Browse

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

ID PMID Title PublicationDate abstract
16982193 Discovery of small molecule inhibitors of integrin alphavbeta3 through structure-based vir 2006 Nov 15 Inhibitors of integrin alphavbeta3 have been implicated in the treatment of a variety of diseases, including tumor metastasis, neovascularization, osteoporosis, and rheumatoid arthritis. It is therefore desirable to develop new types of small molecule inhibitors of integrin alphavbeta3. Here we describe the discovery of novel classes of small molecule inhibitors, via structure-based virtual screening, that target the ligand binding site of integrin alphavbeta3. Application of the docking procedure for screening of a commercially available compound database resulted in a 1774-fold reduction in the size of the screening set (88695 to 50 compounds) and gave a hit-rate of 14% upon biological evaluation (IC50 value ranging from 30 to 200 microM). The best hit, compound 37, 3,4-dichloro-phenylbiguanide, showed inhibitory activity, in a time- and dose-dependent manner, in both cell motility and angiogenesis assays. Based on the best hit, compound 37, a more effective derivative compound 62 has been identified. Furthermore, molecular graphics analyses of a series of substituted phenylbiguanides were carried out to predict the binding mode between the active compounds and integrin alphavbeta3. Our results indicate that the substituted phenylbiguanides might be involved in the inhibition of bivalent cation-mediated ligand binding of integrin alphavbeta3.
16980722 Cardiac arrhythmias and conduction disturbances in autoimmune rheumatic diseases. 2006 Oct Rhythm and conduction disturbances and sudden cardiac death (SCD) are important manifestations of cardiac involvement in autoimmune rheumatic diseases (ARDs). In patients with rheumatoid arthritis (RA), a major cause of SCD is atherosclerotic coronary artery disease, leading to acute coronary syndrome and ventricular arrhythmias. In systemic lupus erythematosus (SLE), sinus tachycardia, atrial fibrillation and atrial ectopic beats are the major cardiac arrhythmias. In some cases, sinus tachycardia may be the only manifestation of cardiac involvement. The most frequent cardiac rhythm disturbances in systemic sclerosis (SSc) are premature ventricular contractions (PVCs), often appearing as monomorphic, single PVCs, or rarely as bigeminy, trigeminy or pairs. Transient atrial fibrillation, flutter or paroxysmal supraventricular tachycardia are also described in 20-30% of SSc patients. Non-sustained ventricular tachycardia was described in 7-13%, while SCD is reported in 5-21% of unselected patients with SSc. The conduction disorders are more frequent in ARD than the cardiac arrhythmias. In RA, infiltration of the atrioventricular (AV) node can cause right bundle branch block in 35% of patients. AV block is rare in RA, and is usually complete. In SLE small vessel vasculitis, the infiltration of the sinus or AV nodes, or active myocarditis can lead to first-degree AV block in 34-70% of patients. In contrast to RA, conduction abnormalities may regress when the underlying disease is controlled. In neonatal lupus, 3% of infants whose mothers are antibody positive develop complete heart block. Conduction disturbances in SSc are due to fibrosis of sinoatrial node, presenting as abnormal ECG, bundle and fascicular blocks and occur in 25-75% of patients.
16978829 Inhibition of macrophage activation and phagocytosis by a novel NF-kappaB inhibitor, dehyd 2006 Nov Previously, we designed and synthesized a new NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ). In the present research we looked into the effect of DHMEQ on the activation of macrophages, especially on the phagocytotic activity of cells of the mouse macrophage-like cell line RAW264.7. DHMEQ inhibited lipopolysaccharide (LPS)-induced NF-kappaB activation by inhibiting its nuclear translocation from the cytoplasm. It also inhibited the expression of inducible NO synthase (iNOS) and nitric oxide (NO) production induced by LPS and interferon-gamma. Using enzyme-linked immunosorbent assays (ELISAs) we showed DHMEQ to inhibit LPS-induced secretion of IL-6, IL-12, interleukin-1beta (IL-1beta), and TNF-alpha. Furthermore, DHMEQ also inhibited the phagocytosis of fluorescently labeled Escherichia coli by RAW264.7 cells treated with LPS or IL-1beta, thus being the first evidence for the involvement of NF-kappaB in the regulation of phagocytosis by use of this inhibitor. Deletion of p65 by siRNA also inhibited the phagocytosis. DHMEQ inhibited the LPS-induced but not IL-1beta-induced phagocytosis of glass beads, indicating that activation of not only NF-kappaB but also Toll-like receptor 4 (TLR-4) is essential for the phagocytosis of E. coli. Previously we found that DHMEQ inhibited type 2 collagen-induced rheumatoid arthritis and the growth of various human carcinomas in mice. It is thus likely that inhibition of macrophage activation is involved in the mechanism of these anti-inflammatory and antitumor activities of DHMEQ in mice.
