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ID PMID Title PublicationDate abstract
16284094 Trichostatin A sensitises rheumatoid arthritis synovial fibroblasts for TRAIL-induced apop 2006 Jul BACKGROUND: Histone acetylation/deacetylation has a critical role in the regulation of transcription by altering the chromatin structure. OBJECTIVE: To analyse the effect of trichostatin A (TSA), a streptomyces metabolite which specifically inhibits mammalian histone deacetylases, on TRAIL-induced apoptosis of rheumatoid arthritis synovial fibroblasts (RASF). METHODS: Apoptotic cells were detected after co-treatment of RASF with TRAIL (200 ng/ml) and TSA (0.5, 1, and 2 micromol/l) by flow cytometry using propidium iodide/annexin-V-FITC staining. Cell proliferation was assessed using the MTS proliferation test. Induction of the cell cycle inhibitor p21Waf/Cip1 by TSA was analysed by western blot. Expression of the TRAIL receptor-2 (DR5) on the cell surface of RASF was analysed by flow cytometry. Levels of soluble TRAIL were measured in synovial fluid of patients with RA and osteoarthritis (OA) by ELISA. RESULTS: Co-treatment of the cells with TSA and TRAIL induced cell death in a synergistic and dose dependent manner, whereas TRAIL and TSA alone had no effect or only a modest effect. RASF express DR5 (TRAIL receptor 2), but treatment of the cells with TSA for 24 hours did not change the expression level of DR5, as it is shown for cancer cells. TSA induced cell cycle arrest in RASF through up regulation of p21Waf1/Cip1. Levels of soluble TRAIL were significantly higher in RA than in OA synovial fluids. CONCLUSION: Because TSA sensitises RASF for TRAIL-induced apoptosis, it is concluded that TSA discloses sensitive sites in the cascade of TRAIL signalling and may represent a new principle for the treatment of RA.
17977486 Efficacy results from pivotal clinical trials with abatacept. 2007 Sep Rheumatoid arthritis (RA) is a prevalent systemic disease that causes significant joint dysfunction and disability. Dramatic improvements in the management of RA have been achieved with the use of biologic therapies aimed at cytokines, and B and T lymphocytes. Abatacept, a soluble receptor-IgG fusion protein that interferes with T-cell co-stimulation, has now been shown to improve symptoms, signs and function in RA, while also slowing radiographic progression. The degree of improvement in these measures is comparable to that seen with other biologic agents.Abatacept is effective in a range of RA patients that are encountered in clinical practice, namely methotrexate-inadequate responders, as well patients with inadequate responses to tumor necrosis factor inhibitors and patients with co-morbidities common in an aging population. When used for up to 2 years, abatacept appears to be safe and remains efficacious, although there is a trend toward increased infection rates when used in combination with other biologic therapies, as well as a trend toward more adverse events when used in a background of chronic obstructive pulmonary disease. Backed by these data, ongoing extensions of these trials, and additional new studies, abatacept represents the first co-stimulation modulator approved for RA, and is a welcome addition to the biologic therapies available for the management of this disease.
18565244 Imbalanced expression of RANKL and osteoprotegerin mRNA in pannus tissue of rheumatoid art 2008 Mar OBJECTIVE: To test if the pannus tissue is characterized by a high receptor activator of nuclear factor kappaB ligand to osteoprotegerin (RANKL:OPG) ratio, which could explain local osteoclastogenesis and formation of bony erosions. METHODS: Messenger RNA and protein expressions of RANKL and OPG in rheumatoid and osteoarthritic tissue samples were measured using quantitative real-time RT-PCR and Western blot/densitometry. Pannus and synovitis fibroblasts explanted from tissue samples were cultured in vitro without and with TNF-alpha, IL-1Beta or IL-17 and analyzed quantitatively for RANKL expression. The ability of pannus fibroblasts to induce formation of multinuclear osteoclast-like cells from human monocytes, with macrophage-colony stimulating factor (M-CSF) but without RANKL added, was tested. Histochemical staining was used to assess the eventual presence of RANKL and tartrate resistant acid phosphatase positive osteoclast-like cells at the pannus-bone interface. RESULTS: RANKL:OPG ratios of messenger RNA (p<0.05) and protein level were high in pannus (2.06+/-0.73 and 2.2+/-0.65) compared to rheumatoid (0.62+/-0.13 and 1.31+/-0.69) and osteoarthritis (0.62+/-0.32 and 0.52+/-0.16) synovial membranes. Resting and stimulated (p dependent on the cytokine used) pannus fibroblasts produced RANKL in excess (p=0.0005) and unstimulated pannus fibroblasts also effectively induced osteoclast-like cell formation from monocytes in vitro without any exogenous RANKL added. Compatible with these findings, multinuclear osteoclasts-like cells were frequent in the fibroblast- and macrophage-rich pannus tissue at the soft tissue-to-bone interface. CONCLUSION: The high RANKL:OPG ratio, together with close fibroblast-to-monocyte contacts in pannus tissue, probably favor local generation of bone resorbing osteoclasts at the site of erosion in rheumatoid arthritis.
