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ID PMID Title PublicationDate abstract
15638737 Targeting C5a: recent advances in drug discovery. 2005 Activation of complement via the innate and adaptive immune system is vital to the body's defences in fighting infections. Unregulated complement activation is likely to play a crucial role in the pathogenesis of several diseases including psoriasis, adult (acute) respiratory distress syndrome (ARDS), bullous pemphigoid (BP), rheumatoid arthritis (RA) and ischemia-reperfusion (I/R) injury. The 74 amino acid peptide C5a is released after complement activation at sites of inflammation and is a potent chemoattractant for neutrophils, basophils, eosinophils, leukocytes, monocytes and macrophages. Recombinant proteins and humanized anti-C5 antibodies have been recently developed for blocking specific proteins of the complement system bringing renewed attention towards complement inhibition. Pharmacological studies have been highlighting the complement fragment C5a as an interesting target for the management of complement mediated diseases. Specific inhibition of C5a biological activity could gain therapeutic benefit without affecting the protective immune response. In the last few years several peptide and non-peptide antagonists of C5a have been discovered and tested in relevant pharmacological models; the availability of orally active compounds is rapidly helping to delineate the precise role of C5a in immunoinflammatory disorders. Moreover, mutagenesis data for the C5a/C5a receptor (C5aR) couple make C5aR a valuable model for mechanistic studies of peptidergic G-protein coupled receptors (GPCRs). The aim of this review is to outline the recent advances in C5a inhibition, especially highlighting the value of a multidisciplinary integrated approach in drug discovery.
20641300 (111)In-TA138. 2004 Integrins are a family of cell surface heterodimeric glycoproteins that mediate diverse biological events involving cell-cell and cell-matrix interactions (1). They consist of an α and a β subunit and are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor class affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (2-7). The α(v)β(3) integrin is strongly expressed on tumor cells, activated endothelial cells (3), and arterial smooth muscle cells (8). In contrast, expression of α(v)β(3) integrin is weak on resting endothelial cells and most normal tissues. The α(v)β(3) antagonists are being studied as anti-tumor and anti-angiogenic agents (4, 9, 10), and the agonists are being studied as angiogenic agents for coronary angiogenesis (11, 12). A tripeptide sequence consisting of Arg-Gly-Asp (RGD) was identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins including α(v)β(3). Various radiolabeled antagonists and peptides were introduced for imaging of tumors and tumor angiogenesis (13). TA138, an antagonist to the α(v)β(3) integrin, was developed based on SH066 (a quinolone-based vitronectin receptor antagonist) (14). TA138 contains a DOTA moiety for (111)In labeling. (111)In-TA138 (RP748) was found to have a high accumulation in a spontaneous mammary adenocarcinoma (α(v)β(3)-positive) in the c-Neu Oncomouse model (14, 15). The binding of (111)In-TA138 to the integrin receptor was found to be specific both in vitro and in vivo.
16970805 Factors influencing general practitioner referral of patients developing end-stage renal f 2006 Sep 13 BACKGROUND: To understand why treatment referral rates for ESRF are lower in Ireland than in other European countries, an investigation of factors influencing general practitioner referral of patients developing ESRF was conducted. METHOD: Randomly selected general practitioners (N = 51) were interviewed using 32 standardised written patient scenarios to elicit referral strategies. MAIN OUTCOME MEASURES: General practitioner referral levels and thresholds for patients developing end-stage renal disease; referral routes (nephrologist vs other physicians); influence of patient age, marital status and co-morbidity on referral. RESULTS: Referral levels varied widely with the full range of cases (0-32; median = 15) referred by different doctors after consideration of first laboratory results. Less than half (44%) of cases were referred to a nephrologist. Patient age (40 vs 70 years), marital status, co-morbidity (none vs rheumatoid arthritis) and general practitioner prior specialist renal training (yes or no) did not influence referral rates. Many patients were not referred to a specialist at creatinine levels of 129 micromol/l (47% not referred) or 250 micromol/l (45%). While all patients were referred at higher levels (350 and 480 micromol/l), referral to a nephrologist decreased in likelihood as scenarios became more complex; 28% at 129 micromol/l creatinine; 28% at 250 micromol/l; 18% at 350 micromol/l and 14% at 480 micromol/l. Referral levels and routes were not influenced by general practitioner age, sex or practice location. Most general practitioners had little current contact with chronic renal patients (mean number in practice = 0.7, s.d. = 1.3). CONCLUSION: The very divergent management patterns identified highlight the need for guidance to general practitioners on appropriate management of this serious condition.