16970925 The alternative NF-kappaB pathway from biochemistry to biology: pitfalls and promises for 2006 Oct 30 The past two decades have led to a tremendous work on the transcription factor NF-kappaB and its molecular mechanisms of activation. The nuclear translocation of NF-kappaB is controlled by two main pathways: the classical and the alternative NF-kappaB pathways. The classical NF-kappaB pathway activates the IKK complex that controls the inducible degradation of most IkappaB family members that are IkappaBalpha, IkappaBbeta, IkappaBvarepsilon and p105. The alternative NF-kappaB pathway induces p100 processing and p52 generation through the activation of at least two kinases, which are NIK and IKKalpha. Genetic studies have shown that IKKgamma is dispensable for the alternative pathway, which suggests the existence of an alternative IKKalpha-containing complex. It is noteworthy that activation of particular p52 heterodimers like p52/RelB requires solely the alternative pathway while activation of p52/p65 or p52/c-Rel involves a "hybrid pathway". Among others, LTbetaR, BAFF-R, CD40 and RANK have the ability to induce the alternative pathway. The latter plays some roles in biological functions controlled by these receptors, which are the development of secondary lymphoid organs, the proliferation, survival and maturation of B cell, and the osteoclastogenesis. Exacerbated activation of the alternative pathway is potentially associated to a wide range of disorders like rheumatoid arthritis, ulcerative colitis or B cell lymphomas. Therefore, inhibitors of the alternative pathway could be valuable tools for the treatment of inflammatory disorders and cancers.
16913667 [Clinical aspects of the complement system]. 2006 Jul The complement system consists of more than 30 proteins and has 3 types of activation pathways: classical, lectin and alternative pathways. The complement system not only has a role in innate immunity but also works as an antibody-dependent effecter to eliminate pathogens. It is useful to measure serum levels of CH50, C3 and C4 in patients with immune-mediated diseases. While increased levels of CH50 are associated with non-specific inflammation, decreased levels of CH50 in combination with normal or decreased levels of C3 and C4 are associated with specific immune-mediated diseases. Recent studies have demonstrated that the defect in the clearance of immune complexes and apoptotic cells is associated with autoimmune disease. Mice deficient in Clq show a lupus-like phenotype with the appearance of antinuclear antibodies and glomerulonephritis due to a defect in the clearance of immune complexes and apoptotic cells. This at least explains the paradox that, in humans, deficiency in an early complement component is a major risk factor for SLE. It is demonstrated that mutations in factor H, membrane cofactor protein (MCP) and factor I gene are associated with atypical hemolytic uremic syndrome. Since the complement system is a central mediator of inflammation, it is recognized as a promising therapeutic target. Anti-C5 monoclonal antibody was developed to block the final stage of complement activation. Pexelizumab is a single chain, short-acting anti-C5 antibody and is used for reperfusion after myocardial infarction, or for coronary artery bypass graft surgery with cardiopulmonary bypass. Eculizumab is a long-acting anti-C5 antibody used for paroxysmal nocturnal hemoglobinuria, rheumatoid arthritis, membranous glomerulonephritis with promising results.
