ESR) and loss of joint function (HAQ, functional class; p < 0.05). During therapy, clinical and laboratory parameters (DAS28, ESR) improved in both groups without any statistically significant difference between them, whereas the difference in HAQ remained after 36 months of treatment (p < 0.05). Anti-TNFalpha therapy was discontinued by 123 of the elderly (42%) and 282 of the younger patients (36.6%) because of loss of efficacy (17.4% vs. 16.7%), severe adverse events (21.8% vs. 16.9%) or other reasons (2.7% vs. 3%). The number of adverse events was significantly higher in the elderly patients (p < 0.05). Anti-TNFalpha treatment reduced disease activity and led to functional improvement in both groups, although the baseline difference in HAQ remained statistically significant at the end of the follow-up. The elderly patients experienced more infective events.
20975833 The PTPN22 locus and rheumatoid arthritis: no evidence for an effect on risk independent o 2010 Oct 21 OBJECTIVES: The Trp(620) allotype of PTPN22 confers susceptibility to rheumatoid arthritis (RA) and certain other classical autoimmune diseases. There has been a report of other variants within the PTPN22 locus that alter risk of RA; protective haplotype '5', haplotype group '6-10' and susceptibility haplotype '4', suggesting the possibility of other PTPN22 variants involved in the pathogenesis of RA independent of R620W (rs2476601). Our aim was to further investigate this possibility. METHODS: A total of 4,460 RA cases and 4,481 controls, all European, were analysed. Single nucleotide polymorphisms rs3789607, rs12144309, rs3811021 and rs12566340 were genotyped over New Zealand (NZ) and UK samples. Publically-available Wellcome Trust Case Control Consortium (WTCCC) genotype data were used. RESULTS: The protective effect of haplotype 5 was confirmed (rs3789607; (OR = 0.91, P = 0.016), and a second protective effect (possibly of haplotype 6) was observed (rs12144309; OR = 0.90, P = 0.021). The previously reported susceptibility effect of haplotype 4 was not replicated; instead a protective effect was observed (rs3811021; OR = 0.85, P = 1.4×10(-5)). Haplotypes defined by rs3789607, rs12144309 and rs3811021 coalesced with the major allele of rs12566340 within the adjacent BFK (B-cell lymphoma 2 (BCL2) family kin) gene. We, therefore, tested rs12566340 for association with RA conditional on rs2476601; there was no evidence for an independent effect at rs12566340 (P = 0.76). Similarly, there was no evidence for an independent effect at rs12566340 in type 1 diabetes (P = 0.85). CONCLUSIONS: We have no evidence for a common variant additional to rs2476601 within the PTPN22 locus that influences the risk of RA. Arg620Trp is almost certainly the single common causal variant.
20472591 Association of variation in Fcgamma receptor 3B gene copy number with rheumatoid arthritis 2010 Sep OBJECTIVE: There is increasing evidence that variation in gene copy number (CN) influences clinical phenotype. The low-affinity Fcgamma receptor 3B (FCGR3B) located in the FCGR gene cluster is a CN polymorphic gene involved in the recruitment to sites of inflammation and activation of polymorphonuclear neutrophils (PMNs). Given recent evidence that low FCGR3B CN is a risk factor for systemic but not organ-specific autoimmune disease and the potential importance of PMN in the pathophysiology of rheumatoid arthritis (RA), the authors hypothesised that FCGR3B gene dosage influences susceptibility to RA. METHODS: FCGR3B CN was measured in 643 cases of RA and 461 controls from New Zealand (NZ), with follow-up analysis in 768 cases and 702 controls from the Netherlands and 250 cases and 211 controls from the UK. All subjects were of Caucasian ancestry. RESULTS: Significant evidence for an association between CN <2 and RA was observed in the Dutch cohort (OR 2.01 (95% CI 1.37 to 2.94), p=3 x 10-4) but not in the two smaller cohorts (OR 1.45 (95% CI 0.92 to 2.26), p=0.11 and OR 1.33 (95% CI 0.58 to 3.02), p=0.50 for the NZ and UK populations, respectively). The association was evident in a meta-analysis which included a previously published Caucasian sample set (OR 1.67 (95% CI 1.28 to 2.17), p=1.2 x 10-4). CONCLUSIONS: One possible mechanism to explain the association between reduced FCGR3B CN and RA is the reduced clearance of immune complex during inflammation. However, it is not known whether the association between RA and FCGR3B CN is aetiological or acts as a proxy marker for another biologically relevant variant. More detailed examination of genetic variation within the FCGR gene cluster is required.
