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ID PMID Title PublicationDate abstract
20732650 Therapeutic opportunities in fibroblasts in inflammatory arthritis. 2010 Aug The Identification of key players of inflammation and pathologic immune response in rheumatoid arthritis (RA) has resulted in the development of novel therapeutic strategies revolutionising the treatment of disease. However, these new therapeutics only indirectly affect the mesenchymal compartment of the inflamed synovium and, in particular, the specific phenotype of activated fibroblast-like cells. These cells have been demonstrated to trigger not only the progressive destruction of articular cartilage and bone but also the switch from acute to chronic inflammation. Therefore, targeting of this population of fibroblast-like cells may provide interesting opportunities to go beyond the mere inhibition of inflammation and to interfere with key disease processes in RA. This review summarises our current knowledge on the role of fibroblast-like cells in RA and points to potentials ways of modulating their disease-specific activation.
19235673 Doppler ultrasonography and dynamic magnetic resonance imaging for assessment of synovitis 2009 Mar Rheumatoid arthritis (RA) activity is closely correlated with inflammation. The synovial membrane is the principal site of inflammation in which the inflammatory process enhances capillary perfusion and permeability. Doppler ultrasonography (DUS), using the amount of color pixels in the region of interest, and dynamic magnetic resonance imaging (DE-MRI), using the early enhancement rate and relative enhancement of the synovium, are both able to detect this inflammation in the wrist and hand. Although these techniques are both capable of monitoring synovium inflammation modifications after RA treatment, DE-MRI may be better for quantifying inflammation changes. It yields additional information about joint inflammation and complements clinical and biological examination, the current reference standard. DUS could become an essential tool for RA joint monitoring in routine practice in view of its sensitivity in the detection of synovitis, feasibility in outpatient clinics, and low cost, whereas DE-MRI could become a valid imaging gold standard against which other measures should be compared, especially in clinical trials.
20740612 Serum IgA rheumatoid factor and pyridinoline in very early arthritis as predictors of eros 2010 Dec OBJECTIVE: To identify, in conservatively treated, very early arthritis patients, predictors of ≥1 erosion(s) at 2 years, and to construct a prediction model. METHODS: Community-based adults (n=310) who had never taken disease-modifying antirheumatic drugs (DMARDs) or steroids with swelling of ≥2 joints persisting for >4 weeks and lasting <6 months were recruited. Erosion status was assessed at 0, 6, 12, and 24 months; evaluations were comprised of clinical criteria (Disease Activity Score, Health Assessment Questionnaire), C-reactive protein level, erythrocyte sedimentation rate, autoantibodies, bone and cartilage markers, hand densitometry, and HLA class II shared epitopes. Patients meeting American College of Rheumatology rheumatoid arthritis (RA) criteria or with undifferentiated arthritis (UA) were followed and treated conservatively: one-third of RA patients and three-fourths of UA patients received no DMARDs during 2 years; a biologic agent was given to 1.8% of the patients during the first year. The main judgment criterion was ≥1 erosion(s) at 2 years. RESULTS: At 2 years, 219 patients were assessed; 31.3% with RA and 10.6% with UA had ≥1 erosion(s). Logistic regression analysis at that time showed erosion(s) strongly associated with serum IgA rheumatoid factor (IgA-RF) and pyridinoline levels for the 190 patients with no baseline erosions, with the corresponding receiver operating characteristic curve having an area under the curve of 0.77 (95% confidence interval 0.64-0.86). A prediction model was constructed with IgA-RF thresholds of 5 and 25 IU/ml and a pyridinoline threshold of 10 nM/liter; odds ratios ranged from 1 for IgA-RF<5 IU/ml and pyridinoline <10 nM/liter to 50.75 for the association of IgA-RF≥5 IU/ml and pyridinoline≥10 nM/liter. CONCLUSION: This model, using serum IgA-RF and pyridinoline concentrations, was able to predict≥1 erosion(s) at 2 years in very early arthritis patients.
