Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
18041889 Abatacept: a novel treatment for moderate-to-severe rheumatoid arthritis. 2007 Dec Rheumatoid arthritis is a chronic autoimmune disease that often leads to functional disability and reduced quality of life. The pathogenesis of synovial inflammation that is associated with this disease is thought to result from T-cell activation. To become fully activated, T cells require an antigen-specific signal through the T-cell receptor and a second signal through a costimulatory receptor. Abatacept is the first drug in a new class of disease-modifying antirheumatic drugs (DMARDs) known as selective costimulation modulators. Costimulation modulators block the second signal and decrease T-cell activation. Abatacept has been approved by the United States Food and Drug Administration for reducing signs and symptoms, inducing major clinical response, slowing the progression of structural damage, and improving physical function in adults with moderate-to-severe active rheumatoid arthritis who have had an inadequate response to at least one other DMARD, such as methotrexate or tumor necrosis factor (TNF)-alpha inhibitors. Randomized controlled trials have shown that abatacept improves both clinical outcomes and health-related quality of life in patients who have had an inadequate response to other DMARDs. Abatacept has been shown to be well tolerated. In clinical trials, however, abatacept treatment was associated with a higher rate of infections compared with placebo. This finding was compounded when abatacept was used with TNF-alpha inhibitors; thus, this combination should be avoided. Abatacept appears to be a useful treatment option for patients with rheumatoid arthritis who have previously failed other DMARDs. However, additional clinical trials evaluating its long-term effect on patient safety and disease outcomes are needed.
18975340 Identification of interleukin-7 as a candidate disease mediator in spondylarthritis. 2008 Nov OBJECTIVE: Understanding of the molecular pathophysiology of spondylarthritis (SpA) remains largely elusive. This is related both to the complexity of the disease (axial versus peripheral disease, inflammation versus tissue remodeling) and to the difficulty in obtaining samples from primary disease sites. This study was undertaken to explore a gene expression approach for identifying novel candidate mediators of SpA. METHODS: Sacroiliac joint fluid aspirates from 3 SpA patients with active sacroiliitis were studied by microarray analysis. The expression of selected candidate molecules in peripheral synovitis was confirmed by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS: Microarray analysis identified 4 sacroiliitis gene clusters, containing a total of 47 messenger RNA (mRNA) transcripts. Two clusters contained genes expressed in all sacroiliitis samples, corresponding to both known and unsuspected candidate mediators of SpA pathology. These included proinflammatory molecules as well as molecules involved in tissue remodeling, such as transforming growth factor beta2. Of the novel candidate genes selected for confirmation, interleukin-7 (IL-7) mRNA expression was higher in SpA peripheral synovial fluid and synovial tissue samples than in osteoarthritis samples, and similar to expression in rheumatoid arthritis (RA) samples. At the protein level, synovial fluid IL-7 levels were even higher in SpA than in RA, despite lower levels of tumor necrosis factor alpha and IL-1beta. CONCLUSION: In the present study, both known and unsuspected candidate mediators of SpA pathogenesis were identified, including IL-7. The specific overexpression of IL-7 at sites of peripheral synovitis in SpA suggests that further functional investigations of the role of this cytokine in SpA pathogenesis are warranted.
17627199 A review of the efficacy and safety of devil's claw for pain associated with degenerative 2007 Jul Harpagophytum procumbens, known as devil's claw, has been used traditionally for the treatment of pain, fevers, and dyspepsia. Recently, it has become popular for the treatment of rheumatoid and osteoarthritis. Studies have yet to establish a clear mechanism of action; however, current research is focusing on pro-inflammatory mediators as well as on potential antioxidant characteristics.
18278835 Anti-20S proteasome antibodies in psoriatic arthritis. 2008 Apr OBJECTIVE: Proteasomes are targets of humoral autoimmune response in patients with connective tissue diseases and other organ-specific autoimmune diseases. The finding of circulating proteasomes in psoriasis, the multiplicity of mechanisms regulated by proteasomes that are also implicated in the pathogenesis of psoriatic arthritis (PsA), and the increasing evidence linking PsA and autoimmunity led us to evaluate whether the 20S proteasome represents an antibody target in PsA. METHODS: Serum samples from 36 patients with PsA and 30 age- and sex-matched healthy subjects were tested for the presence of anti-20S proteasome antibodies (anti-20S antibody). Additional controls included 24 patients with systemic lupus erythematosus (SLE) and 20 with rheumatoid arthritis (RA). The associations of anti-20S antibodies with clinical, laboratory, and therapeutic measures were evaluated. RESULTS: 27.8% of the PsA patients were positive for anti-20S antibody compared to 41.6% of the SLE group and 5% of the RA group. None of the healthy subjects were seropositive for anti-20S antibody. In PsA, anti-20S seropositivity was not associated with the presence of other autoantibodies or with a particular subgroup of articular involvement. CONCLUSION: Immunoreactivity against proteasomes occurs frequently in patients with PsA. This finding supports the concept of PsA as an autoimmune disease and opens new avenues for investigating its pathogenesis.
