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A Rac1 inhibitory peptide suppresses antibody production and paw swelling in the murine collagen-induced arthritis model of rheumatoid arthritis
Joana RF Abreu, Wendy Dontje, Sarah Krausz, Daphne de Launay, Paula B van Hennik, Anne-Marieke van Stalborch, Jean-Paul ten Klooster, Marjolein E Sanders, Kris A Reedquist, Margriet J Vervoordeldonk, Peter L Hordijk, Paul P Tak
Arthritis Research & Therapy , 2010, DOI: 10.1186/ar2900
Abstract: CIA was induced in DBA/1 mice, and in either early or chronic disease, mice were treated three times per week by intraperitoneal injection with control peptide or Rac1 inhibitory peptide. Effects on disease progression were assessed by measurement of paw swelling. Inflammation and joint destruction were examined by histology and radiology. Serum levels of anti-collagen type II antibodies were measured by enzyme-linked immunosorbent assay. T-cell phenotypes and activation were assessed by fluorescence-activated cell sorting analysis. Results were analyzed using Mann-Whitney U and unpaired Student t tests.Treatment of mice with Rac1 inhibitory peptide resulted in a decrease in paw swelling in early disease and to a lesser extent in more chronic arthritis. Of interest, while joint destruction was unaffected by Rac1 inhibitory peptide, anti-collagen type II antibody production was significantly diminished in treated mice, in both early and chronic arthritis. Ex vivo, Rac1 inhibitory peptide suppressed T-cell receptor/CD28-dependent production of tumor necrosis factor α, interferon γ and interleukin-17 by T cells from collagen-primed mice, and reduced induction of ICOS and CD154, T-cell costimulatory proteins important for B-cell help.The data suggest that targeting of Rac1 with the Rac1 carboxy-terminal inhibitory peptide may suppress T-cell activation and autoantibody production in autoimmune disease. Whether this could translate into clinically meaningful improvement remains to be shown.Rheumatoid arthritis (RA) is marked by de-regulated recruitment, activation, and retention of inflammatory white blood cells in affected joints [1]. Subsequent autoantibody production, release of cytokines, and cell-cell contacts may perpetuate inflammation and lead to joint destruction through activation of stromal fibroblast-like synoviocytes (FLSs) and osteoclasts [2]. Many of the cellular processes required for perpetuation of inflammation and joint destruction in RA are regulated
Benign rheumatoid nodules  [cached]
Murthy P,Malik A,Rajagopal R,Aggarwal S
Indian Journal of Dermatology, Venereology and Leprology , 2002,
Abstract: Rheumatoid nodules occur usually in advanced seropositive rheumatoid arthritis, signifying poor prognosis. However rarely rheumatoid nodules can be encountered in patients with no antecedent evidence of arthritis. Herein a case of an arthritic benign rheumatoid nodules is described.
Cancer Risk of Anti-TNF-α at Recommended Doses in Adult Rheumatoid Arthritis: A Meta-Analysis with Intention to Treat and per Protocol Analyses  [PDF]
Guillaume Moulis, Agnès Sommet, Johana Béné, Fran?ois Montastruc, Laurent Sailler, Jean-Louis Montastruc, Maryse Lapeyre-Mestre
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0048991
Abstract: Background The risk of malignancies on TNF-α antagonists is controversial. The aim of this survey was to assess cancer risk on TNF-α antagonists in adult rheumatoid arthritis patients, including the five marketed drugs (infliximab, etanercept, adalimumab, golimumab and certolizumab) used in line with the New Drug Application. Furthermore, the relative interest of modified intention to treat or per protocol analyses to assess such sparse events remains unknown. Methodology/Principal Findings Data sources were MEDLINE, CENTRAL, ISI Web of Science, ACR and EULAR meeting abstracts, scientific evaluation of the drugs leading to their marketing approval, and clinicaltrials.gov, until 31 December 2012.We selected double-blind randomized controlled trials in adult rheumatoid arthritis patients, including at least one treatment arm in line with New Drug Application. We performed random effect meta-analysis, with modified intention to treat and per protocol analyses. Thirty-three trials were included. There was no excess risk of malignancies on anti-TNF-α administered in line with New Drug Application in the per protocol model (OR, 0.93 95%CI[0.59–1.44]), as well as in the modified intention to treat model (OR, 1.27 95%CI[0.82–1.98]). There was a non-significant tendency for an excess non-melanoma skin cancer risk in both models (respectively, 1.37 [0.71–2.66] and 1.90 [0.98–3.67]). With fixed effect Peto model restricting to trials during at least 52 weeks, the overall cancer risk was respectively 1.60 [0.97–2.64] and 1.22 [0.72–2.08]. Whatever the model, modified intention to treat analysis led to higher estimations than per protocol analysis. The later may underestimate the treatment effect when assessing very sparse events and when many patients dropped out in placebo arms. In metaregression, there was no differential risk among the five drugs. Conclusions/Significance This study did not find any evidence for an excess cancer risk on TNF-α antagonists in adult rheumatoid arthritis patients, but an excess cancer risk after several years of exposure cannot be ruled out. Both modified intention to treat and per protocol analyses should be presented in such safety analyses.