16785554 IL-17 plays an important role in the development of experimental autoimmune encephalomyeli 2006 Jul 1 IL-17 is a proinflammatory cytokine that activates T cells and other immune cells to produce a variety of cytokines, chemokines, and cell adhesion molecules. This cytokine is augmented in the sera and/or tissues of patients with contact dermatitis, asthma, and rheumatoid arthritis. We previously demonstrated that IL-17 is involved in the development of autoimmune arthritis and contact, delayed, and airway hypersensitivity in mice. As the expression of IL-17 is also augmented in multiple sclerosis, we examined the involvement of this cytokine in these diseases using IL-17(-/-) murine disease models. We found that the development of experimental autoimmune encephalomyelitis (EAE), the rodent model of multiple sclerosis, was significantly suppressed in IL-17(-/-) mice; these animals exhibited delayed onset, reduced maximum severity scores, ameliorated histological changes, and early recovery. T cell sensitization against myelin oligodendrocyte glycoprotein was reduced in IL-17(-/-) mice upon sensitization. The major producer of IL-17 upon treatment with myelin digodendrocyte glycopritein was CD4+ T cells rather than CD8+ T cells, and adoptive transfer of IL-17(-/-) CD4+ T cells inefficiently induced EAE in recipient mice. Notably, IL-17-producing T cells were increased in IFN-gamma(-/-) cells, while IFN-gamma-producing cells were increased in IL-17(-/-) cells, suggesting that IL-17 and IFN-gamma mutually regulate IFN-gamma and IL-17 production. These observations indicate that IL-17 rather than IFN-gamma plays a crucial role in the development of EAE.
16760194 The PTPN22 C1858T functional polymorphism and autoimmune diseases--a meta-analysis. 2007 Jan OBJECTIVE: To assess whether combined evidence shows the association between the protein tyrosine phosphatase non-receptor 22 (PTPN22) C1858T polymorphism and autoimmune diseases, and to summarize the effect size of the polymorphism associated with susceptibility of autoimmune diseases. METHODS: We surveyed studies on the PTPN22 C1858T polymorphism and autoimmune diseases using comprehensive Medline search and review of the references. Meta-analysis was performed for genotypes T/T (recessive effect), T/T + C/T (dominant effect) and T-allele in random effects models. RESULTS: Twenty-nine studies with 43 comparisons including 13 rheumatoid arthritis (RA), six systemic lupus erythematosus (SLE), six type-1 DM (T1D), three Grave's disease (GD), four inflammatory bowel diseases (IBD), three juvenile idiopathic arthritis (JIA), two psoriasis, two multiple sclerosis, two Addison's disease and two Celiac disease were available for the meta-analysis. The overall odds ratios (ORS) for T-allele, T/T and T/T + C/T genotypes were significantly increased in RA, SLE, GD and T1D (OR for T-allele = 1.58, 1.49, 1.85, 1.61, respectively, P < 0.00001). This meta-analysis showed the association between the T-allele and the T/T genotype and JIA (OR = 1.34, P = 0.03; OR = 1.97, P = 0.02) but did not reveal the association between the PTPN22 C1858T polymorphism and IBD, psoriasis, multiple sclerosis, Addison's disease and Celiac disease. CONCLUSION: This meta-analysis demonstrates that the PTPN22 1858T allele confers susceptibility to RA, SLE, GD, T1D and JIA, supporting evidence of association of the PTPN22 gene with subgroup of autoimmune diseases.