18253729 Variable responses of formyl peptide receptor haplotypes toward bacterial peptides. 2008 Feb The chemoattractant neutrophil formyl peptide receptor (FPR) binds bacterial and mitochondrial N-formylated peptides, which allows the neutrophils to find the bacterial source and/or site of tissue damage. Certain inflammatory disorders may be due in part to an impaired innate immune system that does not respond to acute bacterial damage in a timely fashion. Because the human FPR is encoded by a large number of different haplotypes arising from ten single-nucleotide polymorphisms, we examined the possibility that some of these haplotypes are functionally distinct. We analyzed the response of three common FPR haplotypes to peptides from Escherichia coli, Mycobacterium avium ssp. paratuberculosis, and human mitochondria. All three haplotypes responded similarly to the E. coli and mitochondrial peptides, whereas one required a higher concentration of the M. avium peptide fMFEDAVAWF for receptor downregulation, receptor signaling, and chemotaxis. This raises the possibility of additional bacterial species differences in functional responses among FPR variants and establishes a precedent with potentially important implications for our innate immune response against bacterial infections. We also investigated whether certain FPR haplotypes are associated with rheumatoid arthritis (RA) by sequencing FPR1 from 148 Caucasian individuals. The results suggested that FPR haplotypes do not significantly contribute toward RA.
17659758 Influence of the BsmI polymorphism of the vitamin D receptor gene on rheumatoid arthritis 2007 Sep OBJECTIVE: The etiopathogenesis of rheumatoid arthritis (RA) is not fully known; vitamin D has been shown to have immunomodulatory effects and could be implicated in it. BsmI polymorphism of vitamin D receptor (VDR) gene is involved in the pathogenesis of osteoporosis in RA. We analyzed the effect of this polymorphism on clinical activity in 123 Spanish postmenopausal women with RA. METHODS: Patients with RA were enrolled consecutively during outpatient clinic visits. RA severity and activity measures were recorded and a blood sample was extracted. Genetic analysis was made by DNA extraction techniques, amplification by polymerase chain reaction, and restriction using endonuclease BsmI. RESULTS: Mean age of the patients was 62.9 +/- 8.4 years. The mean time of the evolution of RA was 12.5 +/- 7.3 years and mean time since menopause was 15.2 +/- 9.4 years. Seventy-six percent of the patients were rheumatoid factor-positive; mean Health Assessment Questionnaire (HAQ) score was 1.3 +/- 0.7; 92% of the patients had been treated with low-dose glucocorticoids. Twenty-eight patients (23%) had genotype BB, 48 (39%) Bb, and 47 (38%) bb. Patients with BB or Bb genotype had statistically significantly higher HAQ scores, erythrocyte sedimentation rate, current and accumulated dose of glucocorticoids, and number of disease modifying antirheumatic drugs taken, and lower serum hemoglobin and albumin than patients with bb genotype (p < 0.05). CONCLUSION: Among patients with RA, the bb genotype of the BsmI polymorphism of the VDR gene is associated with less severe disease.
