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ID PMID Title PublicationDate abstract
15229956 Are there clinical or serological differences between male and female patients with primar 2004 Jul OBJECTIVE: Sjögren's syndrome (SS) is a chronic inflammatory autoimmune disease. It can be primary (pSS) or secondary (sSS) and is observed 90% more in women than in men, mainly in the fourth and fifth decades of life. We investigated the prevalence of serological and clinical manifestations in male and female patients with primary SS. METHODS: We analyzed 521 female and 28 male patients with pSS between 1993 and 2001. All patients fulfilled > or = 4 of the 1993 European Community Study Group criteria. RESULTS: Men presented higher concentrations of IgA, rheumatoid factor, and antinuclear antibodies than women. A higher percentage of women than men reported fibromyalgia, thyroidal manifestations, and carpal tunnel syndrome. There were no statistical differences between the 2 groups in relation to the presence of Raynaud's phenomenon, arthritis, erosive osteoarthritis, liver disease, or other visceral manifestations. CONCLUSION: The pattern of SS in our cohort of patients reveals a difference between male and female patients, in contrast with earlier studies.
15171815 Opposing regulation of interleukin-8 and NF-kappaB responses by lipoxin A4 and serum amylo 2004 May Lipoxin A4 (LXA4) is a potent eicosanoid that inhibits IL-1beta-induced activation of human fibroblast like synoviocytes (FLS) via the ALX4 receptor. Serum amyloid A (SAA) is an acute phase reactant with cytokine-like properties. SAA has been shown to bind the same seven transmembrane G protein-coupled receptor ligated by LXA4. Here we compared the inflammatory responses of lipid (LXA4) and peptide (SAA) ligands in human FLS via the shared ALX, and characterized their downstream signaling. LXA4 induced stimulation of tissue inhibitors of metalloproteinase-2, whereas SAA induced interleukin-8 and matrix metalloproteinase-3 production. SAA up-regulated NF-kappaB and AP-1 DNA binding activity, while LXA4 markedly inhibited these responses after IL-1beta stimulation. A human IL-8 promoter luciferase construct was transfected into CHO cells stably expressing ALXR in order to determine the role of NF-kappaB and/or AP-1 in the regulation of IL-8 gene expression. The NF-kappaB pathway proved to be the preeminent for the biological responses elicited by both ligands. These findings suggest that two endogenous molecules, targeting a common receptor, could participate in the pathogenesis of inflammatory arthritis by differentially regulating inflammatory responses in tissues expressing the ALXR.
12355486 Autoantibodies against granulocyte colony-stimulating factor in Felty's syndrome and neutr 2002 Sep OBJECTIVE: Cytokines and growth factors can be a target of autoantibodies in systemic inflammatory diseases. We examined whether patients with neutropenia and either Felty's syndrome (FS) or systemic lupus erythematosus (SLE) have autoantibodies against granulocyte colony-stimulating factor (G-CSF) and whether these autoantibodies are functionally relevant. METHODS: Fifteen patients with neutropenia due to FS were matched for age, sex, and disease activity with 16 normocytic rheumatoid arthritis (RA) control patients. Sixteen patients with SLE and neutropenia were matched with 16 normocytic SLE control patients. Antibodies against G-CSF were measured by enzyme-linked immunosorbent assay and Western blotting. Antibody specificity was verified by competitive inhibition using recombinant human G-CSF. The effect of anti-G-CSF antibodies on the functional activity of their target molecule was measured in a bioassay using G-CSF-sensitive murine 32D cells. RESULTS: IgG anti-G-CSF was found in 11 FS patients, 6 SLE patients with neutropenia, 6 SLE control patients, and none of the RA control patients. IgM anti-G-CSF was found in 6 neutropenic and 3 normocytic SLE patients. Anti-G-CSF antibodies were associated with an exaggerated serum level of G-CSF and a low neutrophil count. A neutralizing effect of anti-G-CSF antibodies on its target molecule was found in 3 of the 9 patients tested. Irrespective of the presence or absence of anti-G-CSF antibodies, neutropenic patients with FS and SLE had exaggerated serum levels of G-CSF. CONCLUSION: Anti-G-CSF autoantibodies are common in neutropenia due to FS and SLE. In individual patients, these autoantibodies have a neutralizing capacity. In patients without neutralizing antibodies, hyposensitivity of the myeloid cells to G-CSF appears to be central to the pathogenesis of the neutropenia in FS and SLE.