19491524 [Elderly-onset rheumatoid arthritis distinguished from polymyalgia rheumatica with maligna 2009 Mar The differential diagnosis between polymyalgia rheumatica and elderly-onset rheumatoid arthritis is difficult because these diseases share similar clinical findings, especially at onset. We report a case of elderly-onset rheumatoid arthritis that was distinguished from polymyalgia rheumatica with malignancy. A 77-year-old woman was admitted to our hospital because of pain and bilateral stiffness in her shoulders and her hips. Tests for rheumatoid factor and anti-cyclic citrullinated peptide antibody were negative. Bone erosions and joint space narrowing were not detected radiographically, and polymyalgia rheumatica was suspected. Her arthralgia disappeared with a few days after treatment with prednisolone (10 mg per day) was started, and ESR and CRP were normalized. Computed tomographic scanning of the chest showed a nodular lesion in the right lower lobe, and biopsy revealed lung cancer. Positron-emission tomography with 18F-fluorodeoxyglucose (FDG) performed before lung surgery showed increased uptake of FDG in the bilateral shoulder joints and wrist joints. Enhanced MRI showed synovitis and bone erosions in the right acromioclavicular joint and bilateral carpal bones and also radiographically bone erosions were seen in the carpometacarpal joint of the right thumb. Therefore, a diagnosis of elderly-onset rheumatoid arthritis was made. In patients with polymyalgia rheumatica, the detection of rheumatoid synovitis should be routinely evaluated.
19604448 Selective modulation of T-cell co-stimulation: a novel mode of action for the treatment of 2009 May Disease-modifying antirheumatic drug therapy, including biological treatments that act via tumour necrosis factor (TNF)-alpha blockade, have benefited numerous patients suffering from rheumatoid arthritis (RA). However, a portion of the patient population is unresponsive to initial therapy, experience a decline in response over time or may develop side effects to treatment. These factors illustrate the requirement for additional therapy options, with novel modes of action, in order to treat this chronic and disabling disease. Activated T cells predominate in the disease processes of RA. Therefore, one rational approach to therapy is to modulate or target T cells. Abatacept is a first-in-class agent that targets T-cell modulation via the co-stimulatory CD80/CD86:CD28 pathway. Preclinical studies and clinical trials have demonstrated both the rationale and efficacy of using T-cell modulation as a therapeutic approach and, as a result, abatacept is currently approved in the European Union for the treatment of RA in adults with moderately to severely active disease who have not responded to TNF-alpha antagon-ist therapy. This review will highlight abatacept as an important treatment option in the therapeutic repertoire for RA that selectively modulates T-cell co-stimulation.
20883640 Relationships among vitamin D, disease activity, pain and disability in rheumatoid arthrit 2010 Sep BACKGROUND AND OBJECTIVES: Vitamin D is a steroid hormone with important skeletal and non-skeletal biologic functions. Vitamin D deficiency is common and manifests with musculoskeletal symptoms. In rheumatoid arthritis (RA), vitamin D deficiency may be associated with increased disease activity and disability. We aimed to estimate the relationship between Vitamin D level and disease activity, pain, and disability in RA. METHODS: Data were drawn from 62 RA patients seen in an academic arthritis clinic. 25(OH)D levels were evaluated along with markers of RA disease activity, physician and patient global assessments, pain (VAS) and HAQ. DAS-28 was calculated. Vitamin D deficiency was defined as 25(OH)D levels<30ng/ml. RESULTS: Sixty-one percent of RA patients were classified as vitamin D deficient. In patients with active RA (DAS 28 score≥2.6), 25(OH)D was moderately and inversely associated with DAS 28 (-0.38), pain (-0.49) and HAQ (-0.54) (p<0.01). However, no significant associations were found between 25(OH)D and these variables in patients in remission (DAS 28<2.6). Vitamin D deficient patients with active RA had six times the odds (OR=6.0, 95% CI 1.2-31.2) of being moderately or severely disabled (HAQ≥1.25). CONCLUSIONS: Vitamin D deficiency was common in this RA group. In patients with moderate to high disease activity, vitamin D deficiency was associated with higher DAS scores, pain and disability. Clinicians in northern climates may wish to monitor vitamin D status in their RA patients.