16437400 Our first clinical experience with radiosynoviorthesis by means of (166)Ho-holmium-boro-ma 2005 BACKGROUND: In this paper, we evaluate the therapeutic and adverse effects of the application of 166-holmium-boro-macroaggregates (HMBA) in radiosynovectomy (RSO) of the knees. We assessed the efficacy and safety of (166)Ho-HBMA in a prospective clinical trial in patients suffering from chronic synovitis. MATERIAL AND METHODS: An effective component of radiopharmaceutical (166)Ho-boro-macroaggregates is radionuclide (166)Ho which has both beta-emission and gamma-emission. The physical half-life time of 166 Ho is 26.8 hours. After application of the radiopharmaceutical into a joint cavity, the effect of beta-emission causes radiation necrosis of pathologically changed (inflamed) synovial membrane. From 15th April 2005, we have started RSO of knees by means of new radiopharmaceutical (166)Ho-boro-macroaggregates in patients with gonarthrosis, rheumatoid arthritis, chronic synovitis, psoriatic arthritis, gout arthropathy. Seventeen intra-articular injections were performed in fifteen patients receiving a mean activity of 972 MBq (range: 904-1,057 MBq) (166)Ho-HMBA. The patients were hospitalized for three days. Side effects were evaluated during hospital stay and after 6-8 weeks. Static scintigraphy of knee joints and measurements of blood radioactivity were performed. Therapeutic effects were evaluated after 6-8 weeks. RESULTS: In 2 hours and 2 days after application, we proved, by means of knee and inguinal scintigraphy, only insignificant radiopharmaceutical leakage from the joint cavity to the inguinal lymph nodes in four patients. In treated patients, no serious adverse effects occurred. Nine patients were without complaints; 4 patients had slight knee exsudation and 2 patients had great exsudation. Therapeutic effects after 6-8 weeks were as follows: 2 patients were without pain, 9 with lower pain, 3 with the same pain and 1 patient with increased pain. Joint motion was improved in 7 patients, remained the same in 7 patients and was impaired in 1 patient. Analgesics consumption was lower in 5 patients, the same in 9 patients and greater in 1 patient. Knee exsudation was absent in 2 patients, lower in 4 patients, the same in 6 patients and greater in 3 patients. CONCLUSIONS: We proved only insignificant radiopharmaceutical leakage from the joint cavity to the inguinal lymph nodes. Six patients had early slight or great radiation synovitis. The possible cause could be rather high applicated activity. One can take into consideration its reduction. Therapeutic effects can be precisely evaluated after a longer time interval than was possible for us (6-8 weeks after RSO). (166)Ho-boro-macroaggregates can extend the scale of clinically used radiopharmaceuticals for RSO. This paper is presented in the scope of the first stage of clinical evaluation of synovectomy application of holmium-boro-macroaggregates.
16337314 Effect of a derivatized tetrapeptide from lactoferrin on nitric oxide mediated matrix meta 2006 Jun Matrix metalloproteinases (MMPs) constitute a family of zinc-dependent proteolytic enzymes, which degrade several components of extracellular matrix, in arthritic synovial cells. In cultured synovial fibroblasts, both nitric oxide (NO) and reactive oxygen species (ROS) are potent inducers of MMPs production. PEP1261, a tetrapeptide derivative used in this study, corresponds to residues of 39-42 human lactoferrin. The parent protein lactoferrin is able to inhibit the production of free radicals in rheumatoid joints and it regulates many aspects of inflammation. This study is aimed to examine the effects of PEP1261 on MMP-2 production in the presence of nitric oxide donor in cultured synovial fibroblasts from collagen-induced arthritic rats. PEP1261 affects a significant reduction in nitrite levels as well as in MMP-2 production in SNAP stimulated synovial fibroblasts and this is validated by gelatin zymography and immunoblot analysis. Furthermore, RTPCR analysis has demonstrated that PEP1261 inhibits MMP-2 mRNA expression in SNAP treated synovial fibroblasts. The results of this study suggest that PEP1261 possesses antiarthritic activity by inhibiting nitrite levels as well as MMP-2 expression better than control peptides viz., KRDS and RGDS.