14707510 Enzyme replacement therapy in heterozygous females with Fabry disease: results of a phase 2003 Fabry disease is an X-linked glycosphingolipid storage disorder caused by a deficiency of alpha-galactosidase A. Affected patients experience debilitating neuropathic pain and have premature mortality due to renal failure, cardiovascular disease or cerebrovascular complications. The disease may be X-linked dominant, since most females heterozygous for Fabry disease are affected clinically. We evaluated the safety, efficacy and pharmacokinetics of agalsidase alfa (Replagal) administered intravenously to female patients with Fabry disease in an open-label, single-centre study. Fifteen severely affected patients received agalsidase alfa at 0.2 mg/kg every other week for up to 55 weeks. Agalsidase alfa was safe and well-tolerated in female patients. None of the patients developed antibodies or experienced an infusion reaction to agalsidase alfa. The pharmacokinetic profile of agalsidase alfa in female patients is comparable to the pharmacokinetics of agalsidase alfa in male patients. Mean urine sediment and plasma Gb3 levels decreased from baseline at 13, 27 and 41 weeks. A significant decrease in left ventricular mass from baseline was seen at weeks 27 (p = 0.003) and 41 (p = 0.039), and a significant reduction in QRS durations was seen at week 27 (p = 0.007). Furthermore, there was a significant improvement in quality of life. Renal function did not deteriorate in these 15 female patients over the 13- to 41-week period of observation. We conclude that enzyme replacement therapy with agalsidase alfa was safe and effective in female patients heterozygous for Fabry disease.
15642134 Increased interleukin-17 production via a phosphoinositide 3-kinase/Akt and nuclear factor 2005 Inflammatory mediators have been recognized as being important in the pathogenesis of rheumatoid arthritis (RA). Interleukin (IL)-17 is an important regulator of immune and inflammatory responses, including the induction of proinflammatory cytokines and osteoclastic bone resorption. Evidence for the expression and proinflammatory activity of IL-17 has been demonstrated in RA synovium and in animal models of RA. Although some cytokines (IL-15 and IL-23) have been reported to regulate IL-17 production, the intracellular signaling pathways that regulate IL-17 production remain unknown. In the present study, we investigated the role of the phosphoinositide 3-kinase (PI3K)/Akt pathway in the regulation of IL-17 production in RA. Peripheral blood mononuclear cells (PBMC) from patients with RA (n = 24) were separated, then stimulated with various agents including anti-CD3, anti-CD28, phytohemagglutinin (PHA) and several inflammatory cytokines and chemokines. IL-17 levels were determined by sandwich enzyme-linked immunosorbent assay and reverse transcription-polymerase chain reaction. The production of IL-17 was significantly increased in cells treated with anti-CD3 antibody with or without anti-CD28 and PHA (P < 0.05). Among tested cytokines and chemokines, IL-15, monocyte chemoattractant protein-1 and IL-6 upregulated IL-17 production (P < 0.05), whereas tumor necrosis factor-alpha, IL-1beta, IL-18 or transforming growth factor-beta did not. IL-17 was also detected in the PBMC of patients with osteoarthritis, but their expression levels were much lower than those of RA PBMC. Anti-CD3 antibody activated the PI3K/Akt pathway; activation of this pathway resulted in a pronounced augmentation of nuclear factor kappaB (NF-kappaB) DNA-binding activity. IL-17 production by activated RA PBMC is completely or partly blocked in the presence of the NF-kappaB inhibitor pyrrolidine dithiocarbamate and the PI3K/Akt inhibitor wortmannin and LY294002, respectively. However, inhibition of activator protein-1 and extracellular signal-regulated kinase 1/2 did not affect IL-17 production. These results suggest that signal transduction pathways dependent on PI3K/Akt and NF-kappaB are involved in the overproduction of the key inflammatory cytokine IL-17 in RA.
12672398 Diagnostic and pathogenetic role of antineutrophil cytoplasmic autoantibodies. 2003 Feb Anti-neutrophil cytoplasmic antibodies (ANCA) are mostly known as a useful diagnostic tool in patients with small-vessel vasculitides. With the accumulating knowledge of these autoantibodies, however, it becomes clear that the role of ANCA may not be only limited to a diagnosis of such disorders. The current review addresses, in addition to classical diagnostic associations, other diseases connected with ANCA positivity, both in adults and in children. The etiology of ANCA remains unknown, but still, the importance of both genetic and environmental factors is undoubted. The role of infection and chemicals in the etiology of ANCA-associated diseases is stressed in particular. A pathogenetic role of ANCA is suggested because of clinical observations based on the correlation of the vasculitis activity and the titer of ANCA. Many experiments show the effects of ANCA in various steps of an inflammatory process, particularly on leukocyte microbicidal activity and oxidative burst. Recent findings are analyzed in the experimental field and they are correlated with clinical significance.