Mast cell activation and its relation to proinflammatory cytokine production in the rheumatoid lesion
David E Woolley, Lynne C Tetlow
Arthritis Research & Therapy , 1999, DOI: 10.1186/ar70
Abstract: Increased numbers of mast cells (MCs) are found in the synovial tissues and fluids of patients with rheumatoid arthritis (RA), and at sites of cartilage erosion. MC activation has been reported for a significant proportion of rheumatoid specimens. Because the MC contains potent mediators, including histamine, heparin, proteinases, leukotrienes and multifunctional cytokines, its potential contributions to the processes of inflammation and matrix degradation have recently become evident.Proinflammatory cytokines are important mediators of inflammation, immunity, proteolysis, cell recruitment and proliferation. Tumour necrosis factor (TNF) reportedly plays a pivotal role in the pathogenesis of RA, especially its ability to regulate interleukin (IL)-1β expression, this being important for the induction of prostanoid and matrix metalloproteinase production by synovial fibroblasts and chondrocytes. IL-15 has been assigned numerous biological effects and has been implicated as an important factor in TNF-α expression by monocyte/macrophages. Some in vitro studies have placed IL-15 upstream from TNF-α in the cytokine cascade, suggesting an interdependence between TNF, IL-1 and IL-15 for the promotion of proinflammatory cytokine expression in the rheumatoid joint.To examine the in situ relationships of TNF-α, IL-1β and IL-15 in relation to MC activation in rheumatoid tissues by use of immunolocalization techniques; and to compare quantitatively the proinflammatory cytokine production by specific cell cultures and rheumatoid synovial explants with and without exposure to a MC secretagogue.Samples of rheumatoid synovial tissue and cartilage–pannus junction were obtained from patients (n = 15) with classic late-stage RA. Tissue sections were immunostained for MC (tryptase) and the proinflammatory cytokines IL-1, TNF-α and IL-15. Rheumatoid synovial tissue explants were cultured in Dulbecco's modified Eagles medium (DMEM) containing either the MC secretagogue rabbit antihuman imm
Extra-articular manifestations of rheumatoid arthritis: A hospital-based study  [cached]
Al-Ghamdi Aisha,Attar Suzan
Annals of Saudi Medicine , 2009,
Abstract: Background and Objective: The frequency of extra-articular manifestations in rheumatoid arthritis (ExRA) differs from one country to another, so we investigated ExRA frequency in a well-defined hospital patient popula--tion with rheumatoid arthritis (RA) in Saudi Arabia. We also examined possible predictors of the development ExRA. Methods: A retrospective analysis was conducted of all patients diagnosed with RA at a university hospital dur--ing a 4-year period. Cases were classified according to the 1987 American College of Rheumatology criteria for RA, and the frequency of ExRA was recorded. Results: Of 140 patients who fulfilled the criteria for the diagnosis of RA, 98 (70%) developed ExRA features. Anemia occurred in 61%, thrombocytosis in 16%, pulmonary involvement in 10%, and renal amyloidosis, vas--culitis and Felty syndrome were present in 6%, 2% and 1%, respectively. The mortality rate was high (16%) in patients with ExRA. The predictors for mortality were lung involvement, age over 50 years and kidney amyloidosis. Conclusion: ExRA were present in a substantial proportion of our patients, which lead to a worse disease outcome. Anemia, thrombocytosis and respiratory system involvement were the commonest. Early recognition and treatment are important to decrease mortality.
Rehabilitation in patients with Rheumatoid Arthritis  [PDF]
Evaggelos Giavasopoulos,Paraskevi Gourni
To Vima tou Asklipiou , 2008,
Abstract: Rehabilitation of patients with rheumatoid arthritis aims to the management of the consequences of disease. It is widely accepted that, no drug therapy at present leads to long‐term orremission f everyone with rheumatoid arthritis (R.A.). Consequently, patients experience physical, psychological, functional, social and role negative effects of the disease. AIM : The am of the present article was to evaluate the role of rehabilitation to patients with rheumatoid arthritis sMethod and material: The methodology followed included reviewof tudies which were related to rehabilitation of patients with rheumatoid arthritis Results :The majority of the studies claims that rehabilitation of patients with rheumatoid arthritis, is a matter of primary importance. The importance of early provision of specialist rheumatologycare, patient education and promotion of self‐ management; and the evidence for the effectiveness of therapeutic interventions and multidisciplinary care. Conclusions : Individuals who suffer from rheumatoid arthritis can derive significant benefits from rehabilitation programmes. To provide best care, rehabilitation standards and services should be based on the best available evidence.
