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ID PMID Title PublicationDate abstract
16548447 The yin and yang of tumor necrosis factor inhibitors. 2006 Mar Tumor necrosis factor (TNF) inhibitors have proven highly effective against a number of autoimmune diseases but have been disappointing in treating others. An increase in the risk of Mycobacterium tuberculosis and other opportunistic infections has been noted in patients treated with these agents. If we use these drugs, we need to weigh their beneficial and adverse effects.
16343992 Altered collagen II peptides inhibited T-cell activation in rheumatoid arthritis. 2006 Feb It has been reported that collagen II (CII)-derived peptide induced T-cell activation via its amino acids responsible for T-cell receptor (TCR) recognition. In this study, three altered CII263-272 peptide ligands (APL) containing multiple substitutions of TCR contact residues were synthesized. Their roles in inhibition of T-cell activation were evaluated in peripheral blood lymphocytes (PBL) of rheumatoid arthritis (RA) in vitro. It was shown that 41% (25/61) of RA patients were responsive to the wild-type antigenic CII263-272. In contrast, marginal or silent T-cell responses to the three APLs were found, accompanied by inhibitory effects on secretion of Th1 type cytokines and expression of cell surface markers, CD69 and CD25. In addition, T-cell activation induced by the wild-type antigenic CII263-272 was inhibited by all the three APLs in a dose-dependent manner. It is demonstrated that APLs with substitutions of TCR contact residues are capable of down-regulating T-cell responses in PBLs of RA, suggesting that the CII-derived APLs are potentially therapeutic in RA.
17319096 Ongoing clinical trials of the pleiotropic effects of statins. 2005 BACKGROUND: The multiple effects (ie, pleiotropic effects of statins) have received increasing recognition and may have clinical applicability across a broad range of cardiovascular and noncardiovascular conditions. OBJECTIVE: To determine the relevance and significance of ongoing clinical trials of the pleiotropic effects of statins, focusing on nonlipid effects. METHOD: Ongoing trials were identified through personal communication, reports presented at scientific meetings (2000-2004), and queries made to AstraZeneca, Bristol-Myers Squibb Co, Merck & Co, Novartis, and Pfizer, manufacturers of the currently marketed statins. Published trials and other source material were identified through electronic searches on MEDLINE (1990-2003), abstract books, and references identified from bibliographies of pertinent articles. Eligible studies were the clinical trials of statins currently under way in which primary or secondary outcomes included the statins' nonlipid (ie, pleiotropic) effect(s). Data were extracted and trial quality was assessed by the authors. RESULTS: Of the 22 ongoing trials of the nonlipid effects of statins identified, 10 assessed inflammatory markers and plaque stabilization, 4 assessed oxidized low density lipoprotein/vascular oxidant stress, 3 assessed end-stage renal disease, 3 assessed fibrinogen/viscosity, 2 assessed endothelial function, 2 assessed acute coronary syndrome, 2 assessed aortic stenosis progression, and 1 each assessed hypertension, osteoporosis, ischemic burden, Alzheimer's disease, multiple sclerosis, and stroke (outcomes often overlapped). CONCLUSION: Given the excellent safety and tolerability of statins as a class, full exploration of their pleiotropic effects has the potential to provide additional benefits to many patients.
16313339 Role of RANKL in physiological and pathological bone resorption and therapeutics targeting 2005 Dec Osteoclasts are primary cells for physiological and pathological bone resorption, and receptor activator of nuclear factor-kappaB ligand (RANKL) is critically involved in the differentiation, activation, and survival of these cells. Recently, therapeutics for pathological bone destruction targeting RANKL pathways has attracted a great deal of attention. Herein, we review the recent advances in the research on osteoclast biology and discuss the advantages and disadvantages of anti-RANKL therapies.
16045727 Insights into the role of fibroblasts in human autoimmune diseases. 2005 Sep Traditional wisdom has considered fibroblasts as contributing to the structural integrity of tissues rather than playing a dynamic role in physiological or pathological processes. It is only recently that they have been recognized as comprising diverse populations of cells exhibiting complex patterns of biosynthetic activity. They represent determinants that react to stimuli and help define tissue remodelling through the expression of molecules imposing constraints on their cellular neighbourhood. Moreover, fibroblasts can initiate the earliest molecular events leading to inflammatory responses. Thus they must now be viewed as active participants in tissue reactivity. In this short review, I will provide an overview of contemporary thought about the contribution of fibroblasts to the pathogenesis of autoimmune processes through their expression of, and responses to, mediators of inflammation and tissue remodelling.