18043364 CT of the foot: selected inflammatory arthridites. 2007 Nov Although the primary imaging modality for the evaluation of inflammatory arthritis of the foot and ankle is currently magnetic resonance imaging, computed tomography may be performed in some patients and can aid in diagnosis. This article reviews a number of inflammatory arthritic conditions that involve the feet. Computed tomographic findings and the role of computed tomography in diagnosing infection, gout, and rheumatoid arthritis of the foot are discussed.
16125248 Natural resistance-associated macrophage protein 1 gene polymorphisms in rheumatoid arthri 2006 Jan 15 OBJECTIVES: To investigate the association of natural resistance-associated macrophage protein 1 gene (NRAMP1) polymorphisms with rheumatoid arthritis (RA) in Taiwan. METHODS: NRAMP1 polymorphisms were determined from 113 RA patients and 74 healthy controls using the polymerase chain reaction/restriction fragment length polymorphism method. RESULTS: The genotype frequencies of NRAMP1 823 C/C, 1703G/G (543D/D), and 1729+55 del 4 TGTG+/+ (244/244) were significantly higher in patients with RA than in controls. Similar findings were also evident in allele frequencies and allele carriage frequencies of 823C, 1703G (543D), and 1729+55 del 4 TGTG+ (244). The associations of these polymorphisms with RA were independent of HLA-DR4. Linkage disequilibria could be found between 823C and 1703G, and between 1703G and 1729+55 del 4 TGTG+. The estimated haplotype frequency of NRAMP1 823C/1703G/1729+55 del 4 TGTG+ was significantly increased in RA patients compared with controls. We also found that patients with 823 C/C had a significantly lower prevalence of rheumatoid nodule than those without 823 C/C. CONCLUSION: NRAMP1 823C, 1703G (543D), and 1729+55 del 4 TGTG+ (244) are precipitating factors for the development of RA in Taiwan. The estimated NRAMP1 823C/1703G/1729+del 4 TGTG+ haplotype is associated with susceptibility to RA. NRAMP1 823 C/C prevents the development of rheumatoid nodule in RA patients.
18697775 Rheumatoid arthritis versus diabetes as a risk factor for cardiovascular disease: a cross- 2009 Sep OBJECTIVES: Patients with rheumatoid arthritis (RA) have an increased cardiovascular risk, but the magnitude of this risk is not known precisely. A study was undertaken to investigate the associations between RA and type 2 diabetes (DM2), a well-established cardiovascular risk factor, on the one hand, and cardiovascular disease (CVD) on the other. METHODS: The prevalence of CVD (coronary, cerebral and peripheral arterial disease) was determined in 353 randomly selected outpatients with RA (diagnosed between 1989 and 2001, aged 50-75 years; the CARRE study) and in participants of a population-based cohort study on diabetes and CVD (the Hoorn study). Patients with RA with normal fasting glucose levels from the CARRE study (RA, n = 294) were compared with individuals from the Hoorn study with normal glucose metabolism (non-diabetic, n = 258) and individuals with DM2 (DM2, n = 194). RESULTS: The prevalence of CVD was 5.0% (95% CI 2.3% to 7.7%) in the non-diabetic group, 12.4% (95% CI 7.5% to 17.3%) in the DM2 group and 12.9% (95% CI 8.8% to 17.0%) in those with RA. With non-diabetic individuals as the reference category, the age- and gender-adjusted prevalence odds ratio (OR) for CVD was 2.3 (95% CI 1.1 to 4.7) for individuals with DM2 and 3.1 (95% CI 1.6 to 6.1) for those with RA. There was an attenuation of the prevalences after adjustment for conventional cardiovascular risk factors (OR 2.0 (95% CI 0.9 to 4.5) and 2.7 (95% CI 1.2 to 5.9), respectively). CONCLUSIONS: The prevalence of CVD in RA is increased to an extent that is at least comparable to that of DM2. This should have implications for primary cardiovascular prevention strategies in RA.