19596176 Invasive potential of human rheumatoid tenosynovial cells is in part MT1-MMP dependent. 2009 Sep PURPOSE: In rheumatoid arthritis, tenosynovial invasion of tendon is associated with an increased rate of tendon rupture and a worse clinical prognosis compared to noninvasive disease. Tendon is composed predominantly of type I collagen, which can be efficiently degraded by collagenolytic matrix metalloproteinases (MMPs), one of which, MT1-MMP, is membrane bound and inhibited by tissue inhibitor of metalloproteinase-2, but not by TIMP-1. The role of MT1-MMP in tendon disease is unknown. In this report, we investigate the potential role of MT1-MMP in invasion of tenosynovium into tendon. METHODS: Matched synovial specimens were obtained from different regions of the wrist in 36 rheumatoid patients having extensor tenosynovectomy in most instances. The tenosynovium that was removed was surrounding tendons (termed encapsulating) invading tendons (termed invasive), and wrist joint synovium. Samples of tenosynovium were tested for MT1-MMP using Western blotting, and the MT1-MMP activity was quantified using commercial assays. Next, a 3-dimensional collagen assay was created, using freshly isolated tenosynovium. Transwell collagen invasion assays were then performed, using isolated tenosynovial cells to determine MT1-MMP's effect on tendon invasion. RESULTS: The MT1-MMP was present in 9 of 10 joint samples, 4 of 6 encapsulating tenosynovial samples, and 5 of 5 invasive tenosynovial samples. Activity assays demonstrated that mean levels of active MT1-MMP produced by joint samples was 6.1 +/- 4.1 ng/mL; by encapsulating tenosynovium was 3.9 +/- 4.2 ng/mL, and by invasive tenosynovium was 6.2 +/- 1.1 ng/mL. The 3-dimensional gel assays demonstrated that cell invasion was reduced by the addition of TIMP-2 and GM-6001(a broad spectrum matrix metalloproteinase inhibitor) but not by TIMP-1. The addition of TIMP-2 to invasion assays reduced the mean number of cells that invaded the collagen membrane from 11 +/- 5 cells/field to 7 +/- 3 cells/field in treated samples (p = .04). CONCLUSIONS: Our results demonstrate that MT1-MMP is present in rheumatoid tenosynovium and that MT1-MMP facilitates tenosynovial cell invasion into a type I collagen matrix, suggesting that MT1-MMP plays a crucial role in tendon invasion. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.
20444754 Influence of anti-TNF therapy on mortality in patients with rheumatoid arthritis-associate 2010 Jun BACKGROUND: Anti-tumour necrosis factor (anti-TNF) therapy has been associated with reports of rapid severe progression of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). However, reports also exist of favourable responses to anti-TNF therapy in patients with ILD. The aim of this study was to examine the influence of anti-TNF therapy on mortality in patients with pre-existing RA-ILD. METHODS: Using data from the British Society for Rheumatology Biologics Register, a national prospective observational study, 367 patients with pre-existing RA-ILD were identified (299 treated with anti-TNF therapy and 68 treated with traditional disease-modifying antirheumatic drugs (DMARDs)). RESULTS: 70/299 patients (23%) in the anti-TNF cohort died after a median follow-up of 3.8 years compared with 14/68 (21%) in the DMARD cohort after a median follow-up of 2.1 years. The mortality was 68 deaths/1000 person years (pyrs) (95% CI 53 to 86) in the anti-TNF cohort and 92/1000 pyrs (95% CI 50 to 155) in the DMARD cohort, generating an age- and sex-adjusted mortality rate ratio (aMRR) of 1.26 (95% CI 0.69 to 2.31). After further adjustment for potential confounders, the aMRR fell to 0.81 (95% CI 0.38 to 1.73) for the anti-TNF cohort compared with the DMARD cohort. RA-ILD was the underlying cause of death in 15/70 (21%) and 1/14 (7%) patients in the anti-TNF and DMARD cohorts, respectively. CONCLUSION: The mortality in patients with RA-ILD is not increased following treatment with anti-TNF therapy compared with traditional DMARDs. The proportion of deaths attributable to RA-ILD is higher in patients treated with anti-TNF therapy, although reporting bias may exist.