16821276 Anti-tumor necrosis factor-alpha-induced psoriasis. 2006 Jul We describe a patient with rheumatoid arthritis who developed psoriasis during treatment with etanercept; psoriatic lesions resolved completely after the drug was discontinued, but returned on rechallenge. No such adverse skin reaction occurred after switching therapy to infliximab. Through a Medline search we identified 11 reports involving 32 patients who developed psoriasis/psoriasiform eruptions during therapy with tumor necrosis factor-alpha (TNF-alpha) inhibitors. All TNF-alpha blocking agents have been reported to lead to or exacerbate psoriasis. In some cases skin changes were severe enough to discontinue the medication.
16545987 Angiogenesis--a new target for future therapy. 2006 May Development of blood vessels from in situ differentiating endothelial cells (EC) is called vasculogenesis, whereas sprouting of new blood vessels from the pre-existing ones is termed angiogenesis or neovascularisation. Angiogenesis, the growth of new blood vessels, is essential during tissue repair, foetal development, and female reproductive cycle. In contrast, uncontrolled angiogenesis promotes tumor and retinopathies, while inadequate angiogenesis can lead to coronary artery disease. A balance between pro-angiogenic and anti-angiogenic growth factors and cytokines tightly controls angiogenesis. With the identification of several proangiogenic molecules such as the vascular endothelial cell growth factor (VEGF), the fibroblast growth factors (FGFs), and the angiopoietins, and the recent description of specific inhibitors of angiogenesis such as platelet factor-4, angiostatin, endostatin, and vasostatin, it is recognized that therapeutic interference with vasculature formation offers a tool for clinical applications in various pathologies. Inhibition of angiogenesis can prevent diseases such as cancer, diabetic nephropathy, arthritis, psoriasis, whereas stimulation of angiogenesis is beneficial in the treatment of coronary artery disease (CAD), cardiac failure, tissue injury, etc. One of the most specific and critical regulators of angiogenesis is vascular endothelial growth factor (VEGF), which regulates endothelial proliferation, permeability, and survival. Substantial evidence also implicates VEGF as an angiogenic mediator in tumors and intraocular neovascular syndromes, and numerous clinical trials are presently testing the hypothesis that inhibition of VEGF may have therapeutic value.
16646029 Linkage analysis of rheumatoid arthritis in US and UK families reveals interactions betwee 2006 May OBJECTIVE: HLA is the most strongly associated locus in rheumatoid arthritis (RA), accounting for up to one-third of the genetic contribution. Conditioning on the effect of true disease loci such as HLA can lead to increased power to detect effects at other loci and, in addition, allows investigation of the underlying disease models, including interactions. The aim of this study was to detect susceptibility loci for RA by conditioning on HLA in a large sample of affected sibling pairs (ASPs) and to test for evidence of interaction between novel loci and HLA. METHODS: Genotype data from 3 whole-genome linkage scans for RA in a US population and a UK population were pooled, resulting in a combined data set of 886 ASPs. This pooling of data increased the power to detect loci showing low levels of heterogeneity. Nonparametric linkage analysis was performed to identify regions of interest. Joint 2-locus analysis was then performed for HLA and each of the loci that demonstrated evidence of linkage in the 886 ASPs. RESULTS: Evidence for linkage was most significant at HLA (P = 4 x 10(-16)), with 7 non-HLA loci showing some evidence for linkage (P = 0.05-0.003). Joint modeling of these loci with HLA provided evidence for linkage at a genome-wide significance level for loci on 6q (P = 2.7 x 10(-6)) and 16p (P = 2 x 10(-4)). CONCLUSION: These data provide the most convincing evidence to date that 6q and 16p harbor susceptibility genes. In addition, these loci may interact with HLA, facilitating the search for candidate genes within this region.