17909741 Does low-dose and short-term glucocorticoids treatment increase the risk of osteoporosis i 2008 May Rheumatoid arthritis (RA) is frequently complicated by peri-articular and generalized osteoporosis due to increased bone resorption by activated osteoclasts. Pro-inflammatory cytokines, such as TNF-alpha, interleukin 1 (IL1), and interleukin 6 (IL6) are thought, among other factors, to be directly responsible for this extra-articular complication of RA. Glucocorticoids (GCS) commonly prescribed in RA due to their strong anti-inflammatory effect are also well known for causing secondary osteoporosis during a prolonged use. An influence of low-dose GCS therapy (8.7 mg per day) on a bone turnover in female RA patients with or without previous history of GCS treatment was investigated by measuring bone mineral content (BMC), bone mineral density (BMD), and various biochemical markers of inflammation and bone metabolism in comparison to results obtained from: (1) RA patients who have not been treated with GCS and (2) the control group of healthy individuals. Sixty-two female patients with established active RA and 178 healthy individuals from the control group have been investigated. The RA patients were divided into three groups: 21 treated with GCS before the trial--these patients have continued GCS therapy using low doses during the observation; 21 with low-dose GCS therapy launched at the beginning of the trial; and 20 left without GCS treatment. All patients have been assessed twice: at the beginning and after 12 months of observation. BMC and BMD have been measured in all patients in a distal part of forearm. Additionally, several different biochemical markers of osteoporosis and inflammation have been determined. We did not notice any increase in bone metabolism between RA patients receiving GCS therapy for the first time and those treated without GCS after 12 months of observation. Results of BMC, BMD osteocalcin level, total and bone alkaline phosphatase, carboxy-terminal collagen cross links, carboxy-terminal propeptides of type 1 collagen, deoxypyridynoline, and calcium/creatinine ratio were comparable in both groups at the end of the study. There was a significant decrease of the level of IL-6 in patients who had GCS therapy launched at the beginning of observation (p<0.01). However, levels of C-reactive protein (CRP) and alpha1-acid-glycoprotein (AGP) have not changed; the level of ESR dropped significantly (p<0.05) in this group. In contrast, in the group of patients with the previous history of prolonged GCS treatment receiving low doses of GCS during the trial, statistically significant increase of CRP and AGP could be observed (p<0.05) along with further significant worsening of the primary low BMD (p<0.05). Based on the obtained data, we came to the conclusion that anti-inflammatory effect of the low-dose GCS therapy in RA patients without previous history of their use may balance their direct negative effect on BMC and BMD. In this group of RA patients, benefits resulting from the 12-month GCS therapy prevail over adverse effects, even if calcium with vitamin D3 supplementation, biphosphonians, or estrogens have not been introduced. On the other hand, low-dose GCS therapy could have no benefit for RA patients with the previous history of their prolonged use, as a rise of markers of inflammation and bone turnover, resulting in the further bone loss, has been observed.
17878209 Aggressive combination therapy with intra-articular glucocorticoid injections and conventi 2008 Jun OBJECTIVE: To investigate whether clinical and radiographic disease control can be achieved and maintained in patients with early, active rheumatoid arthritis (RA) during the second year of aggressive treatment with conventional disease-modifying antirheumatic drugs (DMARDs) and intra-articular corticosteroid. This paper presents the results of the second year of the randomised, controlled double-blind CIMESTRA (Ciclosporine, Methotrexate, Steroid in RA) study. METHODS: 160 patients with early RA (duration <6 months) were randomised to receive intra-articular betamethasone in any swollen joint in combination with step-up treatment with either methotrexate and placebo-ciclosporine (monotherapy) or methotrexate plus ciclosporine (combination therapy) during the first 76 weeks. At week 68 hydroxychlorochine 200 mg daily was added. From week 76-104 ciclosporine/placebo-ciclosporine was tapered to zero. RESULTS: American College of Rheumatology 20% improvement (ACR20), ACR50 and ACR70 levels were achieved in 88%, 79% and 59% of patients in the combination vs 72%, 62% and 54% in the monotherapy group (p = 0.03, 0.02 and 0.6 between groups). The patients globally declined from 50 to 12 vs 52 to 9, with 51% and 50% in Disease Activity Score (DAS) remission, respectively. Mean (SD) progressions in total Sharp-van der Heijde scores were 1.42 (3.52) and 2.03 (5.86) in combination and monotherapy groups, respectively (not significant). Serum creatinine levels increased by 7% in the combination group (4% in monotherapy), but hypertension was not more prevalent. CONCLUSION: Continuous methotrexate and intra-articular corticosteroid treatment resulted in excellent clinical response and disease control at 2 years, and the radiographic erosive progression was minimal. Addition of ciclosporine during the first 76 weeks resulted in significantly better ACR20 and ACR50 responses, but did not have any additional effect on remission rate and radiographic outcome.