12615627 Histoplasmosis after treatment with anti-tumor necrosis factor-alpha therapy. 2003 May 1 Anti-tumor necrosis factor-alpha (TNF-alpha) antibodies are frequently used to treat inflammatory diseases. However, these drugs also have immunosuppressive effects. We report on three patients who developed disseminated histoplasmosis on therapy with TNF-alpha inhibitors. In vitro assays were used to characterize the role of these agents in host defense against Histoplasma capsulatum. Intracellular proliferation of H. capsulatum was measured in alveolar macrophages and peripheral monocytes of normal volunteers in the presence and absence of the TNF-alpha antibody, infliximab. Both infliximab and control antibody enhanced fungal growth in monocytes and alveolar macrophages, suggesting this was a nonspecific antibody response. Despite similar intracellular fungal loads in the presence of both antibodies, lymphocyte proliferation in response to blood monocytes and alveolar macrophages infected with H. capsulatum was inhibited by the addition of physiologic doses of infliximab, whereas control antibody had no effect. The production of H. capsulatum-induced interferon-gamma and TNF-alpha was assessed in 5-day cultures containing lymphocytes and alveolar macrophages or monocytes. Interferon-gamma secretion was significantly reduced in the presence of infliximab. In summary, patients receiving anti-TNF-alpha therapy are at risk for developing disseminated histoplasmosis. This may be due to a defect in the TH1 arm of cellular immunity.
14715662 ESE-1 is a novel transcriptional mediator of angiopoietin-1 expression in the setting of i 2004 Mar 26 Angiogenesis is a critical component of the inflammatory response associated with a number of conditions. Angiopoietin-1 (Ang-1) is an angiogenic growth factor that promotes the chemotaxis of endothelial cells and facilitates the maturation of new blood vessels. Ang-1 expression is up-regulated in response to tumor necrosis factor-alpha (TNF-alpha). To begin to elucidate the underlying molecular mechanisms by which Ang-1 gene expression is regulated during inflammation, we isolated 3.2 kb of the Ang-1 promoter that contain regulatory elements sufficient to mediate induction of the promoter in response to TNF-alpha, interleukin-1beta, and endotoxin. Surprisingly, sequence analysis of this promoter failed to reveal binding sites for transcription factors that are frequently associated with mediating inflammatory responses, such as NF-kappaB, STAT, NFAT, or C/EBP. However, putative binding sites for ETS and AP-1 transcription factor family members were identified. Interestingly, among a panel of ETS factors tested in a transient transfection assay, only the ETS factor ESE-1 was capable of transactivating the Ang-1 promoter. ESE-1 binds to specific ETS sites within the Ang-1 promoter that are functionally important for transactivation by ESE-1. ESE-1 and Ang-1 are induced in synovial fibroblasts in response to inflammatory cytokines, with ESE-1 induction slightly preceding that of Ang-1. Mutation of a high-affinity ESE-1 binding site leads to a marked reduction in Ang-1 transactivation by ESE-1, inducibility by inflammatory cytokines, and DNA binding to the ESE-1 protein. Transcriptional profiling of cells transiently transfected with an ESE-1 expression vector demonstrates that the endogenous Ang-1 gene is directly inducible by ESE-1. Finally, Ang-1 and ESE-1 exhibit a similar and strong expression pattern in the synovium of patients with rheumatoid arthritis. Our results support a novel paradigm for the ETS factor ESE-1 as a transcriptional mediator of angiogenesis in the setting of inflammation.
12734913 Interleukin 18 and hepatocyte growth factor in fulminant hepatic failure of adult onset St 2003 May Adult onset Still's disease (AOSD) is a rheumatoid disorder characterized by polyarthritis, intermittent high fever, and salmon colored rashes. Liver dysfunction is usually mild and fulminant liver failure is rare. We describe a 20-year-old woman with AOSD and severe hepatic necrosis leading to hepatic failure requiring liver transplant. This severe liver disorder developed after decreases in fever, arthritis, and C-reactive protein. Interleukin 18 (IL-18), but not ferritin, increased in association with liver dysfunction. Hepatocyte growth factor (HGF) increased at the time of hepatic failure. IL-18 and HGF elevation may have contributed to this rare severe liver injury in AOSD.