18674945 Herpes zoster in patients taking TNFalpha antagonists for chronic inflammatory joint disea 2008 Oct OBJECTIVE: To assess the rate of occurrence and outcomes of herpes zoster in patients taking TNFalpha antagonists. METHODS: Retrospective review of the medical records of 300 patients who received TNFalpha antagonists to treat chronic inflammatory joint disease. RESULTS: We identified 9 (9/300, 3%) patients who experienced herpes zoster, 6 women and 3 men, with rheumatoid arthritis (n=7) or ankylosing spondylitis (n=2). The drug was infliximab in 4 patients, adalimumab in 2 patients, and etanercept in 3 patients, including 2 patients with a prior history of infliximab therapy (for 12 and 36 months, respectively). Mean treatment duration at the occurrence of herpes zoster was 27 months (range, 6-42 months). DISCUSSION: Glucocorticoid therapy (n=7) and methotrexate therapy (n=6) were the only risk factors identified in our study. Mean follow-up was 26 months. All 9 patients achieved a full recovery with antiviral treatment and interruption of the TNFalpha antagonist. One patient experienced a recurrence after resuming TNFalpha antagonist therapy. CONCLUSION: The scant data in the literature suggest a higher risk of herpes zoster with anti-TNFalpha antibodies than with the soluble receptor. The role for concomitant treatments (glucocorticoids and methotrexate) should be taken into account.
18709537 An asymptomatic case of pulmonary cryptococcosis with endobronchial polypoid lesions and b 2008 Aug A case of pulmonary cryptococcosis with focal endobronchial polypoid lesions is described. A 64-year-old woman consulted our hospital for further evaluation of an abnormal shadow on a chest radiograph. She had been prescribed corticosteroid for rheumatoid arthritis. Chest radiographs revealed an infiltrative shadow in the right lower and left middle and lower lung fields, and chest computed tomography (CT) revealed bilateral airspace consolidations and multiple nodules. A bronchoscopic finding revealed white polypoid lesions at the orifice of the posterior basal bronchus in the left lower lobe. Histopathological examination of transbronchial biopsy specimens demonstrated cryptococcal organisms. After fluconazole therapy for 4 months, the infiltrate had decreased in size and the bronchial polypoid lesions had disappeared.
16947779 Insulin resistance and impaired beta cell function in rheumatoid arthritis. 2006 Sep OBJECTIVE: To identify factors that regulate glucose metabolism in rheumatoid arthritis (RA). METHODS: We evaluated the homeostatic model assessment of insulin resistance (HOMA-IR) and beta cell function (HOMA-B) in 94 RA patients. We investigated the relationship between characteristics known to affect glucose metabolism in the general population (age, abdominal obesity [waist circumference], hypertension, antihypertensive therapy) as well as characteristics of RA (disease activity, glucocorticoid therapy) and insulin resistance and beta cell function. RESULTS: Patients with high-grade inflammation (high-sensitivity C-reactive protein value >1.92 mg/liter) (n = 81) were more insulin resistant than patients with low-grade inflammation (n = 13), whereas beta cell function was similar in both groups. Insulin resistance and beta cell function were similar in both groups after adjustment for waist circumference. All recorded characteristics except for age were associated with HOMA-IR or/and HOMA-B in univariate analyses. In mixed regression models, abdominal obesity and patient's assessment of disease activity (by visual analog scale) were predictors of insulin resistance. The Disease Activity Score assessed using 28-joint counts for swelling and tenderness, tender joint count, and patient's assessment of disease activity were associated with reduced beta cell function, and the cumulative dose of glucocorticoids was associated with enhanced beta cell function. The cumulative glucocorticoid dose in all study patients was a mean of only 536 mg (95% confidence interval 239-1,173). In patients with high-grade inflammation, age was further associated with impaired beta cell function, whereas use of angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers was associated with enhanced beta cell function. CONCLUSION: The modifiable factors of abdominal obesity, antihypertensive therapy, disease activity, and use of glucocorticoids appear to affect glucose metabolism in RA.
16810668 Daily interpersonal events in pain patients: applying action theory to chronic illness. 2006 Sep Action theory proposes that individuals actively shape and then respond to their environments, highlighting the role of stable person characteristics in the development and maintenance of life's interpersonal difficulties. In this study, the authors adopt the action perspective in their examination of predictors of daily interpersonal events among chronic pain patients with rheumatoid arthritis. They probe the extent to which stable symptoms of illness explained between-person variation, and fluctuating symptoms explain day-to-day variation in both positive and negative events. Their evaluation of patients' daily diary reports indicate that between-person differences accounted for more variance in the occurrence of positive events relative to negative events (48% vs. 31%, respectively). Likewise, between-person factors accounted for more variance in appraisals of positive compared to negative events across relationship domains. Both intractable illness symptoms and disability, and daily fluctuations in pain and fatigue, were only weakly related to patients' reports of their interpersonal experiences. Consistent with action theory, these results suggest that stable person characteristics are strongly related to daily stressors and particularly daily positive events in pain patients, but still account for less than 50% of the variance in events and their appraisals. In contrast, elevations in illness-related features, both between individuals and within individuals from day-to-day, are not robust predictors of positive or negative social exchanges. These findings point to the value of capturing the experiences of individuals intensively over time, an approach that can help to elaborate the contributions of both stable factors and circumstance in shaping social contexts in chronic illness.