17929133 Elevation of serum matrix metalloproteinase-3 as a predictive marker for the long-term dis 2007 Matrix metalloproteinases (MMPs) are the proteases responsible for the destruction of cartilage in rheumatoid arthritis (RA) patients; especially the role of MMP-3 in RA has been highlighted from both pathophysiological studies and clinical studies. However, the role of serum MMP-3 in a large observational cohort of RA patients has not been well demonstrated. In a large observational cohort of RA patients in our Institute (IORRA, October 2000-October 2005, n=3834-5049/phase), disease activity and functional status were routinely assessed biannually. In October 2001, serum MMP-3 was measured in 1265 patients in this cohort, and the data of these patients in the subsequent 4 years were analyzed. The functional status of disability was assessed by JHAQ, the verified Japanese version of HAQ. A cut-off point of 121.0 ng/ml (men) and 59.7 ng/ml (women) was used for MMP-3 positive/negative categorization. The baseline data of these 1265 patients include 81.5% women, mean age 57.9, mean duration 11.1 years, and 71.7% of patients were rheumatoid factor (RF)-positive. Serum MMP-3 levels at the baseline (195.1+227.9 ng/ml) were weakly correlated with C-reactive protein (CRP), but qualitative elevation of serum MMP-3 using cut-off points correlated significantly with corticosteroids use, DAS28, CRP, erythrocyte sedimentation rate, JHAQ, or other markers for the disease activity, but not with age or the disease duration. Thus, elevation of serum MMP-3 level represents the disease activity of RA patients regardless of age or the disease duration. In the longitudinal analysis, the slope of JHAQ progression in patients with MMP-3 positive and RF positive, MMP-3 positive and RF negative, MMP-3 negative and RF positive and MMP-3 negative and RF negative were 0.0179, 0.0162, 0.0156, and 0.0119, respectively, indicating that JHAQ increased most progressively in RA patients with MMP-3 positive and RF positive patients, although statistically apparent differences were not identified. In 502 female patients without talking corticosteroid, patients with MMP-3 positive and RF positive were statistically more progressive in the disability than patients with MMP-3 negative and RF negative. In conclusion, elevation of serum MMP-3 in RA patients is an indicator of inflammation, and together with RF, elevation of serum MMP-3 is a predictive marker for the progression in disability especially in female patients without corticosteroid.
18723008 Efficacy of Siddha formulation Kalpaamruthaa in ameliorating joint destruction in rheumato 2008 Nov 25 BACKGROUND: Rheumatoid arthritis (RA) is a kind of chronic inflammatory autoimmune disease. The degradation of extracellular matrix and cartilage pave way in understanding the molecular mechanisms in RA. Degradation of cartilage is a more complex event involving the local release of metallaoproteases and lysosomal enzymes that mediate inflammation in joints and in the synovial fluid in RA. OBJECTIVES: In the present study, the efficacy of a Siddha preparation named Kalpaamruthaa (KA) in ameliorating the disease process via markedly reducing the joint destruction was demonstrated in adjuvant induced arthritis rat model. KA consists of Semecarpus anacardium nut milk extract (SA), dried powder of Emblica officinalis fruit and honey. MATERIAL AND METHODS: Both SA and KA were administered at dose of 150 mg/kg b.wt. for 14 days after 14 days of adjuvant injection in rats. The activity of lysosomal enzymes, the level of collagen, glycosaminoglycans (GAGs) and its degradative products were analyzed in control and experimental animals. RESULTS AND CONCLUSION: The study revealed that KA exhibited a profound reduction (p<0.05) in the activities of lysosomal enzymes and thereby decreasing (p<0.05) the levels of GAGs and its fractions when compared to arthritis rats. The latter was confirmed by Safrannin O staining for GAGs in the interphalangeal joints of control and experimental animals. The effect of KA was found to be improved than SA and this might be due to the combined interactions of phytoconstituents present in KA.
