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ID PMID Title PublicationDate abstract
20848160 "Old drugs" for the treatment of rheumatoid arthritis: will the cholinergic anti-inflammat 2010 Dec Based on the newly discovered cholinergic anti-inflammatory pathway, on the anti-nociceptive pathway and on our preliminary research, we raise a new strategy for the treatment of rheumatoid arthritis (RA) which mainly focuses on the application of old drugs that can activate both of the above mentioned pathways. It has been reported that nicotinic receptor agonists used for the treatment of neurological diseases were expected to be applied to the therapy of inflammatory diseases (RA). Therefore, it is promising that old drugs available in clinics may exert new functions for the treatment of RA, which may greatly reduce the expense of such treatment, once applied. These currently-used old drugs should be considered as another new resource in exploring anti-rheumatic agents under the guidance of the newly discovered cholinergic anti-inflammatory pathway and the anti-nociceptive pathway.
20889601 Disease activity, physical function, and radiographic progression after longterm therapy w 2010 Nov OBJECTIVE: To evaluate the efficacy and safety of initial combination treatment with adalimumab (ADA) and methotrexate (MTX) versus monotherapy with ADA or MTX during an open-label extension of PREMIER. METHODS: Patients with early rheumatoid arthritis (RA) received blinded ADA plus MTX, ADA alone, or MTX alone for 2 years in PREMIER. At Year 2, patients could enroll in an open-label extension and receive ADA monotherapy; MTX could be added at the investigator's discretion. Longterm efficacy results are presented as observed data. RESULTS: In the open-label period, 497 of the original 799 randomized patients had ≥ 1 dose of ADA (by original randomization: ADA plus MTX, n = 183; ADA, n = 159; MTX, n = 155). In the completers cohort [patients with available Year-5 ACR responses and modified total Sharp scores (mTSS)], the Year-5 mean change from baseline in mTSS for the ADA+MTX arm (n = 124) was 2.9, compared with 8.7 and 9.7 in the ADA (n = 115) and MTX (n = 115) arms. Comprehensive disease remission, defined as the combination of DAS28 remission, normal function (Health Assessment Questionnaire ≤ 0.5), and radiographic nonprogression (ΔmTSS ≤ 0.5), was achieved by more patients in the initial ADA+MTX arm (35%) than in the ADA (13%) or MTX (14%) arms. CONCLUSION: Initial combination treatment with ADA plus MTX, followed by open-label ADA, led to better longterm clinical, functional, and radiographic outcomes than either initial ADA or MTX monotherapy during 5 years of treatment.
19850657 An analysis of joint replacement in patients with systemic lupus erythematosus. 2009 Dec A small but important group of patients in our lupus cohort has needed total joint replacement (TJR). Arthritis was identified in 94% of our lupus patients. We have determined how many of our patients needed TJR, explored the risk factors for this procedure in patients with SLE and reviewed the outcome for these patients. Records of the cohort of patients with SLE who have attended our lupus clinic at University College of London Hospital/Middlesex from 1978 to 2008 were reviewed and patients who underwent TJR were identified. We recorded demographic data, other major systemic manifestations of SLE, autoantibody profile, previous use of steroids, other major systemic illnesses, smoking and alcohol habits. Nineteen patients with SLE from our cohort of 500 were found to have at least one TJR. Avascular necrosis (AVN) or concomitant rheumatoid arthritis (RA) was present in the majority of these patients. In contrast, age at disease onset, the presence of anti-cardiolipin antibodies, Raynaud's phenomenon and smoking habits were not found to be contributing factors for the need to replace joints. Four of our 19 patients (21.1%) had complications of the joint replacement: two of them had infections of the replaced joint, one had a large haematoma immediately after the surgery requiring surgical evacuation and the other had a deep vein thrombosis. None of the patients so far has required joint re-replacement. In conclusion, 4% of SLE patients in our cohort have one or more joints replaced, the majority because of AVN or RA.