16984938 Real-time quantitative PCR to detect changes in synovial gene expression in rheumatoid art 2007 Apr Synovial biomarkers are increasingly important in the development of novel therapeutic agents for the treatment of rheumatoid arthritis (RA). To identify biomarkers correlating with changes in clinical disease activity, real-time quantitative PCR (Q-PCR) was used to evaluate changes in synovial gene expression after treatment with corticosteroids. Patients with active RA received either oral prednisolone (n=10, 60 mg daily for the first week and 40 mg daily for the second week) or placebo (n=11) for 14 days. Real-time Q-PCR was used to quantify gene expression of tumour necrosis factor (TNF)alpha, IL1beta, IL8 and matrix metalloproteinase (MMP) 1 in synovial tissue samples obtained through an arthroscopic procedure before and after treatment. mRNA levels were reported as relative expression units compared with a cell-based standard. Statistical analysis was performed using an analysis of covariance model. Prednisolone markedly decreased IL8 and MMP1 expression compared with placebo, and the CIs excluded the likelihood of no effect. A trend towards reduction was seen in IL1beta and TNFalpha mRNA expression in the prednisolone group, although CIs included the value for no effect. These data suggest that Q-PCR can be used to measure synovial mRNA expression of mediators implicated in the pathogenesis of RA in small proof-of-concept trials.
17200802 Lymphomatoid granulomatosis and diffuse alveolar damage associated with methotrexate thera 2007 Sep We report on a patient of rheumatoid arthritis (RA) who sequentially developed an axillary mass and a fatal interstitial pneumonia during a 2-year course of methotrexate (MTX) therapy. Autopsy revealed a systemic lymph node involvement and the diagnosis of Epstein-Barr virus (EBV)-related lymphoproliferative disease (LPD) with the features of lymphomatoid granulomatosis was made. The lung tissue specimens revealed a typical diffuse alveolar damage (DAD), and small nodules consisting of atypical B lymphocytes showing positive staining for EBV were sparsely recognized only in basal lungs. This is the first report of a RA patient receiving MTX therapy sequentially developing MTX-associated lymphomatoid granulomatosis and DAD.
17551383 Strongyloides stercoralis hyperinfection in a patient with rheumatoid arthritis after anti 2007 Jun Strongyloidiasis is epidemic in tropical and subtropical regions where the regional prevalence may exceed 25%. In the United States, highest infection rates are found in immigrants. Many infected individuals are asymptomatic, whereas others may have mild and nonspecific cutaneous, intestinal, and pulmonary symptoms. Strongyloides stercoralis may remain as a dormant infection, but replication and dissemination can be fatal in immunocompromised patients. We report on a 63-year-old native Filipino man with a history of rheumatoid arthritis who developed Escherichia coli sepsis, filariform larvae characteristic of S. stercoralis bronchoalveolar lavage, and adult respiratory distress syndrome 3 weeks after he presented with vague gastrointestinal symptoms. We believe that the addition of a tumor necrosis factor (TNF)-alpha inhibitor to his treatment with prednisone and methotrexate for rheumatoid arthritis further suppressed his cellular immunity leading to hyperinfection and life-threatening S. stercoralis infection. This is another, often latent, infection that should be considered in patients in or from endemic areas before institution of antitumor necrosis factor therapy.
16945726 An unusual presentation of methotrexate-induced B-cell lymphoma of the metacarpophalangeal 2006 Sep We report a unusual presentation of B-cell lymphoma in the chronically inflamed synovium of a 64-year-old man with an 18-year history of rheumatoid arthritis that was treated with methotrexate.
19120157 Sympathetic nervous system response to orthostatic stress in female patients with rheumato 2008 Dec Sympathoneural and adrenomedullary impairments have been suggested in patients with rheumatoid arthritis (RA). In the present study, sympathoneural and adrenomedullary responses to orthostasis were evaluated in eight female RA patients and in eight matched healthy controls. The testing consisted of sequence of stabilization period in supine position, legs-up position, orthostasis, and supine position. In each body position, blood samples were drawn and ECG was recorded. Plasma levels of epinephrine (EPI), norepinephrine (NE) and neuropeptide Y (NPY) were measured and sympathoneural activity was evaluated by analysis of heart rate variability (HRV). Higher baseline NE levels were found in RA patients (P= 0.034), without any difference in response to orthostasis between the study groups. Levels of EPI tended to be lower in RA patients in base line (P= 0.053) and in response to orthostasis (P= 0.079). The RA and control groups did not differ in NPY levels or in HRV parameters considered to reflect sympathetic activity. A subtle tendency to decreased adrenomedullary reactivity but no evidence for abnormal sympathetic responses to orthostasis was found in RA females.