16162000 Novel inhibitor of p38 MAP kinase as an anti-TNF-alpha drug: discovery of N-[4-[2-ethyl-4- 2005 Sep 22 The p38 mitogen-activated protein (MAP) kinase has been implicated in the proinflammatory cytokine signal pathway, and its inhibitors are potentially useful for the treatment of chronic inflammatory diseases such as rheumatoid arthritis (RA) and inflammatory bowel disease. To develop a new drug for RA, we synthesized a novel series of 4-phenyl-5-pyridyl-1,3-thiazoles and evaluated their inhibition of p38 MAP kinase, lipopolysaccharide (LPS)-stimulated release of tumor necrosis factor-alpha (TNF-alpha) from human monocytic THP-1 cells in vitro, and LPS-induced TNF-alpha production in vivo in mice. During the course of the study, we found that these compounds risk the inhibition of cytochrome P450 (CYP) isoforms by coordination of the 4-pyridyl nitrogen with heme iron. We therefore investigated the effects of substitution at the 2-position of the pyridyl ring on the inhibitory activity of p38 MAP kinase and CYPs in more detail. As a result, N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (8h, TAK-715) exhibited potent inhibitory activity in these assays (inhibition of p38alpha, IC50 = 7.1 nM; LPS-stimulated release of TNF-alpha from THP-1, IC50 = 48 nM; LPS-induced TNF-alpha production in mice, 87.6% inhibition at 10 mg/kg, po) and no inhibitory activity for major CYPs, including CYP3A4. This compound also showed good bioavailability in mice and rats and significant efficacy in a rat adjuvant-induced arthritis model. Compound 8h was selected as a clinical candidate and is now under clinical investigation for the treatment of RA.
16785259 Tumour necrosis factor-alpha blockers: potential limitations in the management of advanced 2006 Sep Several studies have shown that tumour necrosis factor (TNF)-alpha levels are increased in the peritoneal fluid of women with endometriosis, with correlation between TNF-alpha concentrations and the degree of disease. It is also likely that elevation of peritoneal fluids' TNF-alpha levels may play a role in the pathogenesis of infertility associated with endometriosis. Use of drugs such as etanercept, a TNF-alpha receptor immunoglobulin fusion protein which inhibits TNF-alpha activity, showed in an animal study to reduce the severity of the disease, and the size of endometriotic foci. TNF-alpha blockers were recommended as a possible new line of therapy for endometriosis. Our case involved a 35-year-old Para 0, with rheumatic arthritis and stage 4 endometriosis. After 6 years of constant use of etanercept, she showed no improvement of endometriosis as demonstrated at laparoscopy. However, she underwent a successful IVF after the first attempt. TNF-alpha-blocker medications might not be beneficial for patients with advanced endometriosis. However, we cannot exclude the possible effect of these medications on early-stage endometriosis, and further study is required. Some of the immunologic abnormalities in the pelvis of patients with endometriosis could be the consequence of the disease and not the cause, and possibly suppression of immune cells and their products may not have a major effect on endometriotic lesions at an advanced stage. This also could explain why suppression of TNF-alpha showed no effect on infertility. However, use of TNF-alpha-blockers before IVF might increase the success rate in advanced endometriosis.
16297573 Molecular cloning, characterization and localization of chicken type II procollagen gene. 2006 Jan 17 Chicken type II procollagen (ccol2a1) has become as an important oral tolerance protein for effective treatment of rheumatoid arthritis. However, its molecular identity remains unclear. Here, we reported the full-length cDNA and nearly complete genomic DNA encoding ccol2a1. We have determined the structural organization, evolutional characters, developmental expression and chromosomal mapping of the gene. The full-length cDNA sequence spans 4837 bp containing all the coding region of the ccol2a1 including 3' and 5' untranslation region. The deduced peptide of ccol2a1, composed of 1420 amino acids, can be divided into signal peptide, N-propeptide, N-telopeptide, triple helix, C-telopeptide and C-propeptide. The ccol2a1 genomic DNA sequence was determined to be 12,523 bp long containing 54 exons interrupted by 53 introns. Comparison of the ccol2a1 with its counterparts in human, mouse, canine, horse, rat, frog and newt revealed highly conserved sequence in the triple helix domain. Chromosomal mapping of ccol2a1 locates it on 4P2. While the ccol2a1 mRNA was expressed in multiple tissues, the protein was only detected in chondrogenic cartilage, vitreous body and cornea. The ccol2a1 was found to contain two isoforms detected by RT-PCR. The distribution of the ccol2a1 lacking exon 2wasfrequently detected in chondrogenic tissues, whereas the exon 2-containing isoform was more abundant in non-chondrogenic tissues. These results provide useful information for preparing recombinant chicken type II collagen and for a better understanding of normal cartilage development.