19767388 Influence of recent exercise and skin temperature on ultrasound Doppler measurements in pa 2009 Dec OBJECTIVE: Use of ultrasound Doppler (USD) in diagnosing and treatment monitoring of patients with RA has increased considerably. Hyperaemia is an integral part of the inflammatory response, and the amount of USD activity in an inflamed synovium may therefore be used to quantify the inflammatory activity. It is unclear, however, whether the hyperaemia alone reflects the disease activity or may be influenced by other factors. METHODS: Twenty-nine patients with RA underwent USD examination of the wrist before and immediately after three interventions. The interventions were carried out on three separate days. The interventions were (i) isometric exercise of the muscles of the hand and forearm, (ii) heating and (iii) cooling of the hand. The amount of Doppler in the wrist joint was quantified by measuring the percentage of colour in the synovium-the colour fraction (CF). The CF values estimated before and after each intervention were compared to see if any intervention affected the amount of Doppler in the synovium. RESULTS: The CF decreased significantly after cooling of the hand (P = 0.018 and <0.0001). Despite being highly significant, the numerical decrease in CF was only modest, 0.78-1.33 percentage points. The other interventions did not affect the CF significantly, with P-values of 0.65 and 0.59 in the heating intervention and 0.49 in the exercise intervention. CONCLUSIONS: Cooling of the hand should, if possible, be avoided before a USD examination of the wrist in patients with RA, because the amount of Doppler activity might be affected by low skin temperatures.
18952639 Orthopaedic surgery in 255 patients with inflammatory arthropathies: longitudinal effects 2009 Oct OBJECTIVE: To examine the effectiveness of orthopaedic surgery in patients with inflammatory arthropathies with regard to longitudinal changes in pain, physical function and health-related quality of life and explore differences in effectiveness between replacement versus non-replacement surgery and surgery in the upper versus the lower limb. METHODS: 255 patients (mean age 57.5 years (SD 13.1), 76.7% female) with inflammatory arthropathies underwent orthopaedic surgical treatment and responded to mail surveys at baseline and during follow-up (3, 6, 9 and 12 months). The booklet of questionnaires included the arthritis impact measurement scales 2 (AIMS2), health assessment questionnaire (HAQ), short form 36 (SF-36), EQ-5D and visual analogue scales (VAS) addressing patient global, fatigue, general pain and pain in the actual joint. Standardised response means (SRM) were calculated to estimate the magnitude of improvement. RESULTS: Significant improvement was seen for most of the dimensions of health, the largest improvement for pain in the actual joint (SRM 1.17) at one year follow-up. SRM for AIMS-2 physical, SF-36 physical and HAQ were 0.1, 0.48 and 0.05, respectively. The overall numeric improvement (SRM) in utility was 0.10 (0.37) with EQ-5D and 0.03 (0.27) with SF-6D. Improvement overall was similar after surgery in the upper versus the lower limb, but was larger in patients undergoing replacement surgery than in patients undergoing other surgical procedures (SRM 1.54 vs 1.08 for pain in the actual joint). CONCLUSIONS: Surgical procedures have a major positive impact on pain in the actual joint, but improvement is less in other dimensions of health. Health benefits were larger after replacement surgery than after other surgical procedures.
