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ID PMID Title PublicationDate abstract
16467033 Progress and regression within primary Sjögren's syndrome. 2006 Jan The purpose of this review is to give a modern view and an update of important areas in primary Sjögren's syndrome (SS), which may be the most common of the autoimmune systemic rheumatic diseases. Interest in aspects of primary SS including clinical manifestations, pathogenesis, aetiology, treatment, prognosis, etc has increased during the past three decades, the volume of scientific papers and the number of theses being the indicators. However, only a fraction of the money that is used for research into rheumatoid arthritis (RA) is used for SS, and the statement that SS is under-diagnosed, under-treated and under-researched will still be valid for several years to come. The topics that are focused on in this review are: (a) clinical areas with subsections on signs and symptoms, terminology, predictors for development of non-Hodgkin malignant lymphoma (NHML) and prognosis, (b) treatment, (c) the Danger model (aetiopathogenesis) and (d) pathology, including immunoglobulin G4 (IgG4)-positive cells.
15529178 Pulmonary lymphohistiocytic reactions temporally related to etanercept therapy. 2005 May This report details the pulmonary pathologic findings in four patients with rheumatoid arthritis, who developed new onset of pulmonary signs and symptoms with alveolar infiltrates temporally related to the institution of etanercept therapy. Biopsy findings showed an interstitial and air space lymphohistiocytic infiltrate with non-necrotizing granulomas, in the setting of negative cultures and special stains for microorganisms. The association with etanercept therapy and granulomatous reactions is discussed along with the differential diagnosis.
15695534 Tumour necrosis factor blockers do not increase overall tumour risk in patients with rheum 2005 May OBJECTIVE: To determine whether TNF blockers increase tumour risk in patients with RA. MATERIALS AND METHODS: The South Swedish Arthritis Treatment Group register (SSATG) comprises over 90% of anti-TNF treated patients with RA in the area. 757 patients treated with etanercept or infliximab included between 1 February 1999 and 31 December 2002 were identified. 800 patients with conventional antirheumatic treatment in a community based cohort served as a comparison cohort. Tumours and deaths were identified in the cancer registry and population census registers. Patients were followed up from initiation of anti-TNF treatment or 1 July 1997 for the comparison group, until death or 31 December 2002. RESULTS: In the anti-TNF group, 16 tumours (5 lymphomas) were identified in 1603 person-years at risk, and in the comparison group 69 tumours (2 lymphomas) in 3948 person-years. Standardised incidence ratios (SIRs) for total tumour relative risk for the anti-TNF group and the comparison group were 1.1 (95% confidence interval (CI) 0.6 to 1.8) and 1.4 (95% CI 1.1 to 1.8), respectively. The lymphoma relative risk (RR) was 11.5 (95% CI 3.7 to 26.9) and 1.3 (95% CI 0.2 to 4.5), respectively The total tumour RR excluding lymphoma was 0.79 (95% CI 0.4 to 1.42) and 1.39 (95% CI 1.08 to 1.76), respectively. Proportional hazard analysis for lymphomas yielded RR 4.9 (95% CI 0.9 to 26.2) in anti-TNF treated versus untreated patients. CONCLUSION: Community based patients with RA treated conventionally had an increased overall tumour risk compared with the background population. A possible additional increased risk for lymphoma associated with TNF blockers was based on few cases and needs confirmation.
16996245 The outcome of pregnancy following pre-pregnancy or early pregnancy alendronate treatment. 2006 Nov In spite of a substantial increase in the use of bisphosphonates at child bearing age, very little is known regarding its use in pregnancy. We describe the outcome of 24 pregnancies after pre-pregnancy or early pregnancy alendronate therapy. Based on the pregnancy outcome it seems that alendronate does not impose a major teratogenic risk.