15921672 Autoactivation profiles of calcium-dependent matrix metalloproteinase-2 and -9 in inflamma 2005 Aug BACKGROUND: The presence of matrix metalloproteinase-2 and -9 (MMP-2, MMP-9), gelatinase A and B, in synovial fluid is typical in inflammatory connective tissue diseases especially rheumatoid arthritis (RA). Because MMPs are synthesized as latent proforms, a pathophysiologic understanding of MMP regulation has focused on mechanisms of activation that remain to date largely unresolved. METHODS: Synovial fluid was collected by aseptic aspiration from RA patients and incubated with and without physiologic levels of calcium and other modifiers (pyrophosphate, bisphosphonates, and the tissue inhibitors of MMPs (TIMPs), under conditions that activate MMPs. MMP-2 and -9 were then characterized by substrate gel electrophoresis (gelatin zymography) to resolve both latent and activated 'partially proteolyzed' forms. RESULTS: Gelatin zymography revealed that RA synovial fluid contained latent neutrophil MMP-9 (92, 130, 225 kDa) and fibroblast MMP-2 (72 kDa). A small amount of activated MMP-2 (64 kDa) was also noted. Incubation of synovial fluid without calcium resulted in MMP-9 activation to 87, 116, and 209 kDa forms. MMP-9 activation was, however, substantially delayed in the presence of physiologic calcium (2.5 mmol/l). MMP-2 did not demonstrate any appreciable activation with or without physiologic calcium. MMP-9 activation likely occurred via an autoactivation mechanism since it was susceptible to inhibition by the tissue inhibitor of MMP-9 (TIMP-1). Pyrophosphate and bisphosphonates (alendronate and risedronate) were ineffective in blocking synovial fluid MMP-9 autoactivation. Some early MMP-9 activation was noted with alendronate despite the presence of physiologic calcium. DISCUSSION: Although RA synovial fluid contained abundant MMP-2 and MMP-9, only MMP-9 underwent autoactivation to lower molecular weight forms. MMP-9 was transiently stable in the presence of physiologic calcium concentration, whereas autoactivation was more pronounced without exogenous calcium. The apparent lack of MMP-2 autoactivation with or without calcium, likely resulted from the coexistence of its bound endogenous inhibitor, TIMP-2. The role of differential autoactivation of MMPs activity in inflammatory arthritic disease is discussed.
15642150 The role and clinical implications of G6PI in experimental models of rheumatoid arthritis. 2005 The antigens that trigger the pathogenic immune response in rheumatoid arthritis (RA) remain unknown. Until recently it was assumed that either viral or microbial antigens, or joint-specific antigens were the target of arthritogenic T and B lymphocytes in RA. Consequently, murine models of arthritis are induced by immunization with either joint-specific antigens such as type II collagen or microbial products such as streptococcal cell wall. In the K/BxN T-cell receptor transgenic mouse model arthritis is caused by a systemic autoimmune response to the ubiquitously expressed glycolytic enzyme glucose-6-phosphate isomerase (G6PI). The autoreactive transgenic T cells recognize G6PI and provide help for the production of arthritogenic IgG antibodies against G6PI. More recently it was shown that G6PI immunization induces severe symmetrical peripheral polyarthritis in genetically unaltered DBA/I mice. In that model CD4+ T cells are necessary not only for the induction but also for the effector phase of arthritis. Here we review the pathomechanisms that lead from systemic autoreactivity to arthritis in these models, consider the relevance of anti-G6PI immune reactivity for RA, and discuss the insights into the pathogenesis of RA and possibly other autoimmune conditions that can be gained from these models.