18539621 Polymorphisms within the adenosine receptor 2a gene are associated with adverse events in 2008 Aug OBJECTIVE: To examine the role of adenosine receptor 2a gene (ADORA2a) polymorphisms on outcome of MTX treatment in RA. METHODS: Subjects included 309 RA patients with a defined response to MTX. Patients were included if they were (i) good responders (n = 147) (ESR <20 for >6/12 on stable dose of MTX) (ii) inefficacy failures (n = 101) (physician statement and failure to reduce ESR/CRP by 20%) or (iii) adverse event (AE) failures (n = 61) (verified by medical record review). AEs were sub-divided into gastrointestinal (GI) (n = 24), abnormal LFTs (n = 20) or other (n = 17). 8 single nucleotide polymorphisms (SNPs) within ADORA2a were genotyped using the Sequenom MALDI-TOF platform. RESULTS: Five SNPs within ADORA2a were associated with stopping MTX for AEs (OR 2.1-3.07, P < 0.05 for all). Analysis by AE type showed that the association was specific for GI toxicity. No association was observed between ADORA2a and inefficacy outcomes. CONCLUSION: Genetic variation within ADORA2a is significantly associated with AEs on MTX, specifically GI AEs. Knowledge of the ADORA2a genotype may help to improve identification of patients at high risk of GI toxicity with MTX.
17414960 Effects of glucocorticoids on inflammation and arthritis. 2007 May PURPOSE OF REVIEW: Glucocorticoids are used in the treatment of most rheumatic diseases, and are used chronically in up to 50% of cases of rheumatoid arthritis. The frequency of their use has in the past been incompletely supported by trial evidence of their benefit and by incomplete understanding of their mechanisms of action. The present review will examine significant recent publications relating to glucocorticoids of relevance to rheumatology RECENT FINDINGS: The basic science of glucocorticoid action has advanced considerably in the review period. Major advances include demonstration of the function of glucocorticoid-induced anti-inflammatory proteins such as mitogen-activated protein kinase phosphatase-1, expanded understanding of alternately spliced isoforms of the glucocorticoid receptor, and major steps in understanding factors regulating glucocorticoid sensitivity in disease. Clinical studies have also had major developments, most strikingly with the publication of two randomized prospective studies on the efficacy of glucocorticoids in preventing erosions in rheumatoid arthritis. SUMMARY: Despite over 50 years of glucocorticoid use in rheumatology, basic science and clinical studies continue to yield intriguing new data. The quest for therapeutic agents with the beneficial effects of glucocorticoids but lacking their harmful effects is aided by this progress.
18765427 Type I interferons might form the link between Toll-like receptor (TLR) 3/7 and TLR4-media 2009 Sep BACKGROUND: Rheumatoid arthritis (RA) has been associated with an increased risk of infections, but the underlying pathways have not yet been identified. Toll-like receptors (TLR) probably play a role in synovial inflammation and may also contribute to the understanding of the role of infections in RA. OBJECTIVES: To investigate if the synovial expression of TLR3 and TLR7 in RA correlates with that of inflammatory cytokines, and to assess whether this has functional consequences for local cytokine production and to study potential links between the TLR3/7 axis and TLR4 in RA synovium. METHODS: Immunohistochemistry was used to study the expression of TLR3, TLR7, interferon alpha (IFNalpha), tumour necrosis factor alpha (TNFalpha) and interleukins IL1beta, IL12, IL17 and IL18 in RA synovium obtained by arthroscopy from 34 patients with RA. Monocytes, monocyte-derived dendritic cells (MoDCs) and RA synovial fibroblasts were stimulated via TLR3 (poly-IC) and TLR7 (loxorubin), after which IL1beta, IL6 and TNFalpha were measured by Luminex bead array technology. Following preincubation with IFNalpha, IL1beta and IL18, TLR3 and TLR7 mRNA expression was assessed using real-time PCR. Cytokine production after preincubation with IFNalpha and subsequent TLR stimulation was measured. RESULTS: Synovial TLR3/7 expression was co-expressed with IFNalpha, IL1beta and IL18, but not with TNFalpha, IL12 and IL17. Stimulation of TLR3/TLR7 on monocytes, MoDCs or synovial fibroblasts led to secretion of type I IFN but no biologically active IL1beta or IL18 could be detected. Type I IFNalpha increased TLR3/7 mRNA expression whereas IL1beta and IL18 did not. In spite of the fact that the mRNA level of TLR4 remained unchanged, IFNalpha enhanced the response to TLR4 agonists, a phenomenon that was clearly more marked in patients with RA. CONCLUSION: Type I interferons are highly co-expressed with TLR3/TLR7 in RA synovium. They enhance TLR3/TLR7-mediated cytokine production and also TLR4-mediated responses.