20676797 The psychological impact of arthritis: the effects of illness perception and coping. 2011 Mar BACKGROUND: Coping and illness perception are considered to be important contributors in the relationship between physical and psychological factors in rheumatoid arthritis (RA). AIMS: The aim of this study was to examine the complex relationship of coping and illness perception on physical and psychological factors in RA using a structural model. METHODS: We assessed coping, illness perception, depression, anxiety, pain, arthritis-related disability and perceived social support in 68 adults with RA. RESULTS: Greater pain was detected in patients with increased scores on passive coping scale, greater severity of physical disability and increased depression and anxiety. Illness perception was found to be a mediator in the relationship between physical disability and passive coping on one hand and depression, anxiety and pain on the other. CONCLUSIONS: The hypothesised structural model has proven to be a useful paradigm for understanding the associations between multiple factors in RA presentation: clinical, emotional, personal and cognitive.
20581375 Angiogenesis and nerve growth factor at the osteochondral junction in rheumatoid arthritis 2010 Oct Objectives. The osteochondral junction can be a source of pain in both RA and OA. Growth of blood vessels and nerves from the subchondral bone into articular cartilage may mediate the association between joint pathology and symptoms. We have investigated associations between angiogenesis, inflammation and neurovascular growth factor expression at the osteochondral junction in human arthritis. Methods. Osteochondral junctions from medial tibial plateaux of patients undergoing arthroplasty for RA (n = 10) or OA (n = 11), or from non-arthritic post-mortem controls (n = 11) were characterized by immunohistochemistry for CD34 and smooth muscle α-actin (blood vessels), CD68 (macrophages), CD3 (lymphocytes), proliferating cell nuclear antigen, vascular endothelial, platelet-derived and nerve growth factor (NGF). Results. Osteochondral angiogenesis was demonstrated as increased endothelial cell proliferation and vascular density in non-calcified articular cartilage, both in RA and OA. Osteochondral angiogenesis was associated with subchondral bone marrow replacement by fibrovascular tissue expressing VEGF, and with increased NGF expression within vascular channels. RA was characterized by greater lymphocyte infiltration and PDGF expression than OA, whereas chondrocyte expression of VEGF was a particular feature of OA. NGF was observed in vascular channels that contained calcitonin gene-related peptide-immunoreactive sensory nerve fibres. Conclusions. Osteochondral angiogenesis in RA and OA is associated with growth factor expression by cells within subchondral spaces, vascular channels and by chondrocytes. NGF expression and sensory nerve growth may link osteochondral angiogenesis to pain in arthritis.
19224904 Withdrawal of disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: 2010 Oct OBJECTIVE: To define the effects of withdrawing disease-modifying antirheumatic drug (DMARD) treatment from patients with established rheumatoid arthritis (RA) receiving stable, effective long-term DMARD treatment. METHODS: A systematic literature search was conducted. Studies were included that were of high quality and enrolled adults with RA over 2 years' duration. A meta-analysis was performed on the number of disease flares in groups withdrawn from DMARD treatment compared with those who continued to receive DMARD. RESULTS: The randomised controlled trial data were pooled into a meta-analysis and this showed that patients who withdrew from DMARD had a significantly worse risk of disease flare or deterioration than those who continued DMARD treatment. CONCLUSION: In patients who have their disease adequately controlled by DMARD and wish to reduce the dose or withdraw them, this should be done cautiously. Their disease activity should be monitored carefully so that they recommence DMARD therapy in the event of disease flare or deterioration.
18853167 Incidence of rheumatoid arthritis from 1995 to 2001: impact of ascertainment from multiple 2009 Feb The aim of this study was to describe the mean incidence rate of rheumatoid arthritis over a 7-year period from 1995 to 2001 in a population in the southern part of Denmark, using the data from several sources. Cases fulfilling the 1987 American College of Rheumatology criteria for rheumatoid arthritis were identified at hospitals and private practising rheumatologists (referral centres), and in general practice. The observed incidence was 32/100,000 person-years (95% confidence interval 29-35). Using the ratio between the number of cases known only from general practice and the number known from general practice and referral centres, the estimated incidence was 35/100,000 person-years (95% confidence interval 32-38). We suggest that the estimated rate should be viewed as a plausible upper limit for the incidence of rheumatoid arthritis in the southern part of Denmark.