16311048 Interleukin-17, a regulator of angiogenic factor release by synovial fibroblasts. 2006 Apr OBJECTIVE: Angiogenesis is a process stimulated in inflamed synovium of patients with osteoarthritis (OA), and contributes to the progression of the disease. Synovial fibroblasts secrete angiogenic factors, such as vascular endothelial growth factor (VEGF), an up-regulator of angiogenesis, and this ability is increased by interleukin (IL)-1beta. The purpose of this study was to verify whether IL-17 contributes and/or synergizes with IL-1beta and tumor necrosis factor (TNF)-alpha in vessel development in articular tissues by stimulating the secretion of proangiogenic factors by synovial fibroblasts. DESIGN: We stimulated in vitro synovial fibroblasts isolated from OA, rheumatoid arthritis (RA) and fractured patients (FP) with IL-17 and IL-1beta and from OA patients with IL-17, IL-1beta and TNF-alpha. In the supernatants from the cultures, we assayed the amount of VEGF by immunoassay and other angiogenic factors (keratinocyte growth factor, KGF; hepatocyte growth factor, HGF; heparin-binding endothelial growth factor, HB-EGF; angiopoietin-2, Ang-2; platelet-derived growth factor B, PDGF-BB; thrombopoietin, TPO) by chemiluminescence; semiquantitative RT-PCR was used to state mRNA expression of nonreleased angiogenic factors (Ang-2 and PDGF-BB) and tissue inhibitors of metalloproteinase (TIMP)-1. RESULTS: IL-17, TNF-alpha and IL-1beta increased VEGF secretion by synovial fibroblasts from OA patients. IL-17 and IL-1beta also increased VEGF secretion in RA and FP. Besides, IL-17 increased KGF and HGF secretions in OA, RA and FP; in OA and RA, IL-17 also increased the HB-EGF secretion and the expression of TIMP-1 as protein and mRNA. In OA patients IL-17 had an additive effect on TNF-alpha-stimulated VEGF secretion. CONCLUSIONS: These results suggest that IL-17 is an in vitro stimulator of angiogenic factor release, both by its own action and by cooperating with TNF-alpha.
16755652 Trichostatin A cooperates with Fas-mediated signal to induce apoptosis in rheumatoid arthr 2006 Jun OBJECTIVE: To clarify the effects of trichostatin A (TSA), a histone deacetylase inhibitor, on the growth and survival of rheumatoid arthritis synovial fibroblasts (RA-SF). METHODS: Cell viability was assessed using a WST-8 assay and direct cell counting. Apoptosis was detected by annexin V staining on a flow cytometer. Protein and mRNA expression was determined by Western blotting, flow cytometry, and RT-PCR. RESULTS: TSA suppressed cell growth of RA-SF in a dose-dependent manner, as determined by WST-8 assay and direct cell counting. Other histone deacetylase inhibitors also showed inhibitory effects on RA-SF proliferation. TSA upregulated p21(WAF1/CIP1) cell cycle inhibitor, suggesting that cell cycle arrest is involved in the reduction of cell numbers. In addition, TSA cooperated with Fas-induced pathway to induce cell death, determined by WST-8 assay and annexin V staining. TSA reduced FLICE inhibitory protein (FLIP) expression but not Bcl-2, Bcl-XL, and Fas expression, indicating that the synergistic effect may be through downregulation of FLIP. CONCLUSION: TSA has antirheumatic effects on RA-SF and might be a potential therapeutic tool for the treatment of RA.