12848634 A comparison of the upper gastrointestinal mucosal effects of valdecoxib, naproxen and pla 2003 Jul 1 BACKGROUND: In long-term outcomes studies, cyclooxygenase COX-2 specific inhibitors spare COX-1 at supratherapeutic doses and therefore demonstrate improved gastrointestinal safety over nonspecific nonsteroidal anti-inflammatory drugs (NSAIDs). However, in clinical practice, anti-inflammatory drugs are often used for short-term treatment of pain. AIM: To compare the short-term upper gastrointestinal mucosal effects of naproxen with the new COX-2 specific inhibitor, valdecoxib, or placebo, in elderly subjects. METHODS: In this multicentre, double-blind, randomized, study, elderly subjects (65-76 years old), with a normal baseline esophagogastroduodenoscopy (EGD), received oral valdecoxib (a supratherapeutic 40 mg b.d. dosage, n = 62), naproxen (500 mg b.d., n = 62), or placebo (n = 62) for 6.5 days. Upper gastrointestinal mucosal injury was evaluated post-treatment by EGD (day 7). RESULTS: Subjects receiving naproxen (11/60, 18%) had significantly more gastroduodenal ulcers post-treatment than those receiving placebo (2/61, 3%; P < 0.01) or valdecoxib (0/60, 0%; P < 0.001). A similar significant finding was observed for gastric ulcer rates. All treatments had similar adverse event rates and clinical laboratory findings. CONCLUSIONS: Valdecoxib, even at supratherapeutic doses, was associated with an ulcer rate significantly lower than naproxen but similar to placebo in healthy elderly subjects, despite the short duration of therapy (6.5 days). Naproxen and valdecoxib were as well tolerated as placebo.
12740574 Resistance to CpG DNA-induced autoimmunity through tolerogenic B cell antigen receptor ERK 2003 Jun CpG sequences in self-DNA are an important potential trigger for autoantibody secretion in systemic lupus and other systemic autoimmune disorders. It is not known how this ubiquitous threat may be controlled by active mechanisms for maintaining self tolerance. Here we show that two distinct mechanisms oppose autoantibody secretion induced by CpG DNA in anergic B cells that are constantly binding self-antigen. Uncoupling of the antigen receptor (BCR) from a calcineurin-dependent pathway prevents signals that synergize with CpG DNA for proliferation. The BCR does not become desensitized by activating the extracellular response kinase (ERK) MAP kinase pathway, however, and continuous self-antigen signaling to ERK inhibits CpG DNA-induced plasma cell differentiation. These two mechanisms seem to act as a general control against autoantibody production elicited by Toll-like receptors, and their regulation of T cell-independent responses to Toll-like receptor 9 (TLR9) is probably crucial for resistance to systemic autoimmunity.
11962753 Effects of the antirheumatic remedy hox alpha--a new stinging nettle leaf extract--on matr 2002 Apr Inflammatory joint diseases are characterized by enhanced extracellular matrix degradation which is predominantly mediated by cytokine-stimulated upregulation of matrix metalloproteinase (MMP) expression. Besides tumour necrosis factor-alpha (TNF-alpha), Interleukin-1beta (IL-1beta) produced by articular chondrocytes and synovial macrophages, is the most important cytokine stimulating MMP expression under inflammatory conditions. Blockade of these two cytokines and their downstream effectors are suitable molecular targets of antirheumatic therapy. Hox alpha is a novel stinging nettle (Urtica dioica/Urtica urens) leaf extract used for treatment of rheumatic diseases. The aim of the present study was to clarify the effects of Hox alpha and the monosubstance 13-HOTrE (13-Hydroxyoctadecatrienic acid) on the expression of matrix metalloproteinase-1, -3 and -9 proteins (MMP-1, -3, -9). Human chondrocytes were cultured on collagen type-II-coated petri dishes, exposed to IL-1beta and treated with or without Hox alpha and 13-HOTrE. A close analysis by immunofluorescence microscopy and western blot analysis showed that Hox alpha and 13-HOTrE significantly suppressed IL-1beta-induced expression of matrix metalloproteinase-1, -3 and -9 proteins on the chondrocytes in vitro. The potential of Hox alpha and 13-HOTrE to suppress the expression of matrix metalloproteinases may explain the clinical efficacy of stinging nettle leaf extracts in treatment of rheumatoid arthritis. These results suggest that the monosubstance 13-HOTrE is one of the more active antiinflammatory substances in Hox alpha and that Hox alpha may be a promising remedy for therapy of inflammatory joint diseases.