21149243 Cost of illness in rheumatoid arthritis in Germany in 1997-98 and 2002: cost drivers and c 2011 Apr OBJECTIVE: Comparison of overall RA-related costs and of relative contribution of single-cost domains before and after the introduction of TNF-blocking agents in Germany. METHODS: Two cohorts of RA outpatients (ACR '87 criteria) with long-standing disease are assessed in terms of disease-related costs and cost composition (n = 106 patients in 1997-98 and n = 180 patients in 2002 with similar patient characteristics). Full-cost analyses are performed including direct disease-related costs (medical and non-medical) and productivity costs as collected by patient questionnaires. Absolute costs (€/patient/year) are compared and the impact of single-cost domains on overall costing in RA is estimated (relative proportions of cost components within samples). RESULTS: Overall costs are comparable (1997-98: €4280; 2002: €3830; not significant). Differences can be observed in medication (1997-98: €550; 2002: €1580; P < 0.001) and hospitalization costs (1997-98: €1240; 2002: €500; P < 0.001). Productivity costs are significantly lower (€1480 vs €850; P < 0.05) in 2002. The impact of medication costs is outstanding in the 2002 sample (42 vs 12%), the proportion of hospitalization costs is substantially lower (29 vs 13%). Costs for DMARDs in 2002 are mostly driven by TNF blockers (37%). The number of DMARDs per patient is higher in 2002 as are costs for osteoporosis medication and gastroprotective treatment. CONCLUSION: Although overall costs before and after the introduction of TNF blockers are comparable, the decrease in hospitalization and productivity costs is promising in terms of future long-term cost savings. The development of these aspects and of the increasing medication costs will have to be evaluated with longer time frames.
19737838 A haplotype in STAT4 gene associated with rheumatoid arthritis in Caucasians is not associ 2009 Nov OBJECTIVE: Several studies have shown that a haplotype (rs11889341, rs7574865, rs8179673 and rs10181656) in STAT4 is associated with the development of RA in Caucasian, Korean and Japanese populations. The aim of this study was to investigate the effect of STAT4 on susceptibility to RA in the Han Chinese population. METHODS: Unrelated 750 RA patients and individually matched 750 healthy controls were genotyped for single nucleotide polymorphism (SNP), rs11889341, in STAT4, which tags the susceptibility haplotype. Association analyses were performed on the whole data set and on sex subsets. Significant relationships were determined between clinical variables and rs11889341 for each disease subtype in the studied groups. RESULTS: There was no evidence of a significant association between rs11889341 and RA. The heterozygous CT genotype was associated with RA in female group [P = 0.027; odds ratio (OR) 1.31; 95% CI 1.03, 1.65]. No association was found in male group and in any subsets of RA based on sex, RF and anti-cyclic citrullinated peptide (anti-CCP) antibody. However, in the Han Chinese population with RA disease, we observed a significantly decreased frequency of the minor T allele and TT genotype in the RF-positive subgroup compared with RF-negative subgroup (T allele: P = 0.024; OR 0.73; 95% CI 0.56, 0.95; TT genotype P = 0.013; OR 0.49; 95% CI 0.28, 0.86). CONCLUSION: The STAT4 RA-susceptibility haplotype identified in other previously reported populations has not been replicated in the Han Chinese population with individually matched case-control study design. It is associated only with the presence of RF in the Han Chinese population with RA disease.
19822043 Inflammation and repair mechanisms. 2009 Jul Although both rheumatoid arthritis (RA) and ankyosing spondylitis (AS) belong to the group of chronic inflammatory rheumatic diseases, they are quite different regarding mechanisms of inflammation and repair. While RA is an erosive destructive disease with the synovium as the primary site of inflammation, the immune response in AS takes place primarily at the cartilage/bone interface, and the pathological but also the clinical picture is determined by an until not yet well defined interaction between inflammation and new bone formation. Most recently, first insights into the molecular mechanisms between inflammation and bone destruction or new bone formation could be obtained. Key molecules involved in bone homeostasis seem to differ between RA and AS patients. While the molecules sclerostin and dickkopf 1, both inhibitors of osteoblasts, are elevated in RA they are found to be rather low in AS. It can be expected that the rapidly expanding new field of osteoimmunology will help to clarify the pathogenesis of the these two diseases with possible implications for new treatment targets.