20553969 Patterns of muscle strength loss with age in the general population and patients with a ch 2010 Oct BACKGROUND: There is growing recognition of the serious consequences of sarcopenia on the functionality and autonomy in old age. Recently, the age-related changes in several inflammatory mediators have been implicated in the pathogenesis of sarcopenia. The purposes of this systematic review were two-fold: (1) to describe the patterns of muscle strength loss with age in the general population, and (2) to quantify the loss of muscle strength in rheumatoid arthritis as representative for an underlying inflammatory state. Handgrip strength was used as a proxy for overall muscle strength. RESULTS: Results from 114 studies (involving 90,520 subjects) and 71 studies (involving 10,529 subjects) were combined in a meta-analysis for the general and rheumatoid arthritis population respectively and standardized at an equal sex distribution. For the general population we showed that between the ages of 25 years and 95 years mean handgrip strength declined from 45.5 kg to 23.2 kg for males and from 27.1 kg to 12.8 kg for females. We noted a steeper handgrip strength decline after 50 years of age (rate of 0.37 kg/year). In the rheumatoid arthritis population handgrip strength was not associated with chronological age between the ages of 35 years and 65 years and was as low as 20.2 kg in male and 15.1 in female. Rheumatoid arthritis disease duration was inversely associated with handgrip strength. CONCLUSIONS: This meta-analysis shows distinct patterns of age-related decrease of handgrip strength in the general population. Handgrip strength is strongly associated with the presence and duration of an inflammatory state as rheumatoid arthritis. The putative link between age-related inflammation and sarcopenia mandates further study as it represents a potential target for intervention to maintain functional independence in old age.
21078798 Imaging of inflammation by PET, conventional scintigraphy, and other imaging techniques. 2010 Dec Nuclear medicine imaging procedures play an important role in the assessment of inflammatory diseases. With the advent of 3-dimensional anatomic imaging, there has been a tendency to replace traditional planar scintigraphy by CT or MRI. Furthermore, scintigraphic techniques may have to be combined with other imaging modalities to achieve high sensitivity and specificity, and some may require time-consuming labeling procedures. On the other hand, new developments such as combined SPECT/CT increase the diagnostic power of scintigraphy. Also, the advent of PET had a considerable impact on the use of nuclear medicine imaging techniques. In this review, we aim to provide nuclear medicine specialists and clinicians with the relevant information on rational and efficient use of nuclear medicine imaging techniques in the assessment of patients with osteomyelitis, infected vascular prostheses, metastatic infectious disease, rheumatoid arthritis, vasculitis, inflammatory bowel disease, sarcoidosis, and fever of unknown origin.
19837204 Illness beliefs predict disability in rheumatoid arthritis. 2009 Nov OBJECTIVE: This study examined the relationships between patients' beliefs about rheumatoid arthritis (using Leventhal's Common Sense Model) and their levels of disability, health-related quality of life, and disease activity. A proposed illness beliefs construct of "seriousness" was also investigated, combining beliefs about illness identity (symptoms), consequences, and timeline. METHOD: A cross-sectional study evaluated 125 patients with rheumatoid arthritis from two South East London hospitals. Questionnaires assessed their illness beliefs, disability, and quality of life. An objective measure of disease activity was also obtained. RESULTS: Higher disability scores were associated with beliefs about identity (r=.31, P<.01) and consequences (r=.28, P<.01). Stronger control beliefs were associated with lower disability (r=-.40, P<.01) and better physical (r=.20, P<.05) quality of life. Disease activity scores, although positively related to disability scores (r=.39, P<.01), showed no associations with illness beliefs. Multivariate analysis resulted in models accounting for 45.5%, 27.3%, and 19.3% variance in disability, "physical quality of life" scores, and "mental quality of life" scores, respectively. The hypothesis for a proposed "seriousness" construct was not supported. CONCLUSION: Patients' beliefs about their rheumatoid arthritis are associated with disability and quality of life and cannot be explained by disease status. Longitudinal research is needed to assess the stability of beliefs.