Concomitant gout and rheumatoid arthritis - A case report  [cached]
Khosla Pooja,Gogia Atul,Agarwal P,Pahuja Amit
Indian Journal of Medical Sciences , 2004,
Abstract: We report a case of definite rheumatoid arthritis and co-existing gout. Although gout and rheumatoid arthritis are relatively common entities individually, the co-existence of these two conditions is rare.
Human pregnancy safety for agents used to treat rheumatoid arthritis: adequacy of available information and strategies for developing post-marketing data
Christina D Chambers, Zuhre N Tutuncu, Diana Johnson, Kenneth L Jones
Arthritis Research & Therapy , 2006, DOI: 10.1186/ar1977
Abstract: For female patients with rheumatoid arthritis (RA), the availability of a host of new disease modifying antirheumatic drugs (DMARDs) has raised important questions about fetal safety if a woman becomes pregnant while she is being treated. In addition, there is limited safety information regarding many of the older medications commonly used to treat RA in women of reproductive age.Although pre-marketing clinical trials and post-marketing safety studies can address questions regarding safety in most segments of the population, pregnant women constitute one special group for whom ethical concerns prohibit the establishment of human drug safety information as part of the drug development and approval process. However, once a new drug is marketed or an existing drug is used for a new indication, if women of reproductive age are prescribed the drug, pregnancy exposures will inevitably occur. This is due to the fact that about half of pregnancies in the US are unplanned [1], and overall fewer than 50% of women recognize they are pregnant by the fourth week in gestation [2], leading to the common occurrence of inadvertent exposure to a medication of unknown safety during a critical period in embryonic development.Thus, the rheumatologist and the pregnant patient are frequently faced with the dilemma of assessing the potential risk of an exposure to a medication or combination of medications that has already occurred early in pregnancy, or of making the decision to continue or discontinue a medication regimen during a planned pregnancy or breastfeeding.In the US, the resource that clinicians and patients rely on most heavily in evaluating individual risk is the US Food and Drug Administration's (FDA) Pregnancy Category: A, B, C, D, X [3]. Pregnancy safety cannot be ethically evaluated in pre-marketing human clinical trials. In the post-marketing setting, isolated case reports of adverse pregnancy outcomes are difficult to interpret without a known denominator of exposed wome
Causes of Mortality in Rheumatoid Arthritis  [PDF]
Zafer Gunendi,Asli Gencay Can
Romatizma , 2008,
Abstract: Patients with rheumatoid arthritis have a shorter total life expectancy than the general population of the same age and sex. Generally, mortality due to rheumatoid arthritis occurs 8-10 years after the disease onset. Mortality risk decreases with use of disease modifying antirheumatic drugs. The most common causes of mortality in rheumatoid arthritis are cardiovascular system diseases and infections. Patients with rheumatoid arthritis have a two-fold increase in cardiovascular mortality. Atherosclerosis which is triggered by systemic inflammation is an important factor in the development of cardiovascular disease. The other causes of mortality in rheumatoid arthritis are pulmonary system diseases, renal diseases, drug side effects, amyloidosis, malignancy, vasculitis, crycoarytenoid arthritis, catastrophic antiphospholipid syndrome, Felty’s syndrome and atlantoaxial subluxation.
Large elbow nodules in a patient with rheumatoid nodulosis  [cached]
Faten Frikha,Sameh Ellouz,Moez Trigui,Makram Frigui
Rheumatology Reports , 2010, DOI: 10.4081/rr.2010.e4
Abstract: Rheumatoid nodulosis is an uncommon pathology considered as a particular variant of rheumatoid arthritis associated with subcutaneous rheumatoid nodules, palindromic rheumatism, and mild or no systemic manifest-ation, usually with positive rheumatoid factor and radiological subchondral bone cysts. We describe a 58-year-old man with the diagnosis of seropositive but nondestructive, nondeforming rheumatoid arthritis, who exhibits multiple subcutaneous rheumatoid nodules associated with episodes of intermittent arthralgias and subchondral cystic lesions of the small bones of the hands and feet. Large nodules were surgically removed from the two elbows. They were histologically typical of rheumatoid nodules. All these findings were consistent with the diagnosis of rheumatoid nodulosis.
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