17038274 Arthrodesis of the subtalar and talonavicular joints for correction of symptomatic hindfoo 2006 Sep BACKGROUND: Triple arthrodesis has long been used for the treatment of painful malalignment or arthritis of the hindfoot. However, the effect of fusion on adjacent joints has sparked interest in a more limited arthrodesis in patients without involvement of the calcaneocuboid joint. METHOD: Results of 16 feet in 14 patients who had a modified double arthrodesis for symptomatic flatfoot, cavovarus deformity, or hindfoot arthritis were reviewed retrospectively with a minimum followup of 18 (range 18 to 93) months. The most common diagnosis contributing to the hindfoot deformity was pes planovalgus. All operations were done with a consistent technique using rigid internal fixation with screws. In 15 feet, a concomitant gastrocnemius recession for equinus contracture was done at the time of the primary surgery. Clinical evaluation was based on the American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Scale in addition to subjective assessments of pain, function, shoewear, cosmesis, and overall satisfaction. Radiographic evaluation included measurements of the anterior-posterior talo-second metatarsal angle, lateral talocalcaneal angle, and lateral talo-first metatarsal angle, and notation of arthritic changes of the ankle, calcaneocuboid, and midfoot joints, as well as an assessment of time to union of all arthrodeses. RESULTS: The average AOFAS Ankle-Hindfoot Scale improved from 44.7 preoperatively to 77.0 postoperatively (p < 0.01). Subjectively, patients experienced improvements in pain, function, cosmesis, and shoewear. Overall, all patients were satisfied and would have the procedure again under similar circumstances. Radiographically, all parameters statistically improved. There was an increase in arthritic scores for six ankle, six calcaneocuboid, and five midfoot joints. One talonavicular joint nonunion occurred in a rheumatoid patient, requiring revision arthrodesis. CONCLUSIONS: We have concluded that simultaneous arthrodesis of the talonavicular and subtalar joints is a reasonable treatment in the subset of patients with symptomatic hindfoot malalignment whose calcaneocuboid joints are not involved in the primary disease.
16505597 [The significance of disease-independence in Mikulicz's disease--revival interests in Miku 2006 Feb Mikulicz's disease represents a unique condition involving enlargement of the lacrimal and salivary glands. Mikulicz's disease has been considered part of primary Sjögren's syndrome because both diseases were histologically similar. However, the gland swellings in Mikulicz's disease are persistent, and its decreased secretional function is good responsiveness to glucocorticoid. Serologically, Mikulicz's disease is characterized by few autoantibody including anti-SS-A and anti-SS-B antibodies. Recently, it is revealed elevated IgG4 concentrations in the serum and prominent infiltration by plasmacytes expressing IgG4 in the lacrimal and salivary glands in Mikulicz's disease. Prominent IgG4-positive plasma cells are also detected in systemic lymph tissues. We cannot detect the phenomenon in Sjögren's syndrome. In complications with Mikulicz's disease, there are autoimmune pancreatitis, retroperitoneal fibrosis, tubulointerstitial nephritis, autoimmune hypophysitis, Riedel's thyroiditis, which are related to IgG4 in its pathogenesis. Mikulicz's disease is different from Sjögren's syndrome, and may be a systemic IgG4-related plasmacytic disease.
15953879 A case of reactive plasmacytosis mimicking multiple myeloma in a patient with primary Sjog 2005 Jun Primary Sjogren's syndrome (pSS) is a chronic autoimmune disease with well-documented association of lymphoid malignancies during the progress of the disease. Although several types of malignancy and pseudomalignancy have been reported in pSS, low-grade non-Hodgkin's lymphomas are the most frequently observed. Reactive plasmacytosis mimicking myeloma is a very rare condition in association with pSS. We describe a 72-yr-old woman with pSS who presented with hypergammaglobulinemia, and extensive bone marrow and lymph node plasmacytosis, which mimicked multiple myeloma. In this patient, there was an abnormal differentiation of memory B cells to plasma cells in the peripheral blood suggesting underlying pathogenetic mechanism for this condition.
17109806 Hyposalivation in elderly patients. 2006 Nov Saliva is a key element in oral homeostasis, oral function and maintenance of oral health. Dry mouth has multiple oral health consequences and affects quality of life. The incidence of dry mouth and its public health impact are increasing due to the aging population, the effects of some systemic diseases, and medical management and commonly prescribed medications that reduce saliva production. In this paper, we review the causes of dry mouth and its impact on health. The role of dental providers and current management of dry mouth is presented.