16729287 Anti-interleukin-6 receptor antibody therapy favors adrenal androgen secretion in patients 2006 Jun OBJECTIVE: Proinflammatory cytokines such as tumor necrosis factor (TNF) were demonstrated to inhibit adrenal steroidogenesis in patients with rheumatoid arthritis (RA), and this was particularly evident in the increase in adrenal androgen levels during anti-TNF therapy. This study investigated the influence on steroidogenesis of an interleukin-6 (IL-6)-neutralizing strategy using IL-6 receptor monoclonal antibodies (referred to as MRA). METHODS: In a placebo-controlled, double-blind, randomized study over 12 weeks in 29 patients with RA being treated with prednisolone, 13 of whom received placebo and 16 of whom received 8 mg MRA/kg body weight, the effects of MRA on serum levels of adrenocorticotropic hormone (ACTH), cortisol, 17-hydroxyprogesterone (17OHP), dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), androstenedione (ASD), estrone, and 17beta-estradiol, as well as their respective molar ratios, were determined. RESULTS: MRA therapy markedly improved clinical signs of inflammation (the erythrocyte sedimentation rate, swollen joint score, and Disease Activity Score in 28 joints). Serum levels of ACTH and cortisol and the molar ratio of cortisol to ACTH did not change. Although serum levels of DHEA and DHEAS remained stable during therapy, the DHEAS:DHEA molar ratio significantly decreased in treated patients (P = 0.048). Serum levels of ASD as well as the ASD:cortisol and ASD:17OHP molar ratios increased in MRA-treated patients (minimum P < 0.004). Serum levels of estrone and 17beta-estradiol did not change. but the estrone:ASD molar ratio (an indicator of aromatization) decreased during 12 weeks of MRA treatment (P = 0.001). CONCLUSION: Neutralization of IL-6 increases secretion of biologically active adrenal androgens in relation to that of precursor hormones and estrogens. This is another important indication that proinflammatory cytokines interfere with adrenal androgen steroidogenesis in patients with RA.
16688603 Parkinsonism in Caplan's syndrome. 2006 Apr Parkinsonism is a rare feature of immunological diseases. We describe a 67-year-old man with Caplan's syndrome (CS) and parkinsonism. CS is an immunologic disease characterised by the presence of rheumatoid arthritis associated with a specific form of pneumoconiosis. Parkinsonism as a manifestation of involvement of the central nervous system in this condition has never been reported. Following immunosuppressive treatment both the CS and the parkinsonian signs and symptoms showed a marked improvement. The role of immune mechanisms in these parkinsonian syndromes is discussed.
15827035 A regional audit of the use of COX-2 selective non-steroidal anti-inflammatory drugs (NSAI 2005 Jul OBJECTIVES: Whilst all non-steroidal anti-inflammatory drugs (NSAIDs) can cause adverse gastrointestinal events, COX-2-selective inhibitors (COX-2) may have improved gastrointestinal safety compared with non-selective NSAIDs (NSNSAIDs). In 2001, the National Institute for Clinical Excellence (NICE) published guidance on the use of the COX-2 agents celecoxib, rofecoxib, meloxicam and etodolac for rheumatoid arthritis (RA) and osteoarthritis (OA). This study aimed to audit the appropriateness of NSAID use in relation to NICE guidance in rheumatology out-patients. METHODS: Questionnaires were completed for all patients attending clinics in 18 rheumatology units in the West Midlands over a 2-week period. Data collected included patient demographics, NSAID type, indications, duration of use (> or =3 months was considered prolonged), and concomitant prescription of corticosteroids, warfarin and gastroprotective agents. RESULTS: Data were collected on 2846 patients; 1164 (41%) were taking NSAIDs (791 NSNSAIDs, 373 COX-2). Of the 1164 NSAID users, 753 (65%) had a diagnosis of RA or OA (483 NSNSAIDs, 270 COX-2). Overall, 37% of NSAID prescriptions were appropriate. Of the NSNSAID users, 92% had at least one risk factor for adverse gastrointestinal events and were therefore inappropriately treated. Prolonged use (in 89%) and age > or =65 yr (in 23%) were the most frequent risk factors identified. Of the COX-2 users, 97% had one or more risk factors and were appropriately treated. Analysis of the RA/OA subgroup revealed similar findings. Thirty-six per cent were taking NSAIDs appropriately; 97% of NSNSAID use was inappropriate and 97% of COX-2 use was appropriate treatment. In the whole cohort, gastroprotective agents were used in 26% of NSNSAID users, 56% of gastroprotective agents being proton pump inhibitors. CONCLUSIONS: Ninety-two per cent of patients attending rheumatology clinics who were taking NSNSAIDs should have been prescribed a COX-2-selective agent in relation to NICE guidance. Duration of use and age > or =65 yr emerged numerically as the most important risk factors. Significant numbers of patients taking NSNSAIDs may be at risk from adverse gastrointestinal events and clinicians may wish to review their prescribing patterns. Conversely, 97% of patients taking COX-2 agents were treated appropriately. Although practice overall conformed poorly with NICE guidance, NSAID prescribing also needs to be considered in the context of recent concerns regarding the cardiovascular risks of COX-2 agents.