16902810 Clinical response is associated with elevated plasma interleukin-1 receptor antagonist dur 2006 Sep Depletion of granulocytes and monocytes (GM) by selective apheresis (GMA) with an Adacolumn exerts an anti-inflammatory effect in patients with ulcerative colitis (UC) or rheumatoid arthritis. However, the mechanism of the anti-inflammatory effect of GMA is not fully understood yet. We investigated the effect of GMA on the plasma concentration of interleukin-1 receptor antagonist (IL-1ra), a potent anti-inflammatory cytokine. Twenty-six patients with active UC received GMA at one session per week for 5 consecutive weeks. Clinical response was defined as Deltaclinical activity index (DeltaCAI=CAI at entry - CAI at post)>or=4, while clinical remission was defined as CAI
16882171 Serum levels of BAFF are increased in bullous pemphigoid but not in pemphigus vulgaris. 2006 Aug BACKGROUND: BAFF [B-cell activating factor belonging to the tumour necrosis factor (TNF) family] is a member of the TNF superfamily that regulates B-lymphocyte proliferation and survival. It has been demonstrated that increased levels of soluble BAFF are associated with systemic autoimmunity in patients with systemic lupus erythematosus, rheumatoid arthritis and Sjögren's syndrome, and in animal models of spontaneous autoimmune diseases. However, the significance of circulating BAFF in autoimmune bullous diseases is unknown. OBJECTIVES: To examine whether BAFF levels are elevated in the autoimmune blistering diseases pemphigus vulgaris (PV) and bullous pemphigoid (BP). METHODS: We examined sera obtained from 21 patients with PV, 39 patients with BP and 22 healthy donors. We performed enzyme-linked immunosorbent assays for soluble BAFF and each disease-specific antibody: antidesmoglein-3 antibody for PV and anti-BP180 antibody for BP. RESULTS: Significant elevations of serum BAFF levels were found in the patients with BP, but not with PV. There was apparently no significant association between the serum BAFF levels and titres of anti-BP180 antibodies in the patients with BP. However, serum BAFF levels tended to be more elevated in patients with a shorter disease duration. There was a tendency that BAFF levels increased before the anti-BP180 antibody levels increased at the onset of BP and quickly decreased in response to treatment. CONCLUSIONS: BAFF may be a useful marker for early activation of an autoimmune diathesis and may play a critical role in triggering activation of self-antigen-driven autoreactive B cells in BP.
16603581 Preliminary evidence for cachexia in patients with well-established ankylosing spondylitis 2006 Nov OBJECTIVES: Cachexia, defined as an accelerated loss of skeletal muscle in the context of a chronic inflammatory response, is common in rheumatoid arthritis but it has not been demonstrated in patients with ankylosing spondylitis (AS). The aim of this study was to determine muscle wasting and its functional consequences in a group of patients with well-established AS. METHODS: Nineteen male patients (mean age 53 yrs) with long-standing AS (mean disease duration 19 yrs) and radiological changes (84% had one or more syndesmophytes) were compared with 19 age-matched healthy males with similar levels of habitual physical activity. Body composition was assessed by dual energy X-ray absorptiometry. Muscle strength was measured by isokinetic knee extension and hand grip dynamometry, and by 30 s arm curl and chair sit-to-stand tests. RESULTS: AS patients showed a statistically and clinically significant 12% reduction in arms and legs lean mass, a proxy measure of total body skeletal muscle mass, compared with healthy controls (P < 0.05). This muscle loss was significantly associated with reduced upper and lower body strength (correlation coefficients ranging between 0.37 and 0.79, P < 0.05). CONCLUSION: These results provide preliminary evidence that cachexia is a functionally relevant systemic complication of AS, particularly in patients with long-standing disease and radiological changes. Progressive resistance training and other interventions aimed at stimulating skeletal muscle growth might be beneficial in this population, and further studies on the pathophysiology of cachexia in AS patients are needed.