16890888 The Ro 60 kDa autoantigen comes into focus: interpreting epitope mapping experiments on th 2006 Jul A conserved RNA-binding protein, the Ro 60 kDa (Ro60) autoantigen, is a major target of autoantibodies in patients suffering from the rheumatic diseases Sjogren's syndrome, systemic lupus erythematosus, subacute cutaneous lupus erythematosus and neonatal lupus erythematosus. In both mice and certain bacteria, Ro60 is important for cell survival following ultraviolet irradiation. Although the function of Ro60 was mysterious for many years, recent experiments have demonstrated that this protein binds misfolded noncoding RNAs in vertebrate cells and likely functions in a pathway by which defective RNAs are recognized and targeted for degradation. Recent structural studies have revealed that Ro60 is shaped like a doughnut with an inner hole. Noncoding RNAs called Y RNAs bind on the outer surface of the ring, while the single-stranded ends of misfolded RNAs likely bind within the hole. Comparison of the Ro60 structure with the results of epitope-mapping studies reveals that many of the currently identified epitopes recognized by patient sera overlap regions of Ro60 that function in RNA binding. Moreover, in some patients with anti-Ro60 antibodies, the initial antigenic epitope corresponds to a loop involved in binding single-stranded RNA in the central cavity.
16282751 Arthritis and skin disease. 2005 Sep Skin lesions are frequently a harbinger of an underlying rheumatic disease or may be of great help in achieving the diagnosis of an underlying joint or connective tissue disease. For this reason, the evaluation of the skin is mandatory for the rheumatologist. In fact, the skin is the most accessible organ and often provides valuable diagnostic clues. Pattern recognition of skin lesions is based upon the type, configuration, distribution, and evolution of the lesions; selective laboratory techniques may further assist the diagnosis. This article focuses on the most relevant cutaneous disease in patients with rheumatic disease and emphasizes those characteristic features that will allow the clinician to identify cutaneous lesions that are commonly associated with musculoskeletal syndromes.
16408433 [Three patients with nephrotic syndrome due to membranous nephropathy complicated by Sjög 2005 We describe three females patients (age 40, 62 and 63 y) with nephrotic syndrome due to membranous nephropathy complicated by Sjögren's syndrome(SS). The patients satisfied the criteria for SS, but not those for systemic lupus erythematosus(SLE). All of them developed nephrotic syndrome, and light immunofluorescence as well as electron microscopy of renal biopsy specimens revealed membranous nephropathy. Two were positive for the SS-A antibody, and the other was positive for the SS-B antibody. Two were complicated with primary biliary cirrhosis (PBC) and autoimmune thyroiditis, whereas the other was complicated with interstitial pneumonia, but not with either PBC or autoimmune thyroiditis. Prednisolone (PSL) with or without cyclophosphamide improved the nephrotic syndrome in two of the patients. In conclusion, some patients with SS might become complicated with nephrotic syndrome due to membranous nephropathy if another systemic autoimmune disease exists.
17195353 [Prevalence of antiphospholipid antibodies in patients with primary Sjögren's syndrome]. 2006 May The aim of this study was to determine prevalence of antiphospholipid antibodies (aPL) including anticardiolipin antibodies (aCL), and anti-beta2GP1 in a cohort of 32 patients with primary Sjogren's syndrome (pSS) diagnosed according to revised European criteria. aPL were found in 9/32 (28%) patients (IgG in 8 and IgM in one case). Anti-beta2GPI antibodies were detected only in two patients. Titres were usually low.
15699112 Development of autoimmunity against transcriptionally unrepressed target antigen in the th 2005 Feb 15 Autoimmune regulator (AIRE) gene mutation is responsible for the development of organ-specific autoimmune disease with monogenic autosomal recessive inheritance. Although Aire has been considered to regulate the elimination of autoreactive T cells through transcriptional control of tissue-specific Ags in thymic epithelial cells, other mechanisms of AIRE-dependent tolerance remain to be investigated. We have established Aire-deficient mice and examined the mechanisms underlying the breakdown of self-tolerance. The production and/or function of immunoregulatory T cells were retained in the Aire-deficient mice. The mice developed Sjogren's syndrome-like pathologic changes in the exocrine organs, and this was associated with autoimmunity against a ubiquitous protein, alpha-fodrin. Remarkably, transcriptional expression of alpha-fodrin was retained in the Aire-deficient thymus. These results suggest that Aire regulates the survival of autoreactive T cells beyond transcriptional control of self-protein expression in the thymus, at least against this ubiquitous protein. Rather, Aire may regulate the processing and/or presentation of self-proteins so that the maturing T cells can recognize the self-Ags in a form capable of efficiently triggering autoreactive T cells. With the use of inbred Aire-deficient mouse strains, we also demonstrate the presence of some additional factor(s) that determine the target-organ specificity of the autoimmune disease caused by Aire deficiency.