15213041 Effect of vitamin E supplementation on vitamin K status in adults with normal coagulation 2004 Jul BACKGROUND: Cases of enhanced anticoagulant effect in response to high-dose vitamin E supplementation have been reported among patients taking oral anticoagulants. Although a vitamin E-vitamin K interaction was proposed to underlie this effect, it has not been systematically investigated in adults with normal baseline coagulation status. OBJECTIVE: The objective was to study the effect of 12 wk of supplementation with 1000 IU RRR-alpha-tocopherol/d on biochemical measures of vitamin K status in men and women not taking oral anticoagulants. DESIGN: Vitamin K status, which was assessed with the use of plasma phylloquinone concentrations, the degree of under-gamma-carboxylation of prothrombin (proteins induced by vitamin K absence-factor II, PIVKA-II), and the percentage of undercarboxylated osteocalcin (ucOC), was determined in 38 men and women with rheumatoid arthritis (study A) and in 32 healthy men (study B) participating in 2 independent, 12-wk randomized clinical trials of vitamin E supplementation (1000 IU/d). RESULTS: Mean (+/- SD) PIVKA-II increased from 1.7 +/- 1.7 to 11.9 +/- 16.1 ng/mL (P < 0.001) in study A and from 1.8 +/- 0.6 to 5.3 +/- 3.9 ng/mL (P < 0.001) in study B in response to 12 wk of vitamin E supplementation. An increase in PIVKA-II is indicative of poor vitamin K status. In contrast, the other measures of vitamin K status (ie, plasma phylloquinone concentration and percentage of ucOC) did not change significantly in response to the supplementation. CONCLUSIONS: High-dose vitamin E supplementation increased PIVKA-II in adults not receiving oral anticoagulant therapy. The clinical significance of these changes warrants further investigation, but high doses of vitamin E may antagonize vitamin K. Whether such an interaction is potentially beneficial or harmful remains to be determined.
14677185 Increased severity of lower urinary tract symptoms and daytime somnolence in primary Sjög 2003 Nov OBJECTIVE: Functional antimuscarinic receptor autoantibodies have recently been described in both primary and secondary Sjögren's syndrome (SS) in a mouse bladder contraction assay. Most patients with these antibodies complained of severe lower urinary tract disturbances, which are not a recognized feature of SS. We compared the severity of self-reported urological symptoms, daytime somnolence, and fatigue between a cohort of patients with primary SS and controls with osteoarthritis (OA). METHODS: Female patients were recruited from rheumatology outpatient clinics at 2 hospitals. The American Urological Symptom Index (AUA-7), Epworth Sleepiness Scale, and FACIT-F fatigue self-administered instruments were employed. Results were obtained for 76 patients with primary SS and 43 controls (response rates 85% and 67%, respectively). The patient groups were matched for parity, hormone replacement and diuretic therapy, and number of bladder operations and urinary tract infections, although OA patients were slightly older. RESULTS: AUA-7 urological symptoms were more severe in patients with primary SS compared to OA controls (p = 0.039). Severe urological symptoms were reported by 61% of primary SS patients compared with 40% of OA controls. This difference was predominantly attributable to bladder irritability associated with urgency (p = 0.015) and not nocturia (p = 0.85). Epworth Sleepiness Scale scores were also more severe in primary SS patients compared to OA controls (p = 0.02), independent of nocturia. The FACIT-F fatigue severity scores were not significantly different between patient groups (p = 0.14). CONCLUSION: Urological symptoms and daytime somnolence may be previously unrecognized symptoms of primary SS. These symptoms are consistent with functional disturbances of muscarinic receptors, possibly mediated by muscarinic receptor autoantibodies.