16596274 Increased expression of membrane TNF-alpha on activated peripheral CD8+ T cells in systemi 2006 May Membrane TNF-alpha is a precursor form of soluble TNF-alpha and exerts pro-inflammatory functions in a cell-to-cell contact manner. We showed that membrane TNF-alpha is induced upon activation on the cell surface of CD4+ T cells and CD8+ T cells. In patients with systemic lupus erythematosus (SLE), the percentage of membrane TNF-alpha-bearing CD8+ T cells (41.5+/-12.3%) was significantly higher compared with those of healthy controls (26.7+/-3.9%) (p=0.007) or patients with rheumatoid arthritis (29.8+/-15.4%) (p=0.038). Membrane TNF-alpha-bearing CD8+ T cells from SLE patients displayed cytotoxic activity against L929 cells. It is possible that membrane TNF-alpha may be involved in the increased apoptosis and the generation of autoantigens in SLE.
16462212 Clinical study of a modified Brooks technique for atlanto-axial subluxation using polyethy 2006 Feb Forty-four patients, 15 males and 29 females (3-71 years old; mean age, 52.9), were treated for the control of cervical instability with a modified Brooks operation using Tekmilon tape (an ultrahigh molecular weight polyethylene tape) instead of metal wires. Forty of the patients had rheumatoid arthritis (RA) with atlanto-axial subluxation (AAS), three patients had os odontoideum, and one patient had a cervical spine injury. The mean follow-up period was 8 years and 4 months. These patients were divided into three groups: 30 years or less, 31 to 60 years, and over 60 years. Atlanto-dental interval (ADI), inclination angle of atlanto-axial vertebrae (A-A angle), and bone fusion were examined on plain radiographs. The proportion of patients with reduced neck pain (Ranawat's grade 0 or grade 1) increased from 42.5% to 97.9% at the time of postoperative evaluation. Surgical complications, such as dural tear, lamina fracture, and spinal cord injury did not occur in any cases. Thirty-nine patients (88.6%) achieved bone union. ADI in the maximum flexed position improved from 10.3 to 2.5 mm. There was no statistical difference between ADI in males and females. ADI did not change in any age group both before and after surgery. A-A angle also improved from 9.4 to 24.4 degrees. The polyethylene tapes, used for internal fixation, caused no neurologic complications during sublaminar wiring and produced no MR artifacts. This modified Brooks technique using Tekmilon tape was proved to be a simple and safe treatment of AAS.
16387681 Humanized recombinant vaccinia virus complement control protein (hrVCP) with three amino a 2005 Nov Vaccinia virus complement control protein (VCP) is able to modulate the host complement system by regulating both pathways of complement activation. Efficient downregulation of complement activation depends on the ability of the regulatory protein to effectively bind the activated third (C3b) and fourth (C4b) complement components. Based on native crystallographic structure, molecular modeling, and sequence alignment with other Orthopoxviral complement control proteins (CCPs) and their host homologs, putative sites have been found on VCP as contact points for C3b/C4b. Here, we report that using site-directed mutagenesis, modified proteins have been generated. In addition, we report that the generated modified proteins with postulated contact point substitutions have shown greater ability to regulate both the classical and the alternative pathways of complement activation than the recombinant Western Reserve VCP, with one modified protein showing nearly 100-fold more potency in regulating both complement activation pathways independently. The augmented in vitro inhibitory activity of the modified protein together with the newly created putative heparin binding site suggests its promising potential as a competent therapeutic agent in modulating various complement-mediated ailments, for example, traumatic brain injury, Alzheimer's disease, rheumatoid arthritis, multiple organ dysfunction syndrome, reperfusion injury, and xenorejection.