19421244 Role for TNF in atherosclerosis? Lessons from autoimmune disease. 2009 Jun Inflammatory pathways have been implicated in the initiation and progression of cardiovascular diseases. Accelerated atherosclerosis has been described in patients with chronic inflammatory diseases, particularly rheumatoid arthritis, disproportionate to individuals' detectable traditional vascular risk factors. This finding suggests that other pathways associated with inflammation might account for increased vascular risk in such diseases. Highly specific biologic agents can precisely block the activity of cytokines generated during inflammatory cascades; the effects of these inflammatory moieties on vascular physiology and overall risk of cardiovascular events has been directly evaluated. This review summarizes key epidemiologic, physiologic and model data, which together suggest that tumor necrosis factor, a pivotal cytokine in the inflammatory cascade, is directly involved in vascular pathophysiology and that its inhibition might confer an overall advantage to the recipient. Moreover, such data obtained in chronic inflammatory diseases likely have relevance to primary atherosclerosis.
20211020 Circulating surfactant protein -D is low and correlates negatively with systemic inflammat 2010 INTRODUCTION: Surfactant protein D (SP-D) is a collectin with immuno-regulatory functions, which may depend on oligomerization. Anti-microbial and anti-inflammatory properties have been attributed to multimeric SP-D variants, while trimeric subunits per se have been suggested to enhance inflammation. Previously, we reported low circulating SP-D in early rheumatoid arthritis (RA), and the present investigation aims to extend these data by serial SP-D serum measurements, studies on synovial fluid, SP-D size distribution and genotyping in patients with early RA. METHODS: One-hundred-and-sixty disease-modifying antirheumatic drug (DMARD) naïve RA patients with disease duration less than six months were studied prospectively for four years (CIMESTRA (Ciclosporine, Methotrexate, Steroid in RA) trial) including disease activity measures (C-reactive protein, joint counts and Health Assessment Questionnaire (HAQ) score), autoantibodies, x-ray findings and SP-D. SP-D was quantified by enzyme-linked immunosorbent assay (ELISA) and molecular size distribution was assessed by gel filtration chromatography. Further, SP-D Met11Thr single nucleotide polymorphism (SNP) analysis was performed. RESULTS: Serum SP-D was significantly lower in RA patients at baseline compared with healthy controls (P < 0.001). SP-D increased slightly during follow-up (P < 0.001), but was still subnormal at four years after adjustment for confounders (P < 0.001). SP-D in synovial fluid was up to 2.5-fold lower than in serum. While multimeric variants were detected in serum, SP-D in synovial fluid comprised trimeric subunits only. There were no significant associations between genotype distribution and SP-D. Baseline SP-D was inversely associated to CRP and HAQ score. A similar relationship was observed regarding temporal changes in SP-D and CRP (zero to four years). SP-D was not associated to x-ray findings. CONCLUSIONS: This study confirms that circulating SP-D is persistently subnormal in early and untreated RA despite a favourable therapeutic response obtained during four years of follow-up. SP-D correlated negatively to disease activity measures, but was not correlated with x-ray progression or SP-D genotype. These observations suggest that SP-D is implicated in RA pathogenesis at the protein level. The exclusive presence of trimeric SP-D in affected joints may contribute to the maintenance of joint inflammation. TRIAL REGISTRATION: (j.nr NCT00209859).
21395112 [Mononuclear phagocytes in rheumatoid arthritis: discordance of ingestion]. 2010 Oct The following functions of mononuclear phagocytes of 24 patients with rheumatoid arthritis, 24 their relatives, and 24 women, not hereditary tainted with autoimmune diseases (control) were compared: (1) engulfment and digestion (radioisotope method); (2) release of lysosomal glucuronidase during the interaction of cells with opsonized zymosan (fluorescent method). In rheumatoid arthritis the slowed down process of engulfment and preliminary extracellular digestion was combined with accelerated digestive potential. In relatives, the delayed and suppressed engulfment was associated with the decelerated digestive mononuclear phagocyte potential. The congenital peculiarity of the cell functioning was suggested, being due to the imperfect anti infectious defense in predisposed to the disease individuals, on one hand, and to the excessive damage of the surrounding tissues and to the provocation of autoimmune processes.