17921184 Functional, molecular and proteomic characterisation of bone marrow mesenchymal stem cells 2008 Jun OBJECTIVE: Bone marrow (BM) mesenchymal stem cells (MSCs) are being considered as potential therapeutic agents in various inflammatory autoimmune diseases for their tissue-repair and anti-inflammatory tissue-protective properties. This study investigates the reserves and function, the molecular and proteomic profile and the differentiation potential of BM MSCs in patients with active rheumatoid arthritis (RA). METHODS: We evaluated the frequency of MSCs in the BM mononuclear cell fraction using a limiting dilution assay, the proliferative/clonogenic potential and the capacity of cells to differentiate towards the osteogenic/chondrogenic/adipogenic lineages using appropriate culture conditions. We also assessed the molecular and proteomic characteristics in terms of inflammatory cytokine gene and protein expression, the relative telomere length and the survival characteristics of BM MSCs. RESULTS: MSCs from patients with RA (n = 26) and age- and sex-matched healthy individuals (n = 21) were similar in frequency, differentiation potential, survival, immunophenotypic characteristics, and protein profile. Patient MSCs, however, had impaired clonogenic and proliferative potential in association with premature telomere length loss. Transcriptome analysis revealed differential expression of genes related to cell adhesion processes and cell cycle progression beyond the G1 phase. Previous treatment with methotrexate, corticosteroids, anti-cytokine and biological agents or other disease-modifying anti-inflammatory drugs did not correlate with the clonogenic and proliferative impairment of BM MSCs. CONCLUSION: In spite of some restrictions related to the impaired clonogenic and proliferative potential, our findings support the use of autologous BM MSCs in RA and may have important implications for the ongoing efforts to repair tissue injury commonly seen in the course of the disease.
16980212 Is IL-1 a good therapeutic target in the treatment of arthritis? 2006 Oct Inflammation is an important homeostatic mechanism that limits the effects of infectious agents. However, inflammation might be self-damaging and therefore has to be tightly controlled or even abolished by the organism. Interleukin 1 (IL-1) is a crucial mediator of the inflammatory response, playing an important part in the body's natural responses and the development of pathological conditions leading to chronic inflammation. While IL-1 production may be decreased or its effects limited by so-called anti-inflammatory cytokines, in vitro IL-1 inflammatory effects are inhibited and can be abolished by one particularly powerful inhibitor, IL-1 receptor antagonist (IL-1Ra). Recent research has shown that in the processes of rheumatoid arthritis (RA) IL-1 is one of the pivotal cytokines in initiating disease, and IL-1Ra has been shown conclusively to block its effects. In laboratory and animal studies the inhibition of IL-1 by either antibodies to IL-1 or IL-1Ra proved beneficial to the outcome. Because of its beneficial effects in many animal disease models, IL-1Ra has been used as a therapeutic agent in human patients. The recombinant form of IL-1Ra, anakinra (Kineret, Amgen) failed to show beneficial effects in septic shock and displays weak effects in RA patients. However, IL-1 blockade by anakinra is dramatically effective in systemic-onset juvenile idiopathic arthritis, in adult Still's disease and in several autoinflammatory disorders, most of the latter being caused by mutations of proteins controlling IL-1beta secretion. Importantly, to be efficacious, anakinra required daily injections, suggesting that administered IL-1Ra displays very short-term effects. Better IL-1 antagonists are in the process of being developed.