16369458 Macrophage may responses to androgen via its receptor. 2006 Jan BACKGROUND: Sex hormones have profound effects on immune responses and may influence the disease which caused by intracellular parasite(Leishmania) and bacterial (tuberculosis)and also autoimmune disease such as rheumatoid arthritis (RA). It has also been demonstrated that 5alpha-Dihydrotestosterone (5alpha-DHT) modulate nitric oxide and cytokine release by macrophages. These effects seem to be exerted by specific receptors for androgen in macrophages. MATERIAL/METHODS: Protein secretion: The effect of 5alpha-DHT on protein secretion by peritoneal macrophages of NZBBALBc mice was investigated using radiolabelled protein secretion following SDS-PAGE and Fluorography. Binding assay: Androgen binding was also investigated using an autoradiography method. Peritoneal macrophages were treated with [3H]- 5alpha-DHT and incubated for 2 h before smearing on to microscope slides. Slides were air dried, dipped in Kodak NTB photographic emulsion, sealed in light proof boxes and left at 4 degrees C for 6 weeks. RESULTS: The results showed that protein secretion by macrophages changed under 5alpha-DHT treatment. Analysis of the data according to quantitation of [(3)H]-5alphaDHT binding receptors in fixed-slide mounted cells, identified a high specific androgen binding at physiological concentration. The receptors had a relatively high affinity for the 5alpha-DHT, So that binding affinity was not inhibited in the presence of 100-fold excess of non labelled 17-beta Estradiol. CONCLUSIONS: These results suggest that the immunosuppressive action exerted by androgen is at least partially achieved through a direct influence on macrophages.
16301617 STAT4 expression in human T cells is regulated by DNA methylation but not by promoter poly 2005 Dec 1 STAT4, which plays a pivotal role in Th1 immune responses, enhances IFN-gamma transcription in response to the interaction of IL-12 with the IL-12R. Mice deficient in STAT4 lack IL-12-induced IFN-gamma production and Th1 differentiation and display a predominantly Th2 phenotype. Although these findings indicate that STAT4 expression levels are important for the development of cytokine-producing Th1 cells, the transcriptional and posttranscriptional mechanisms regulating STAT4 expression are unknown. We sought to identify and characterize the transcriptional regulatory elements in the promoter region of the human STAT4 gene. We found that disruption of multiple transcriptional regions covering the CREB, OCT1, and SP1 motifs significantly reduced STAT4 promoter activity. However, genomic DNA isolated from 91 patients with asthma or rheumatoid arthritis showed no evidence of mutations in the defined STAT4 essential promoter region. The 5' flanking region of the promoter was found to contain a -149A/G change in approximately 20-35% of patients, but this polymorphism had no effect on promoter activity. Interestingly, STAT4 expression was drastically increased in human T cells following treatment with a DNA methyltransferase inhibitor, and truncation of methylation sites in the proximal regulatory elements of the STAT4 promoter markedly enhanced transcriptional activity. Thus, our findings provide molecular insight into STAT4 expression and suggest that, in human T cells, STAT4 expressional regulation is associated with DNA hypermethylation, but not promoter polymorphisms.
16250923 Nonhormonal drugs for contraception in men: a systematic review. 2005 Nov Nonhormonal drugs for contraception in men may have advantages over hormonal methods. The nonhormonal methods can have more rapid onset and less interference with androgen-dependent functions. This systematic review summarizes the clinical studies evaluating nonhormonal drugs administered to men for contraception. Relevant clinical results were found for gossypol, which is derived from the cotton plant, and for extracts of Tripterygium, a plant used in Chinese traditional medicine. Randomized, controlled trials were available on the efficacy of gossypol and on the effect of gossypol on potassium levels. Gossypol had problems with low efficacy and toxicity. For Tripterygium, 2 observational studies described men who were treated for rheumatoid arthritis. Although sperm density was lower among those taking Tripterygium, later reports indicated some toxicity. Nonclinical research continues on isolates of Tripterygium. No clinical studies for contraception in men were found for nonhormonal vaccines or neem, which is also a plant used for medicinal purposes. Clinical trials studied injecting styrene maleic anhydride into the vas deferens, but no comparative data were provided. At this time, no safe and effective nonhormonal drug is available for contraception in men. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader should be able to state that the number of studies concerning the use of nonhormonal drugs for male contraception are very limited, point out that the two nonhormonal drugs used to a small degree have varying results and serious side effects, and recall that there are limited clinical studies on use of vas deferens injections and vaccines in humans.