20514776 Cardiac and pulmonary alterations in patients with rheumatoid arthritis. 2010 INTRODUCTION: cardiac and pulmonary clinical manifestations frequently absent in patients with rheumatoid arthritis (RA). The aim of this study was to evaluate cardiac and pulmonary alterations in RA among patients without clinical manifestations. MATERIALS AND METHODS: The study was conducted in 169 patients (127 female and 42 male, with mean age 51.6, SD +/- 12.7 years, P > 0.05) with RA diagnosed on the basis of ACR criteria. All patients underwent a transthoracal echocardiography (TTE), a chest X ray, an electrocardiogram and laboratory tests. Patients with clinical manifestations of cardiac and pulmonary disease were excluded from the study. RESULTS: Pericarditis was evidenced in 16.6%, mitral regurgitation in 21.9%, aortal regurgitation in 26%, and pulmonary diffuse fibrosis in 16.6% of cases The authors found that 158 (93.5%) of patients were CRP positive. CONCLUSION: Our study demonstrated that cardiac and pulmonary alterations are frequently present and prevalence of elevated CRP levels and positive serologic tests was high in asymptomatic patients with RA among patients without clinical manifestations.
21427809 [Can two biologicals be combined to treat rheumatoid arthritis?]. 2010 Selective anticytokine therapy improves clinical outcome in patients with rheumatoid arthritis but does not produce complete remission. The inflammatory network with multiple cell types and cytokines is a multi-factorial phenomenon involving the synovial membrane. Specific inhibition of one factor may result in activation of an alternative (by-pass) route. Thus, the search continues for novel, more aggressive combination therapies. It seems possible to administer a combination of anticytokine drugs or to combine one anticytokine with one B cell-depleting agent (different mechanisms of action). Initial reports on this combination therapy show that it is relatively effective and safe, especially as regards the second option. Results of ongoing clinical trials as well as information on the cost-effectiveness of these therapies are awaited.
20732649 Inhibition of JAK kinases in patients with rheumatoid arthritis: scientific rationale and 2010 Aug CP-690,550 is an orally active and selective inhibitor of the janus kinase (JAK) molecules. The molecular pathways through which the JAK moieties function are described along with the clinical mechanisms associated with their inhibition. Animal models of JAK inhibition are reviewed as a background for the possible inhibition of JAK in humans. The pharmacokinetics of CP-690,550 in humans is described, and the Phase IIA and IIB trials are reviewed in some detail. These trials were dose-ranging and showed a general dose response with relatively robust American College of Rheumatology 20 (ACR20) responses. A proof-of-concept 6-week trial in which CP-690,550 was given as monotherapy was associated with highly efficacious responses at the mid and higher twice-daily dose ranges employed. A subsequent 24 week dose-ranging trial in which CP-690,550 was administered in combination with methotrexate showed ACR20 responses, which were also statistically significant versus placebo interventions. CP-690,550 treatment was associated with side effects, which included headache and nausea. Infections were more common versus placebo as were elevations in transaminase enzymes when administered in combination with methotrexate, and increases in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol. Decreases in haemoglobin and white blood cell (WBC) counts were also observed along with small increases in serum creatinine. Occasional significant decreases of haemoglobin (>2 g dl(-1)) were observed, although decreases of WBC to less than 1000 per mm(3) were not seen. Plans for long-term follow-up of the described trials are described along with the features of five presently ongoing Phase III trials of the CP-690,550 janus kinase (JAK) inhibitor. Future directions include completion and publication of these trials along with study of JAK inhibition for other indications.