20082756 [Efficacy of Shenshi Qianghuo Dihuang Decoction in rheumatoid arthritis: a randomized cont 2010 Jan BACKGROUND: In China, patients with rheumatoid arthritis (RA) are often treated with traditional Chinese herbal medicine. There are certain advantages of traditional Chinese medicine therapy in treatment of RA. OBJECTIVE: To assess the efficacy and adverse reaction of Shenshi Qianghuo Dihuang Decoction (SQDD), a compound traditional Chinese herbal medicine, in treatment of RA. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: This was a 24-week prospective, randomized, controlled trial. Ninety RA patients meeting inclusion criteria from Shanghai Municipal Hospital of Traditional Chinese Medicine were randomly assigned to receive SQDD or methotrexate (MTX) with 45 cases in each group. The patients in SQDD group were orally administered with SQDD twice daily, and the patients in MTX control group were treated by oral administration of 15 mg MTX once a week. All the RA patients were treated for 24 weeks. MAIN OUTCOME MEASURES: The primary outcome was the number of patients achieving the American College of Rheumatology 20% response. Clinical and laboratory parameters including tender joint count and swollen joint count, patient's global assessment and physician's global assessment (using a 0-10 cm visual analogue scale), duration of morning stiffness, plasma C-reactive protein (CRP) level, erythrocyte sedimentation rate (ESR) and value of anti-cyclic citrullinated peptide (CCP) antibody were assessed. RESULTS: After 24-week treatment, the response rates in SQDD group and MTX group were 62.53% (24/41) and 67.5% (28/40) respectively, and there was no statistical difference between the two groups (P>0.05). The patient's global assessment and physician's global assessment, morning stiffness, grip strength, tender joint count, swollen joint count and the levels of ESR, CRP and anti-CCP antibody in SQDD and MTX groups were improved significantly as compared with those before treatment, and there were no significant differences between the two groups. The efficacy of MTX in improving rest pain and joint tenderness was better than that of SQDD (P<0.05). The incidence rate of adverse reactions in SQDD group was 9.75%(4/41), significantly lower than 32.5% (13/40) in MTX group (P<0.05). CONCLUSION: SQDD has a therapeutic effect on RA, and the adverse reactions are less than MTX.
20393970 Methotrexate monotherapy versus methotrexate combination therapy with non-biologic disease 2010 Apr 14 BACKGROUND: Methotrexate (MTX) is among the most effective disease modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) with less toxicity and better tolerability. OBJECTIVES: To evaluate the efficacy and toxicity of MTX monotherapy compared to MTX combination with non-biologic DMARDs in adult with RA. SEARCH STRATEGY: Trials were identified in MEDLINE (1950 to 2009), EMBASE (1980 to 2009), the Cochrane Controlled trials Registry (CENTRAL) (up to 2009), the American and European scientific meeting abstracts 2005-9, the reference lists of all relevant studies, letters, and review articles. SELECTION CRITERIA: Randomized controlled trials comparing MTX monotherapy versus MTX combined with other non-biologic DMARDs of at least 12 weeks of trial duration in adult RA patients. DATA COLLECTION AND ANALYSIS: Two reviewers independently identified eligible studies,extracted the data, and assessed the risk of bias of relevant studies.The efficacy analysis was stratified into 3 groups based on previous DMARDs use: DMARD naive, MTX inadequate response, and non-MTX DMARDs inadequate response. The toxicity analysis was stratified by DMARD combination and pooled across trials for each combination. Our prespecified primary analysis was based on total withdrawal rates for efficacy or toxicity. MAIN RESULTS: A total of 19 trials (2,025 patients) from 6,938 citations were grouped by the type of patients randomised. Trials in DMARD naive patients showed no significant advantage of the MTX combination versus monotherapy; withdrawals for lack of efficacy or toxicity were similar in both groups (risk ratio (RR) 1.16, 95% CI.0.70 to 1.93, absolute risk difference(ARD) 5%, 95%CI-3% to 13%). Trials in MTX or non-MTX DMARDs inadequate responder patients also showed no difference in withdrawal rates between the MTX combo versus mono groups with RR 0.86 95% CI 0.49 to1.51, ARD -2 %, 95% CI-13 % to 8 % and RR 0.75 95% CI 0.41 to 1.35, ARD -10%, 95% CI -31% to 11%, respectively. Significant reductions of pain and improvement in physical function (measured by Health Assessment Questionnaire or HAQ) were found in the MTX combination group, but only in MTX-inadequate responders (absolute risk difference -9.72%, 95%CI -14.7% to -4.75% for pain and mean difference (MD) -0.28, 95%CI -0.36 to -0.21 (0-3) for HAQ). AUTHORS' CONCLUSIONS: When the balance of efficacy and toxicity is taken into account, the moderate level of evidence from our systematic review showed no statistically significant advantage of the MTX combination versus monotherapy. Trials are needed that compare currently used MTX doses and combination therapies.