16101536 Therapeutic targets of misguided T cells in systemic lupus erythematosus. 2005 Jun It is widely accepted that T cells with defective function play a central role in the pathogenesis of systemic lupus erythematosus (SLE). The detailed molecular mechanism underlying the aberrant function of SLE T cells is now being revealed. The TCR zeta chain, transcription factor, elf-1, inflammation signal transducer NF-kB, and PKC theta have been identified as the responsible molecules. In contrast to the defective signal transduction molecules, surface structures such as adhesion molecules, and co-stimulators have been reported to increase in their expression and function. Glucocorticoids and immunosuppressive agents have greatly improved the outcome of acute diseases and 5-year survival rate. However, it is suggested that long-term survival and quality of life appears to be unsatisfactory. Although the medical management of SLE is not sufficient to warrant long-term survival of young patients, recent progress in anti-cytokine biologics therapy against rheumatoid arthritis (RA) has facilitated searching for the molecular targets of SLE. In this report, we briefly review the molecular basis of SLE pathogenesis, and discuss possible therapeutic targets in this disease, focusing particularly on signal transduction and adhesion molecules in T cells.
16101533 Neutrophil-derived cytokines: potential therapeutic targets in inflammation. 2005 Jun Polymorphonuclear neutrophils (PMNs) are usually thought of as the leukocyte population involved in acute inflammatory responses, acting as a first line of defense against invading microorganisms. These terminally differentiated cells are generally not thought of as an important source of de novo synthesis of polypeptide mediators. Recent progress has shown, however, that PMNs are able to synthesize cytokines in response to a variety of inflammatory stimuli and during certain pathological conditions. The expression profiles of PMN-derived cytokines are similar with those of monocytes/macrophages, major professional phagocytes. Like monocytes, PMNs are able to secrete proinflammatory cytokines [e.g., tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta], both CC and CXC chemokines [e.g., IL-8, interferon-inducible protein 10 (IP-10) and macrophage inflammatory protein (MIP)-1alpha], and angiogenic factors [e.g., vascular endothelial growth factor (VEGF)]. The secretion of cytokines by activated PMNs is regulated by immunoregulatory cytokines such as interferon (IFN)-gamma, IL-4, IL-10 and IL-13. In addition to acute inflammatory responses, PMNs and PMN-derived cytokines appear to be involved in the pathogenesis of such chronic inflammatory disorders as rheumatoid arthritis, inflammatory bowel diseases and mycobacterial infections. Conceivably, these findings place PMNs at a pivotal position where they regulate and orchestrate not only acute inflammatory responses but also chronic inflammation and immune regulation. As such, inhibition of PMN-derived cytokines is viewed as a potentially useful strategy for therapeutic immunointervention.
15857301 Therapeutic potential of TACE inhibitors in stroke. 2005 Apr Stroke is the third leading cause of death and the leading cause of permanent disability in western countries and the incidence of stroke is expected to increase in the foreseeable future due to the ageing population. The effective treatment of stroke remains challenging due to the complexity and heterogenicity of the disease. Recombinant tissue plasminogen activator (rt-PA) is the only FDA-approved therapy for stroke during the first 3 hr after the disease onset. However the risk of hemorrhage and its narrow therapeutic window has limited its use in clinic. Inflammation has been known to play a crucial role in the induction and development of stroke and tumor necrosis factor-alpha (TNF-alpha) is a central player in the initiation of multiple inflammatory cascades. The recent success of three anti-TNF biologics in the clinic for the treatment of rheumatoid arthritis as well as other inflammatory diseases has further validated TNF159nflammation. TNF-alpha has also been shown to be associated with ischemic stroke. Anti-TNF biologics have been shown to be effective in reducing the disease symptoms in various pre-clinical stroke models. Small molecule TNF inhibitors are highly desirable due to the limitations of protein therapeutics. Tumor necrosis factor-alpha-converting enzyme (TACE) is the major sheddase of TNF-alpha and is essential for the generation of soluble, mature TNF-alpha. Thus TACE appears to be an attractive target for development of oral small molecule TNF-alpha inhibitors. This review summarizes the role of TNF-alpha in stroke and the effect of several TACE/MMP inhibitors in pre-clinical stroke models. The data strongly suggest that TACE/MMP inhibitors have great therapeutic potential and may be valuable alternatives in treating stroke in the clinic.