16572446 The HLA-DRB1 shared epitope alleles are primarily a risk factor for anti-cyclic citrullina 2006 Apr OBJECTIVE: The shared epitope (SE)-containing HLA-DRB1 alleles represent the most significant genetic risk factor for rheumatoid arthritis (RA). Recent studies indicate that the SE alleles are associated with only RA that is characterized by the presence of anti-cyclic citrullinated peptide (anti-CCP) antibodies, and not with anti-CCP-negative disease. In this study we investigated whether the SE alleles contribute to the development of anti-CCP-positive RA, or whether they are associated solely with the presence of anti-CCP antibodies. We therefore determined the influence of the SE alleles and anti-CCP antibodies on the progression from recent-onset undifferentiated arthritis (UA) to RA. METHODS: Patients with recent-onset UA at the 2-week visit (n=570) were selected from the Leiden Early Arthritis Cohort. SE alleles, rheumatoid factor (RF) status, and anti-CCP antibody levels were determined. Progression to RA or other diagnoses was monitored. RESULTS: One hundred seventy-seven patients with UA developed RA during the 1-year followup, whereas the disease in 393 patients remained unclassified or was given other diagnoses. The SE alleles correlated with the presence of anti-CCP antibodies, but not with the presence of RF. Both in SE-positive and in SE-negative patients with UA, the presence of anti-CCP antibodies was significantly associated with the development of RA. More intriguingly, however, no apparent contribution of the SE alleles to the progression to RA was found when analyses were stratified according to the presence of anti-CCP antibodies. In patients with anti-CCP-positive disease, the presence of SE alleles was associated with significantly higher levels of anti-CCP antibodies, suggesting that the SE alleles act as classic immune response genes. CONCLUSION: The SE alleles do not independently contribute to the progression to RA from UA, but rather contribute to the development of anti-CCP antibodies.
17336839 Pisiform impingement after total wrist arthroplasty. 2007 Mar We present a 64-year-old woman with rheumatoid arthritis who developed increasing pain 3 years after a total wrist arthroplasty. The pain was localized over the ulnar side of the wrist secondary to erosion of the pisiform. Pisiform excision resulted in a resolution of the symptoms. When placing a carpal component, which includes a base plate as part of its design, care should be taken to avoid any overhang of the implant edge into the pisotriquetral joint.
18075630 Clinical use of anti-TNF-alpha biological agents--a guide for GPs. 2007 Dec BACKGROUND: Tumour necrosis factor-alpha (TNF-alpha) inhibitors are a new class of injectable drugs, under the umbrella term 'biological agents', now available for the treatment of rheumatoid arthritis and other chronic inflammatory conditions including juvenile idiopathic arthritis, Crohn disease, psoriasis and psoriatic arthritis. OBJECTIVE: The aim of this review is to provide an overview of TNF-alpha inhibitors and highlight the key practical issues of relevance to general practitioners. DISCUSSION: TNF-alpha inhibitors may have a potent effect in reducing inflammation and possibly inducing remission where conventional disease modifying drugs have failed to do so. These drugs are associated with an increased risk of infection as well as other potentially serious side effects. Their use is restricted to the relevant specialist prescribing the drug and are only available on the Pharmaceutical Benefits Scheme under strict prescribing criteria. The role of the GP is critical in identifying patients suitable for referral to consider commencing treatment and in monitoring patients on long term therapy.
17642240 [Infliximab]. 2007 Jul A number of over-sea study showed the immediate and dramatic anti-inflammatory effects of infliximab(IFX) in patients with rheumatoid arthritis (RA). In addition, significant reduction of bone/joint destruction by IFX was proven in RA patients. On the other hand, some serious adverse effects of IFX were documented. In Japan, IFX was approved as a biological reagent against RA on 2003, and nationwide post marketing surveillance was conducted in the consecutive 5,000 RA patients on IFX. The data showed that 91.6% of patients had overall efficacy as "marked improvement" or "improvement". Serious adverse reaction was reported in 6.2%. Therefore, IFX is very effective and well tolerated in Japanese patients with RA.