20618765 Golimumab therapy of rheumatoid arthritis: an overview. 2010 Aug Golimumab is a new approved humanized antibody for the treatment of rheumatoid arthritis (RA). This antibody belonging to biologic agents is raised against the pro-inflammatory cytokine tumour necrosis factor-alpha playing an essential role in the initiation of RA. To date, Golimumab administration for patients with RA, as indicated by USA Food and Drug Administration, is subcutaneous combined with methotrexate (MTX). Here, we have reviewed current literature with a focus on characteristics of Golimumab and also have exposed the clinical trials either using MTX or not using MTX. We have also highlighted the incoming clinical trials on Golimumab and have proposed some indications for the future studies based on a setting of clinical data and post-marketing observational studies. These studies will advance rheumatologists' decisions in the beginning of RA therapeutic interventions to insure the best outcomes for patients with RA and to improve their quality of life.
20735862 Rationale of using different biological therapies in rheumatoid arthritis. 2010 Due to ongoing developments of novel agents in the field of biological pharmacotherapy, there are now more arrows available in clinicians' quivers for the treatment of rheumatic conditions. As a consequence, however, clear treatment strategies have to be defined in order to guarantee a qualitatively high and individually stage-adapted, state-of-the-art regimen for affected patients. This review summarizes recent evidence regarding the rationale of using different biological therapies to treat rheumatoid arthritis, the most common inflammatory joint disorder after activated osteoarthritis, and draws an actual picture of a possible standardized therapeutic algorithm without claiming exclusive appropriateness.
19798031 Regulatory T cells as therapeutic targets in rheumatoid arthritis. 2009 Oct Regulatory T cells (TREG) are a subset of CD4+ T cells with a critical role in the prevention of autoimmunity. Whether defects in TREG contribute to the pathogenesis of rheumatoid arthritis (RA) is unclear. However, a variety of approved and experimental drugs for RA may work, in part, by promoting the function or increasing numbers of TREG. Furthermore, animal studies demonstrate that direct injection of TREG ameliorates a wide range of experimental models of inflammatory and autoimmune diseases. Thus, cell-based therapy with TREG has the potential to produce durable disease remission in patients with RA.
21173018 Role of oxidative stress in rheumatoid arthritis: insights from the Nrf2-knockout mice. 2011 May OBJECTIVES: Increasing evidence suggests that oxidative stress may play a key role in joint destruction due to rheumatoid arthritis (RA). The aim of this study was to elucidate the role of nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that maintains the cellular defence against oxidative stress, in RA. METHODS: The activation status of Nrf2 was assessed in synovial tissue from patients with RA using immunohistochemistry. Antibody-induced arthritis (AIA) was induced in Nrf2-knockout and Nrf2-wild-type control mice. The severity of cartilage destruction was evaluated using a damage score. The extent of oxidative stress, the activation state of Nrf2 and the expression level of Nrf2 target genes were analysed by immunhistological staining. The expression of vascular endothelial growth factor (VEGF)-A was examined on mRNA and protein using the Luminex technique. A Xenogen imaging system was used to measure Nrf2 activity in an antioxidant response element-luciferase transgenic mouse during AIA. RESULTS: Nrf2 was activated in the joints of arthritic mice and of patients with RA. Nrf2-knockout mice had more severe cartilage injuries and more oxidative damage, and the expression of Nrf2 target genes was enhanced in Nrf2-wild-type but not in knockout mice during AIA. Both VEGF-A mRNA and protein expression was upregulated in Nrf2-knockout mice during AIA. An unexpected finding was the number of spontaneously fractured bones in Nrf2-knockout mice with AIA. CONCLUSION: These results provide strong evidence that oxidative stress is significantly involved in cartilage degradation in experimental arthritis, and indicate that the presence of a functional Nrf2 gene is a major requirement for limiting cartilage destruction.