18834713 Administrative codes combined with medical records based criteria accurately identified ba 2009 Mar OBJECTIVE: To evaluate diagnostic properties of International Classification of Diseases, Version 9 (ICD-9) diagnosis codes and infection criteria to identify bacterial infections among rheumatoid arthritis (RA) patients. STUDY DESIGN AND SETTING: We performed a cross-sectional study of RA patients with and without ICD-9 codes for bacterial infections. Sixteen bacterial infection criteria were developed. Diagnostic properties of comprehensive and restrictive sets of ICD-9 codes and the infection criteria were tested against an adjudicated review of medical records. RESULTS: Records on 162 RA patients with and 50 without purported bacterial infections were reviewed. Positive and negative predictive values of ICD-9 codes ranged from 54%-85% and 84%-100%, respectively. Positive predictive values of the medical records based criteria were 84% and 89% for "definite" and "definite or empirically treated" infections, respectively. Positive predictive value of infection criteria increased by 50% as disease prevalence increased using ICD-9 codes to enhance infection likelihood. CONCLUSION: ICD-9 codes alone may misclassify bacterial infections in hospitalized RA patients. Misclassification varies with the specificity of the codes used and strength of evidence required to confirm infections. Combining ICD-9 codes with infection criteria identified infections with greatest accuracy. Novel infection criteria may limit the requirement to review medical records.
21120996 Most common single-nucleotide polymorphisms associated with rheumatoid arthritis in person 2010 Dec OBJECTIVE: Large-scale genetic association studies have identified >20 rheumatoid arthritis (RA) risk alleles among individuals of European ancestry. The influence of these risk alleles has not been comprehensively studied in African Americans. We therefore sought to examine whether these validated RA risk alleles are associated with RA risk in an African American population. METHODS: Twenty-seven candidate single-nucleotide polymorphisms (SNPs) were genotyped in 556 autoantibody-positive African Americans with RA and 791 healthy African American control subjects. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for each SNP were compared with previously published ORs for RA patients of European ancestry. We then calculated a composite genetic risk score (GRS) for each individual based on the sum of all risk alleles. RESULTS: Overlap of the ORs and 95% CIs between the European and African American populations was observed for 24 of the 27 candidate SNPs. Conversely, 3 of the 27 SNPs (CCR6 rs3093023, TAGAP rs394581, and TNFAIP3 rs6920220) demonstrated ORs in the opposite direction from those reported for RA patients of European ancestry. The GRS analysis indicated a small but highly significant probability that African American patients relative to control subjects were enriched for the risk alleles validated in European RA patients (P = 0.00005). CONCLUSION: The majority of RA risk alleles previously validated for RA patients of European ancestry showed similar ORs in our population of African Americans with RA. Furthermore, the aggregate GRS supports the hypothesis that these SNPs are risk alleles for RA in the African American population. Future large-scale genetic studies are needed to validate these risk alleles and identify novel RA risk alleles in African Americans.
18839399 More powerful haplotype sharing by accounting for the mode of inheritance. 2009 Apr The concept of haplotype sharing (HS) has received considerable attention recently, and several haplotype association methods have been proposed. Here, we extend the work of Beckmann and colleagues [2005 Hum. Hered. 59:67-78] who derived an HS statistic (BHS) as special case of Mantel's space-time clustering approach. The Mantel-type HS statistic correlates genetic similarity with phenotypic similarity across pairs of individuals. While phenotypic similarity is measured as the mean-corrected cross product of phenotypes, we propose to incorporate information of the underlying genetic model in the measurement of the genetic similarity. Specifically, for the recessive and dominant modes of inheritance we suggest the use of the minimum and maximum of shared length of haplotypes around a marker locus for pairs of individuals. If the underlying genetic model is unknown, we propose a model-free HS Mantel statistic using the max-test approach. We compare our novel HS statistics to BHS using simulated case-control data and illustrate its use by re-analyzing data from a candidate region of chromosome 18q from the Rheumatoid Arthritis (RA) Consortium. We demonstrate that our approach is point-wise valid and superior to BHS. In the re-analysis of the RA data, we identified three regions with point-wise P-values<0.005 containing six known genes (PMIP1, MC4R, PIGN, KIAA1468, TNFRSF11A and ZCCHC2) which might be worth follow-up.