15882125 Clinical pharmacology of lumiracoxib, a second-generation cyclooxygenase 2 selective inhib 2005 Apr Although highly selective cyclooxygenase (COX)-2 inhibitors have been shown to be less toxic to the gastrointestinal tract than conventional non-steroidal anti-inflammatory drugs (NSAIDs), their overall safety profile is questioned. Since different selective COX-2 inhibitors were found to be associated with increased cardiovascular thrombotic events, the thrombotic hazard may be a class effect. Furthermore, warnings have been issued regarding serious skin and hypersensitivity reactions associated with valdecoxib. Lumiracoxib is a novel COX-2 selective inhibitor (coxib) with improved biochemical selectivity over that of currently available coxibs. It is structurally distinct from other drugs in the class and has weakly acidic properties. Clinical studies support a once-daily dosing regimen, despite its relatively short plasma elimination half-life (3 - 6 h). In randomised, controlled clinical trials, lumiracoxib 100 - 200 mg/day has been shown to be superior to placebo in patients with symptomatic osteoarthritis, with clinical efficacy similar to diclofenac 150 mg/day, celecoxib 200 mg/day or rofecoxib 25 mg/day. Furthermore, lumiracoxib 200 - 400 mg/day appeared to be effective in patients with rheumatoid arthritis. In patients with acute pain related to primary dysmenorrhoea, dental or orthopaedic surgery, lumiracoxib 400 mg/day was found to be at least as effective as standard doses of traditional NSAIDs and other coxibs. Endoscopic studies have indicated that lumiracoxib is associated with a rate of gastroduodenal ulcer formation that is significantly lower than with ibuprofen and does not differ from celecoxib. In the Therapeutic Arthritis Research and Gastrointestinal Trial, which enrolled 18,325 patients with osteoarthritis, the cumulative 1-year incidence of ulcer complications (primary end point) was significantly reduced by approximately threefold on lumiracoxib 400 mg/day compared with naproxen 1000 mg/day or ibuprofen 2400 mg/day (0.32 versus 0.91%). Reduction in ulcer complications was more pronounced in the population not taking low-dose aspirin (0.2 versus 0.92%, respectively). Conversely, the gastrointestinal advantage of lumiracoxib was abrogated in patients receiving low-dose aspirin (0.69 versus 0.88%, respectively, p = 0.49). Regarding cardiovascular events contributing to the trialists' composite end point (myocardial infarction, stroke or cardiovascular death), there was no significant difference between lumiracoxib (0.65%) versus combined comparator NSAIDs (0.55%). Similarly, no significant difference was recorded in rates of myocardial infarction (clinical and silent) between the lumiracoxib (0.25%) and the combined NSAID (0.19%) treatment groups. Liver function test abnormalities were more frequent with lumiracoxib (2.57%) than with the comparator NSAIDs (0.63%). Whether or not this would result in an increased risk of clinical hepatitis in the real world setting is unforeseeable.
16877466 Sjogren's syndrome is associated with and not secondary to systemic sclerosis. 2007 Feb OBJECTIVES: When Sjögren's syndrome (SS) is secondary to rheumatoid arthritis, the sicca syndrome is less serious and anti-SSA/SSB antibodies are found less frequently than in primary SS (pSS). When SS is associated with systemic lupus erythematosus, clinical and serological patterns are similar to those of pSS. We aimed to determine whether SS, accompanying systemic sclerosis (SSc), could be considered secondary to or associated with SSc and whether the coexistence of both modifies the severity and the outcome of each disease. PATIENTS AND METHODS: A retrospective multicentric study was conducted to compare (i) characteristics and complications of SS between 27 patients with SS and SSc (SS-SSc) and 202 patients with pSS, and (ii) the characteristics of SSc and complications between the SS-SSc group and 94 patients with SSc alone. RESULTS: SS features were similar in both SS-SSc and pSS patients, except for peripheral neuropathy and arthritis, which was more common in SS-SSc than in the pSS patients (P = 0.02 and 0.05, respectively). SSc appears to be less severe in patients with SS-SSc than SSc alone with a lower frequency of lung fibrosis (P = 0.05). Compared with patients with pSS or SSc alone, SS-SSc patients were more likely to have another autoimmune disorder and other autoantibodies (SS-SSc vs pSS, P = 0.02 and P = 0.03, respectively). CONCLUSION: SS seems to be associated with and not secondary to SSc. SS associated with SSc has the same features as pSS, but SSc seems to be less serious. Moreover, the association of SS and SSc is frequently accompanied by a spreading of autoimmunity.