19359260 A diagnostic algorithm for persistence of very early inflammatory arthritis: the utility o 2010 Feb OBJECTIVES: The aim of this study was to assess the value of power Doppler ultrasound (PDUS) in combination with routine management in a cohort of patients with very early inflammatory arthritis (IA). METHODS: 50 patients with < or =12 weeks of inflammatory symptoms with or without signs had clinical, laboratory and imaging assessments. Diagnosis was recorded at 12 months. Assuming a 15% pre-test probability of IA, post-test probabilities for various assessments were calculated and used to develop a diagnostic algorithm. RESULTS: All patients positive for rheumatoid factor (RF) and/or cyclic citrullinated peptide (CCP) developed persistent IA, so the added value of PDUS was assessed in the seronegative (RF and CCP negative) group. The probability of IA in a seronegative patient was 6%. The addition of clinical and radiographic features raised the probability of IA to 30% and, with certain ultrasound features, this rose to 94%. CONCLUSIONS: In seronegative patients with early IA, combining PDUS with routine assessment can have a major impact on the certainty of diagnosis.
20391513 Denosumab-mediated increase in hand bone mineral density associated with decreased progres 2010 Apr OBJECTIVE: Periarticular osteoporosis is one of the earliest radiographic signs of bone damage in rheumatoid arthritis (RA). Denosumab, an investigational fully human monoclonal antibody that binds to RANKL, inhibits bone erosion and systemic bone loss in clinical studies of patients with RA. In this hand bone mineral density (BMD) substudy, we investigated the effects of denosumab on hand BMD and its correlation with hand erosion scores. METHODS: Patients receiving methotrexate for erosive RA were randomized in a 1:1:1 ratio to receive subcutaneous placebo, denosumab 60 mg, or denosumab 180 mg at 0 and 6 months. Measurements included BMD (by dual x-ray absorptiometry [DXA]) of both hands (0, 1, 6, and 12 months), magnetic resonance images of the hands/wrists (0 and 6 months), and radiographs of the hands/wrists and feet (0, 6, and 12 months). RESULTS: There were 56 patients (13 placebo, 21 denosumab 60 mg, and 22 denosumab 180 mg). Mean changes in hand BMD at 6 and 12 months were: +0.8% and +1.0%, respectively, for denosumab 60 mg; +2.0% and +2.5%, respectively, for denosumab 180 mg; and -1.2% and -2.0%, respectively, for placebo. Erosion scores remained near baseline in the denosumab groups and increased from baseline in the placebo group. A negative correlation was observed between hand BMD and erosion scores. CONCLUSION: In patients with RA, denosumab provided protection against erosion, and not only prevented bone loss but increased hand BMD as measured by DXA.
19648085 Validation of the Russian version of the Quality of Life-Rheumatoid Arthritis Scale (QOL-R 2009 PURPOSE: To translate the English version of the Quality of Life-Rheumatoid Arthritis Scale (QOL-RA Scale) into Russian, test the reliability and validity of the Russian version and compare the scaling assumptions, reliability, and validity of the English, Spanish and Russian versions. MATERIALS/METHODS: The development of a Russian version of the Quality of Life-Rheumatoid Arthritis Scale (QOL-RA Scale) involved translating the English version of the instrument into Russian, linguistic adaptation, 50 face-to-face interviews with outpatients with definite rheumatoid arthritis (RA) and testing the reliability and validity. RESULTS: The QOL-RA Scale, an 8-item scale, took about 3 minutes to administer. Psychometric analysis revealed that the psychometric attributes of English, Spanish and Russian questionnaires are satisfactory. CONCLUSIONS: The Russian version of the QOL-RA scale is a reliable and valid measure of RA-specific QOL.
20818150 [Th17 cells and human arthritic diseases]. 2010 Th17 cells, though having been discovered just few years ago, is believed as the pathogenic T cells in many autoimmune diseases and chronic inflammatory diseases, such as rheumatoid arthritis (RA). Biologics targeting IL-17 have already been on clinical trial, and the results were recently reported. Although the importance of Th17 cells in animal models of arthritis is unquestionable, it is not recognized that there are only limited data on the role of Th17 cells and related cytokines in human arthritic diseases. In addition, the characteristics of human Th17 cells have not been fully defined, and there seem to be substantial differences between human and mouse Th17 cells. In this review, I will introduce and discuss about updated findings on human Th17 cells and its relation with human arthritic diseases.