15022331 Sjögren's syndrome associated with systemic lupus erythematosus: clinical and laboratory 2004 Mar OBJECTIVE: To address the clinical, serologic, pathologic, and immunogenetic features of sicca syndrome that occurs in systemic lupus erythematosus (SLE), as well as its similarities to, and differences from, sicca syndrome that occurs in primary Sjögren's syndrome (SS). METHODS: A cohort of 283 consecutive unselected SLE patients was evaluated for the presence of associated SS using the American-European classification criteria. Clinical and laboratory parameters in SLE patients with SS (SLE-SS) were compared with those in SLE patients without SS (SLE-no SS) and with a group of 86 unselected patients with primary SS. RESULTS: SS was identified in 26 SLE patients (9.2%); the SS preceded the development of lupus in 18 of them (69.2%). Compared with the SLE-no SS group, patients with SLE-SS were significantly older, had a higher frequency of Raynaud's phenomenon, anti-Ro/SSA, anti-La/SSB, and rheumatoid factor, but had a significantly lower frequency of renal involvement, lymphadenopathy, and thrombocytopenia. Compared with the primary SS group, SLE-SS patients displayed a clinically similar sicca syndrome, but were significantly younger and had an increased frequency of perivascular infiltrates in the salivary glands associated with anticardiolipin antibodies in the serum. SLE-SS patients had a high frequency of the DRB1*0301 allele. This HLA profile distinguished the SLE-SS group from the SLE-no SS group, who had an increased frequency of DRB1*1501 and DQB1*0602 alleles, but was similar to the HLA profile of the primary SS group, who had an increased frequency of DRB1*0301. CONCLUSION: SLE-SS appears to constitute a subgroup of patients with distinct clinical, serologic, pathologic, and immunogenetic features, in whom SS is expressed as an overlapping entity and is largely similar to primary SS.
12746896 Selective elimination of synovial inflammatory macrophages in rheumatoid arthritis by an F 2003 May OBJECTIVE: To determine whether monocyte/macrophages from rheumatoid arthritis (RA) patients can be selectively eliminated by a toxin-conjugated antibody CD64-ricin A (CD64-RiA) directed toward the high-affinity receptor for IgG (FcgammaRI), exploiting the capacity of FcgammaRI to efficiently endocytose antibody which it has bound. METHODS: Mononuclear cells from peripheral blood (PB) and synovial fluid (SF) obtained from RA patients were cultured in the presence of CD64-RiA. Cell death of monocyte/macrophages was measured by phenotypic changes (light-scatter patterns and CD14 and FcgammaRI expression) and apoptosis (nuclear DNA fragmentation). We then tested whether CD64-RiA-induced cell death of macrophages affected their capacity to stimulate antigen-induced lymphocyte proliferation and to secrete cytokines. Additionally, the capacity of CD64-RiA to inhibit proinflammatory activity and cartilage degradation by RA synovial tissue explants was evaluated. RESULTS: Inflammatory macrophages from RA SF expressed elevated levels of FcgammaRI and were selectively eliminated by CD64-RiA via apoptotic cell death. Monocyte/macrophages from RA PB, which had lower levels of FcgammaRI expression, were much less affected. Induction of SF macrophage apoptosis was associated with efficient inhibition of antigen-induced lymphocyte proliferation and a reduction in tumor necrosis factor alpha (TNFalpha) release. Consistent with these effects on SF macrophages, CD64-RiA also inhibited TNFalpha production, interleukin-1beta production, and cartilage-degrading activity of RA synovial tissue explants. CONCLUSION: Together, these data underscore the crucial role of synovial macrophages in RA joint inflammation and indicate that selective elimination of these cells through FcgammaRI-directed immunotoxins could be a novel approach to the treatment of RA.
12424620 Association between adult-onset Still's disease and interleukin-18 gene polymorphisms. 2002 Nov Recently, we reported that serum concentration of IL-18 is strikingly high in patients with adult-onset Still's disease (AOSD). The aim of the present study was to screen for genetic polymorphisms in the human IL-18 (hIL-18) gene and to determine the association of polymorphisms with susceptibility to AOSD. We investigated the 6.7 kb region upstream of exon 2 of hIL-18 gene, in which a promoter activity had been reported. Sixteen AOSD patients, 144 rheumatoid arthritis (RA) patients and 92 healthy control individuals were studied. We found seven single nucleotide polymorphisms and a single 9 bp insertion which were frequently present in the AOSD patients. Three haplotypes including a unique combination of these polymorphisms were also determined. Of them, haplotype S01 contained all eight of these polymorphisms. The frequency of individuals carrying a diplotype configuration, ie a combination of two haplotypes, of S01/S01 was significantly higher in the AOSD patients than in the healthy controls (P=0.00059, Fischer's exact probability test, odds ratio [OR]=7.81, 95% confidence interval [95% CI]=2.48-24.65) and the RA patients (P=0.015, Fischer's exact probability test, OR=4.0, 95% CI=1.39-11.54). We therefore conclude that possession of the diplotype configuration of S01/S01 is a major genetic risk factor for susceptibility to AOSD.