15678307 Prognosis of patients with systemic rheumatic diseases admitted to the intensive care unit 2005 Apr OBJECTIVE: To determine prognostic factors in patients with systemic rheumatic diseases admitted to the intensive care unit (ICU) and to examine whether the observed mortality rate is predicted using the Acute Physiology And Chronic Health Assessment II (APACHE II) score. DESIGN AND SETTING: Retrospective study with historical controls in a 31-bed medicosurgical ICU at a university hospital. PATIENTS AND PARTICIPANTS: Seventy-one patients admitted to the ICU for an acute illness related to a systemic rheumatic disease and/or its treatment and 353 ICU control patients. RESULTS: Systemic rheumatic diseases were mainly rheumatoid arthritis and vasculitides. In-hospital mortality rate was 28/71 (39%), including 23 patients who died in the ICU. Multivariable logistic regression showed that poor prior health status (Berdit's classification), APACHE II score, and admission for infection were associated with mortality, whereas prior use of immunosuppressive agents was not. APACHE II score at admission was higher in nonsurvivors (22+/-9) than in survivors (17+/-5) (p<0.01). The standard mortality ratio, i.e., the ratio between observed and predicted mortality, was 1.7 in the 71 study patients and 1.0 in the 353 control patients (p<0.0001). CONCLUSIONS: In patients with systemic rheumatic diseases admitted to the ICU for at least 48 h, poor prior chronic health status, APACHE II score, and infection were prognostic factors for in-hospital mortality. SMR was higher than in a control ICU population.
15918993 Novel therapies for ankylosing spondylitis. 2005 Jun Recent interest in therapeutic developments for ankylosing spondylitis has focused primarily on two anti-tumor necrosis factor-a therapies, infliximab and etanercept, with several reports establishing their efficacy in pivotal phase III trials. Open extension analyses of earlier controlled trials have also shown that efficacy is maintained for at least 3 years, that monotherapy is adequate, and that treatment is well tolerated with few serious infections. Treatment is associated with reduction in sick leave and days spent in hospital. Despite induction of antinuclear antibodies and anti-ds DNA antibodies, clinical sequelae are rare. Reduction in magnetic resonance imaging parameters of inflammation and serologic biomarkers of cartilage turnover suggest that these agents may be disease-modifying though direct evidence from plain radiographic studies is still lacking. Conventional second line therapies typically used in rheumatoid arthritis have also been examined and while leflunomide appears to possess limited efficacy, there may be a case for re-examining the value of methotrexate.
16712837 Targeting cytosolic phospholipase A2 by arachidonyl trifluoromethyl ketone prevents chroni 2006 Jun 13 Cytosolic phospholipase A(2) (cPLA(2)) plays a pivotal role in inflammation by catalyzing the release of arachidonic acid, a substrate for lipoxygenase and cyclooxygenase enzymes, from membrane phospholipids. In the present study we examined the role of cPLA(2) in inflammatory responses through the use of a specific inhibitor of the enzyme, cPLA(2), arachidonyl trifluoromethyl ketone (AACOCF3). Interestingly, we observed that AACOCF3 is an inhibitor of chronic but not acute inflammatory responses. Specifically, AACOCF3 inhibited phorbol 12-myristate 13-acetate (PMA)-induced chronic ear edema in mice. Additionally, oral treatment of ovalbumin-sensitized/ovalbumin-challenged BALB/c mice with 20 mg/kg AACOCF3 prevented the development of airway hyper-responsiveness in a model of asthma. Furthermore, AACOCF3 decreased cellular recruitment in the airway lumen and airway inflammation after the ovalbumin challenge. Taken together, these results suggest that a potent and specific chemical inhibitor of cPLA(2) may be useful for the treatment of chronic inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease, psoriasis, and asthma.