19519464 The AKT axis as a therapeutic target in autoimmune diseases. 2009 Jun Autoimmunity affects a substantial fraction of our population. In patients with autoimmune disease, the immune system recognizes self-tissues as foreign. Common autoimmune diseases include rheumatoid arthritis, diabetes mellitus, lupus and multiple sclerosis. Though different target organs may be affected in different autoimmune diseases, aberrations in adaptive or innate immunity underlie all of these diseases. Abnormal functioning, differentiation and/or activation of T-cells, B-cells and myeloid cells have been documented in various autoimmune diseases. More recent studies have also detailed anomalous activation of various signaling axes including various MAPK, AKT, NF-kappaB, Bcl-2 family members, and JAK/STAT molecules in these cells, in the context of systemic autoimmunity. Among these, one molecular pathway that appears to be particularly attractive for therapeutic targeting is the PI3K/AKT/mTOR axis. In this review, we summarize how the AKT axis affects multiple molecular processes in autoimmune diseases and discuss the potential of targeting this axis in these diseases.
20356761 Lymphotoxin-alphabeta heterotrimers are cleaved by metalloproteinases and contribute to sy 2010 Jul Tumor necrosis factor-superfamily (TNF-SF) members, lymphotoxin (LT)-alpha and LTbeta, are proinflammatory cytokines associated with pathology in rheumatoid arthritis. LTalpha3 homotrimers are secreted, whereas LTalpha(1)beta(2) heterotrimers are expressed on the surface of activated lymphocytes. As many TNF-SF members are actively cleaved from cell membranes, we determined whether LTalphabeta heterotrimers are also cleaved, and are biologically active in rheumatoid arthritis (RA) patients. LTalphabeta heterotrimers were detected in culture supernatants from activated human T-helper (Th) 0, Th1, and Th17 cells, together with LTalpha3 and TNFalpha. The heterotimers were actively cleaved from the cell surface by ADAM17 metalloproteinase (MMP) and MMP-8, and cleavage was inhibited by TAPI-1, a TNF-alpha converting enzyme (TACE) inhibitor. Soluble LTalphabeta was detected in serum from both normal donors and RA patients, and was elevated in synovial fluid from RA patients compared to osteoarthritis (OA) patients. Levels of LTalphabeta in RA patient synovial fluid correlated with increased TNFalpha, IL-8, IL-12, IL-1beta, IFN-gamma, and IL-6 cytokines. Moreover, recombinant LTalpha1beta2-induced CXCL1, CXCL2, IL-6, IL-8, VCAM-1, and ICAM-1 from primary synovial fibroblasts isolated from RA patients. Therefore, soluble LTalphabeta in synovial fluid is associated with a proinflammatory cytokine milieu that contributes to synovitis in RA.
20025594 Mouse models of autoimmune diseases. 2009 Dec Significant progress has been made in past decades in our understanding of the basic mechanisms underlying autoimmune diseases. Nevertheless, many questions remain unanswered, in particular regarding the mechanisms at very early stages of these diseases. Reliable animal models are of crucial importance in basic research and may help us to understand central disease pathways. They are also indispensable for pre-clinical drug testing. Here we present and discuss two mouse models of rheumatoid arthritis and multiple sclerosis, respectively. In experimental studies using the models of collagen-induced arthritis and experimental autoimmune encephalomyelitis, the efficacy of new biological agents has been tested, which paved the way for clinical trials. A further interesting field where mouse models may provide valuable informations, is the identification of susceptibility genes for autoimmune diseases. Overall, in some instances studies with inbred strains may have an advantage over human studies, because environmental factors may easily be controlled and the genetic differences between different mouse strains are better characterized.