14655004 [Clinical pharmacology of the selective COX-2 inhibitors]. 2003 Dec The discovery of two isoforms of cyclooxygenases (COX-1 and COX-2) has provided a new insight into the involvement of prostaglandins in the clinical effectiveness and gastrointestinal toxicity of NSAIDs. Currently, there are four selective COX-2 inhibitors available in Germany: celecoxib, rofecoxib, valdecoxib and parecoxib. Orally administered rofecoxib, celecoxib and valdecoxib have been approved for the relief of symptoms of osteoarthritis and rheumatoid arthritis. Parecoxib, the first selective COX-2 inhibitor for parenteral administration, has been approved for the short-term treatment of post-operative pain. The clinical efficacy of the marketed COX-2 inhibitors has been proved in large phase III clinical trials in comparison to both placebo and classical NSAIDs (e.g. diclofenac, naproxen). The incidence of gastrointestinal complications was significantly lower than that with the non-selective NSAIDs. However, the clinical relevance of these effects was, at least in some populations of patients (e.g. patients on low dose aspirin), not as high as initially expected. While not replacing less expensive classical NSAIDs, selective COX-2 inhibitors provide a marked enrichment of the spectrum of anti-inflammatory and analgesic therapeutics.
14673967 Thyroid dysfunction in primary Sjögren's syndrome: a long-term followup study. 2003 Dec 15 OBJECTIVE: To evaluate the prevalence of thyroid dysfunction and related autoantibodies in patients with primary Sjögren's syndrome (pSS), and to determine whether these abnormalities develop over time. METHODS: pSS patients (n = 137) and controls (n = 120) were investigated for thyroid dysfunction and for the presence of anti-thyroid peroxidase antibody (anti-TPO) and antithyroglobulin antibody (ATG). Followup time for patients was 1-16 years, and 72 of the 120 controls were reevaluated 3 years after initial evaluation. RESULTS: Thyroid disease was more frequent in the pSS patients than in the controls (30% versus 4%; P < 10(-4)), as were anti-TPO and ATG (11% versus 3%; P < 0.02, and 3% versus 1%, not significant). Ten of 107 euthyroid pSS patients dropped out of the study, and thyroid dysfunction became apparent at followup in 12 of the remaining 97. Most of the patients with thyroid-related autoantibodies at entry developed autoimmune thyroid disease thereafter. CONCLUSION: Thyroid dysfunction is frequent in pSS patients, and those prone to develop thyroid disorders are identified by thyroid-related autoantibodies, or by rheumatoid factor and anti-Ro/SSA activity.
15642138 Local expression of matrix metalloproteinases, cathepsins, and their inhibitors during the 2005 Cartilage and bone degradation, observed in human rheumatoid arthritis (RA), are caused by aberrant expression of proteinases, resulting in an imbalance of these degrading enzymes and their inhibitors. However, the role of the individual proteinases in the pathogenesis of degradation is not yet completely understood. Murine antigen-induced arthritis (AIA) is a well-established animal model of RA. We investigated the time profiles of expression of matrix metalloproteinase (MMP), cathepsins, tissue inhibitors of matrix metalloproteinases (TIMP) and cystatins in AIA. For primary screening, we revealed the expression profile with Affymetrix oligonucleotide chips. Real-time polymerase chain reaction (PCR) analyses were performed for the validation of array results, for tests of more RNA samples and for the completion of the time profile. For the analyses at the protein level, we used an MMP fluorescence activity assay and zymography. By a combination of oligonucleotide chips, real-time PCR and zymography, we showed differential expressions of several MMPs, cathepsins and proteinase inhibitors in the course of AIA. The strongest dysregulation was observed on days 1 and 3 in the acute phase. Proteoglycan loss analysed by safranin O staining was also strongest on days 1 and 3. Expression of most of the proteinases followed the expression of pro-inflammatory cytokines. TIMP-3 showed an expression profile similar to that of anti-inflammatory interleukin-4. The present study indicates that MMPs and cathepsins are important in AIA and contribute to the degradation of cartilage and bone.