16166104 Smoking is a strong risk factor for rheumatoid nodules in early rheumatoid arthritis. 2006 May OBJECTIVE: To examine whether smoking is a risk factor for rheumatoid nodules in early rheumatoid arthritis, and if so to determine the quantitative effect of smoking. METHODS: From a cohort (n = 1589) in a structured programme for follow up of newly diagnosed cases of rheumatoid arthritis (symptoms of swollen joints < or =12 months), 112 individuals with rheumatoid nodules at inclusion were identified. Nodular patients were each compared with two age and sex matched controls without nodules from the same cohort. A detailed self administered tobacco use questionnaire was answered by 210 patients (63%). RESULTS: Seventy patients were current smokers, 71 former smokers, and 69 had never smoked. Current smoking and former smoking were more common in patients with rheumatoid nodules compared with controls (86% v 59%) in both sexes. Positive rheumatoid factor (RF) was found more often among cases with nodules than controls (78% v 64%). Using detailed information from the questionnaires with conditional logistic regression analyses, ever having smoked was associated with an increased risk of the presence of rheumatoid nodules (odds ratio (OR) = 7.3 (95% confidence interval, 2.3 to 23.6); p = 0.001). The risk of having nodules was not obviously dose dependent when smoking duration as well as smoking amount were examined. A stratified analysis showed that only RF positive smokers had an increased risk of rheumatoid nodules. Smoking was associated with rheumatoid nodules among both men (p = 0.006) and women (p = 0.001). Tobacco use other than smoking (n = 31) was not associated with an increased risk of nodules (OR = 0.8 (0.2 to 3.4); p = 0.813). CONCLUSIONS: There is a strong association between smoking and rheumatoid nodules in early seropositive rheumatoid arthritis.
18458201 Subsequent risk of hospitalization for neuropsychiatric disorders in patients with rheumat 2008 May OBJECTIVE: To analyze the association between rheumatoid arthritis, systemic lupus erythematosus, and ankylosing spondylitis and hospitalization for psychiatric disorders, as well as the association between hospitalization for dementia or delirium and systemic lupus erythematosus, by using a novel, large-scale approach. DESIGN: Cohort study with follow-up between 1973 and 2004. PARTICIPANTS: The entire Swedish population. MAIN OUTCOME MEASURES: Affective, psychotic, neurotic, and personality disorders as well as dementia and delirium. RESULTS: Individuals with rheumatic diseases had a higher risk of psychiatric disorders than the general population. Those with systemic lupus erythematosus and ankylosing spondylitis had a higher risk of subsequent psychiatric disorders than did patients with rheumatoid arthritis. The significant standardized incidence ratios for rheumatoid arthritis, systemic lupus erythematosus, and ankylosing spondylitis were 1.45, 2.38, and 1.69, respectively, for men, and 1.36, 2.16, and 1.95, respectively, for women. Differences were also found based on subtypes of the rheumatic disease and the psychiatric disorder, sex, and various follow-up intervals. Systemic lupus erythematosus carried an increased risk of dementia and delirium. Only women with rheumatoid arthritis and systemic lupus erythematosus had an increased risk of psychotic disorders and severe depression. CONCLUSION: Health care providers who encounter patients with rheumatic diseases should be aware that these patients are more likely to develop neuropsychiatric disorders and that some subgroups seem to be more vulnerable than others.
16756798 [Elbow arthroplasty]. 2006 May 8 Each year, about 80 elbow arthroplasties are performed in Denmark. Approximately two thirds are done due to rheumatoid arthritis, the others due to comminuted fractures of the elbow, especially in elderly patients. The prosthesis is fixed with or without bone cement, and there are two different types of elbow prostheses: linked, in which the humerus and ulna are connected by a sloppy hinge, and non-linked, in which stability is dependent on the soft tissues of the elbow. Good pain relief can be expected, but the range of motion will usually be permanently affected.