16616154 Atypical autoantibodies in patients with primary Sjögren syndrome: clinical characteristi 2006 Apr OBJECTIVES: To analyze the clinical characteristics, follow-up, and fulfillment of classification criteria for other systemic autoimmune diseases (SAD) in patients with primary Sjögren syndrome (SS) and atypical autoantibodies. METHODS: We studied 402 patients diagnosed with primary SS seen consecutively in our Department since 1994. We considered anti-DNA, anti-Sm, anti-RNP, anti-topoisomerase1/Scl70, anticentromere (ACA), anti-Jo1, anti-neutrophil cytoplasmic antibodies (ANCA), anticardiolipin antibodies (aPL), and lupus anticoagulant as atypical autoantibodies. The patients were prospectively followed after inclusion into the protocol, focusing on the development of features that might lead to the fulfillment of classification criteria for additional SAD. As a control group, we selected an age-sex-matched subset of patients with primary SS without atypical autoantibodies. RESULTS: Eighty-two (20%) patients showed atypical autoantibodies (36 had aPL, 21 anti-DNA, 13 ANCA, 10 anti-RNP, 8 ACA, 6 anti-Sm, 2 anti-Scl70, and 1 anti-Jo-1 antibodies). There were 77 (94%) women and 5 (6%) men, with a mean age of 57 years. Patients with atypical autoantibodies had no statistical differences in the prevalence of the main sicca features, extraglandular manifestations (except for a higher prevalence of Raynaud's phenomenon, 28% versus 7%, P=0.001), immunological markers, and in the fulfillment of the 2002 classification criteria, compared with the control group. After a follow-up of 534 patient-years, 13 (16%) of the 82 patients with atypical autoantibodies developed an additional SAD (systemic lupus erythematosus in 5 cases, antiphospholipid syndrome in 4, limited scleroderma in 3, and microscopic polyangiitis in 1) compared with none in the control group (P<0.001). CONCLUSIONS: This study shows an immunological overlap (defined by the presence of autoantibodies considered typical of other SAD) in 20% of our patients with primary SS. However, the clinical significance of these atypical autoantibodies varies widely depending on the autoantibodies detected, with a broad spectrum of prevalence and clinical patterns of disease expression, and a specific predilection for association with some SAD in preference to others.
17177994 The role of synovial macrophages and macrophage-produced cytokines in driving aggrecanases 2006 There is an increasing body of evidence that synovitis plays a role in the progression of osteoarthritis and that overproduction of cytokines and growth factors from the inflamed synovium can influence the production of degradative enzymes and the destruction of cartilage. In this study, we investigate the role of synovial macrophages and their main proinflammatory cytokines, interleukin (IL)-1 and tumour necrosis factor-alpha (TNF-alpha), in driving osteoarthritis synovitis and influencing the production of other pro- and anti-inflammatory cytokines, production of matrix metalloproteinases, and expression of aggrecanases in the osteoarthritis synovium. We established a model of cultures of synovial cells from digested osteoarthritis synovium derived from patients undergoing knee or hip arthroplasties. By means of anti-CD14-conjugated magnetic beads, specific depletion of osteoarthritis synovial macrophages from these cultures could be achieved. The CD14+-depleted cultures no longer produced significant amounts of macrophage-derived cytokines like IL-1 and TNF-alpha. Interestingly, there was also significant downregulation of several cytokines, such as IL-6 and IL-8 (p < 0.001) and matrix metalloproteinases 1 and 3 (p < 0.01), produced chiefly by synovial fibroblasts. To investigate the mechanisms involved, we went on to use specific downregulation of IL-1 and/or TNF-alpha in these osteoarthritis cultures of synovial cells. The results indicated that neutralisation of both IL-1 and TNF-alpha was needed to achieve a degree of cytokine (IL-6, IL-8, and monocyte chemoattractant protein-1) and matrix metalloproteinase (1, 3, 9, and 13) inhibition, as assessed by enzyme-linked immunosorbent assay and by reverse transcription-polymerase chain reaction (RT-PCR), similar to that observed in CD14+-depleted cultures. Another interesting observation was that in these osteoarthritis cultures of synovial cells, IL-1beta production was independent of TNF-alpha, in contrast to the situation in rheumatoid arthritis. Using RT-PCR, we also demonstrated that whereas the ADAMTS4 (a disintegrin and metalloprotease with thrombospondin motifs 4) aggrecanase was driven mainly by TNF-alpha, ADAMTS5 was not affected by neutralisation of IL-1 and/or TNF-alpha. These results suggest that, in the osteoarthritis synovium, both inflammatory and destructive responses are dependent largely on macrophages and that these effects are cytokine-driven through a combination of IL-1 and TNF-alpha.