16982214 Rheumatoid synovial fluid T cells are sensitive to APO2L/TRAIL. 2007 Jan The infiltration and accumulation of T cells in the rheumatoid arthritis (RA) synovial fluid (SF) are hallmarks of disease. We aimed to assess the functional relevance of FasL and of APO2L/TRAIL in the persistence of T cells in the rheumatoid SF. We have analyzed the expression of the activation markers HLA-DR and CD69 and also of the death receptor Fas/CD95 and death ligands FasL or APO2L/TRAIL in CD3+ lymphocytes from SF of 62 RA patients, together with their sensitivity to anti-Fas mAb or to rAPO2L/TRAIL, using as controls T lymphocytes present in SF of 20 patients with traumatic arthritis. T lymphocytes infiltrated in SF of RA patients have a chronically activated phenotype, but they are resistant to Fas-induced toxicity. However, they are more susceptible to rAPO2L/TRAIL than T cells in the SF of traumatic arthritis patients. In addition, we found very low amounts of bioactive FasL and APO2L/TRAIL associated with exosomes in SF from RA patients as compared with SF from traumatic arthritis patients. The observation on the sensitivity of RA SF T cells to rAPO2L could have therapeutic implications because bioactive APO2L/TRAIL could be beneficial as a RA treatment.
16585133 Association between cigarette smoking and release of tumour necrosis factor alpha and its 2006 Oct OBJECTIVE: To investigate the relationship between cigarette smoking and release of TNF-alpha and its soluble receptors (sTNFRI and sTNFRII) by peripheral blood mononuclear cells (PBMCs) from RA patients. METHODS: We studied 71 RA patients with established disease (mean duration 10.6 yr). Smoking history was established by questionnaire. T lymphocytes and monocytes were isolated from peripheral blood and incubated with or without stimulation (phytohaemagglutinin and lipopolysaccharide, respectively). Release of TNF-alpha and sTNFR into culture medium was measured by enzyme-linked immunosorbent assay. RESULTS: TNF-alpha release by stimulated T lymphocytes was significantly higher in patients with a history of smoking than in those who had never smoked (1416.0 vs 767.4 pg/ml, P = 0.04), and showed a relationship with smoking duration and intensity (P for trend < or =0.009). Monocyte TNF-alpha release was not associated with smoking status. Release of sTNFR showed no clear relationships with extent of smoking, although release by stimulated T lymphocytes was higher in past smokers than in those who had never smoked (P < or = 0.03). The ratio of TNF-alpha/sTNFR released from T lymphocytes was higher in past and current smokers, and was associated with extent of smoking. No relationship was found between smoking and plasma TNF-alpha levels, but levels of both receptors were higher in past smokers. CONCLUSION: In RA patients who smoke there is an alteration in the ratio of TNF-alpha/sTNFR released by stimulated T cells that might favour increased TNF-alpha activity. The increased TNF-alpha/sTNFR ratio is associated with extent of smoking, and remains elevated after smoking cessation.
16396287 [Frequency of different infectious agents persistence in mononuclear leukocytes of blood a 2005 Jul The study of persistence in mononuclear leukocytes (ML) of blood and synovial fluid of 218 patients with rheumatoid arthritis (RA) Cytornegalovirus (CMV), the 1-st and 2-nd types of Herpes virus simplex (VH), Epstain-Barr virus (VEB), Mycoplasma arthritidis (Ma), Mycoplasma fermentans (Mf), Ureaplasma urealiticum (U), Chlamidia trachomatis (Ct), viruses of Hepatitis B and C was carry out by direct and indirect immunofruorescence, immunoenzymatic analysis and polymerase chain reaction. An increased frequency of contamination of blood ML with infectious agents in patients with RA was established (57,4% compared with 16,7% in control group). The following infectious agents were revieled more frequently: in ML of blood and synovial fluid the Ma (relatively 20,5% and 15,9%), Mf (15,6% and 13,2%), Ct (18,4% and 13,2%), VH (27,1% and 10,5%), VEB (12,7% and 5,3%) and CMV (11,2% and 7,9%). Types of frequency dynamics of ML contamination with these infectious agents in different time phases of RA were determined.