16325660 Validation of American College of Rheumatology classification criteria for knee osteoarthr 2005 Dec OBJECTIVE: To validate the ability of the American College of Rheumatology (ACR) clinical classification criteria and the ACR clinical plus radiographic classification criteria for osteoarthritis of the knee to predict articular cartilage damage. METHODS: Ninety subjects with knee osteoarthritis (OA) who were enrolled in a prospective study determining the therapeutic efficacy of arthroscopic irrigation were characterized as to whether they fulfilled the ACR clinical classification criteria or the ACR clinical plus radiographic classification criteria. Ten rheumatoid arthritis (RA) patients were included as controls. Cartilage damage was defined using the ACR/Knee Arthroscopy Osteoarthritis Scale (ACR/KAOS) system, which is a validated outcome instrument for knee OA based on arthroscopic visualization. Mean values of the damage scores in each group were calculated and compared by t-test to determine statistical significance between the 3 groups. RESULTS: The mean ACR/KAOS score for the 10 RA patients was 1.8 [SD 1.22; range 0 to 4]. Of the 90 OA patients who underwent arthroscopy, only 73 patients had sufficient videotape to make an accurate assessment by the blinded assessor. The mean ACR/KAOS score for the 6 OA patients who fulfilled only the ACR clinical classification was 17.4 [SD 11.3; range 5 to 34.3] and the mean ACR/KAOS score for the 67 patients who fulfilled the ACR clinical plus radiographic classification criteria was 42.0 [SD 29.1; range 5.1 to 118.4]. These differences were statistically significant (RA versus OA clinical P=0.02; RA versus OA clinical+radiographic P
16368293 The nonspecific anti-inflammatory therapy with methotrexate for patients with chronic hear 2006 Jan BACKGROUND: Inflammatory mediators play an important role in the pathogenesis of chronic heart failure (CHF). Methotrexate (MTX) is used in the treatment of inflammatory-mediated diseases (eg, rheumatoid arthritis) because it modulates the expression of numerous inflammatory cytokines. However, no studies have assessed the effects of MTX on plasma levels of inflammatory mediators in patients with CHF. METHODS: In a prospective, randomized, placebo-controlled, single-blind study, 71 patients receiving conventional treatment were randomly allocated to either MTX group (7.5 mg once a week, n = 35) or placebo group (n = 36) with a follow-up of 12 weeks. The effects of MTX on plasma cytokine expression, left ventricular ejection fraction, left ventricular end-diastolic dimension, New York Heart Association (NYHA) functional class, 6-minute walk test distance, and quality of life (QOL) were determined in patients with CHF. RESULTS: Sixty-two patients completed the study. The circulating levels of inflammatory mediators in patients with CHF were markedly elevated compared with healthy controls (P < or = .002). Methotrexate (n = 30) reduced plasma levels of tumor necrosis factor alpha (-15.6%, P < .05), interleukin 6 (-21.8%, P < .01), monocyte chemoattractant protein-1 (-22.6%, P < .01), soluble intercellular adhesion molecule-1 (-19.2%, P < .05), and C-reactive protein (-27.2%, P < .01) compared with baseline. Furthermore, interleukin 10 (15.8 %, P < .05) and soluble IL-1 receptor antagonist (36.1%, P < .01) expression was increased, whereas improvements in NYHA classification, 6-minute walk test distance, and QOL were found compared with baseline. Monocyte chemoattractant protein-1 expression was lower and soluble IL-1 receptor antagonist expression higher in the MTX than placebo group (n = 32). Furthermore, the left ventricular ejection fraction, left ventricular end-diastolic dimension, and incidence of main adverse cardiac events between the 2 groups were similar. CONCLUSION: These results suggest that the addition of MTX to conventional therapy for CHF has significant anti-inflammatory effects and improves NYHA functional class, 6-minute walk test distance, and QOL.