15642130 Gene expression profiles in the rat streptococcal cell wall-induced arthritis model identi 2005 Experimental arthritis models are considered valuable tools for delineating mechanisms of inflammation and autoimmune phenomena. Use of microarray-based methods represents a new and challenging approach that allows molecular dissection of complex autoimmune diseases such as arthritis. In order to characterize the temporal gene expression profile in joints from the reactivation model of streptococcal cell wall (SCW)-induced arthritis in Lewis (LEW/N) rats, total RNA was extracted from ankle joints from naive, SCW injected, or phosphate buffered saline injected animals (time course study) and gene expression was analyzed using Affymetrix oligonucleotide microarray technology (RAE230A). After normalization and statistical analysis of data, 631 differentially expressed genes were sorted into clusters based on their levels and kinetics of expression using Spotfire profile search and K-mean cluster analysis. Microarray-based data for a subset of genes were validated using real-time PCR TaqMan analysis. Analysis of the microarray data identified 631 genes (441 upregulated and 190 downregulated) that were differentially expressed (Delta > 1.8, P < 0.01), showing specific levels and patterns of gene expression. The genes exhibiting the highest fold increase in expression on days -13.8, -13, or 3 were involved in chemotaxis, inflammatory response, cell adhesion and extracellular matrix remodelling. Transcriptome analysis identified 10 upregulated genes (Delta > 5), which have not previously been associated with arthritis pathology and are located in genomic regions associated with autoimmune disease. The majority of the downregulated genes were associated with metabolism, transport and regulation of muscle development. In conclusion, the present study describes the temporal expression of multiple disease-associated genes with potential pathophysiological roles in the reactivation model of SCW-induced arthritis in Lewis (LEW/N) rat. These findings improve our understanding of the molecular events that underlie the pathology in this animal model, which is potentially a valuable comparator to human rheumatoid arthritis (RA).
15806305 Estrogen specifically stimulates expression and production of osteoprotegerin from rheumat 2005 May We studied the effects of estrogen on human fibroblast-like synovial cells in rheumatoid arthritis (RA-FLS) focusing on receptor activator of NF-kappaB ligand (RANKL) and its decoy receptor osteoprotegerin (OPG), the osteoclast formation and function regulators that have a substantial role in bone erosion of RA. Estrogen influences osteoporosis and the onset of RA clinically. The cellular responses of RA-FLS to estrogen are initiated via two high-affinity estrogen receptors (ERs). Culture of RA-FLS in the presence of 10(-6) M 17beta-estradiol (E2) increased expression of estrogen receptor (ER)-alpha, but not ER-beta. OPG mRNA expression was significantly increased, whereas RANKL mRNA was unaffected. E2 treatment also significantly increased the amount of OPG released in the culture supernatant. The increase of OPG and ER-alpha was specifically antagonized by the pure estrogen antagonist ICI 182780. Tamoxifen, a selective ER moderator, did not increase OPG. The results indicate that estrogen stimulates secretion of OPG from RA-FLS by acting on ER-alpha, which likely prevents bone erosion in RA.
17035286 A qualitative study to identify factors influencing COXIB prescribed by family physicians 2006 Dec INTRODUCTION: Cyclo-oxygenase-2 inhibiting (COXIB) anti-inflammatories have been the drug class prescribed for a large number of cases of musculoskeletal (MSK) disorders in Canada over the past 5 years. The Alberta Improvements for MSK Disorders (AIMS) initiative sought to better understand the COXIB prescribing situation by funding several studies. The objective of this qualitative study was to determine the factors underlying primary care physicians' medication prescribing behaviour during an office visit for an MSK disorder, with particular emphasis on the prescribing of COXIBs. METHODS: The target respondents were Alberta primary care physicians chosen from a stratified random sample to meet a wide range of characteristics. Individual, semi-structured interviews were used to assess decision pathways in four real cases chosen by the physician. A total of 19 interviews were conducted and analysed using an analytic inductive approach. RESULTS: Factors judged as being important to decision pathways in relation to COXIB prescribing for MSK disease included safety, patient characteristics, affordability to patients, availability of samples, drug company marketing practices, habit formation, time contstraints, previous clinical experience of doctors and/or patient with certain drugs and doctors' perception of absolute versus relative risk. Interpretation. Most physicians preferentially prescribed COXIBs subsequent to a complicated, multifactorial, but essentially patient-centred, decision-making process.
16456878 Achilles tendon rupture and its association with fluoroquinolone antibiotics and other pot 2006 Nov BACKGROUND: Case reports and observational studies have implicated fluoroquinolone antibiotic exposure as a risk factor for Achilles tendon rupture (ATR), an uncommon condition for which there are few formal studies. We sought to quantify the strength of association between exposure to fluoroquinolone antibiotics and the occurrence of ATR, accounting for other risk factors. METHODS: This was a case-control study nested within a health insurer cohort. Cases of ATR were identified and confirmed using patterns of health insurance claims that were validated through sampled medical record review. Information on risk factors, including fluoroquinolone exposure, came from health insurance claims. RESULTS: There were 947 cases of ATR and 18 940 controls. A dispensing of a fluoroquinolone antibiotic in the past 6 months was more common among ATR cases than controls, although not significantly so (odds ratio (OR) = 1.2; 95% confidence interval (CI) = 0.9-1.7), and exposure to a higher cumulative fluoroquinolone dose was more strongly associated (OR = 1.5, 95%CI = 1.0-2.3). Other risk factors for ATR were trauma (OR = 17.2, 95%CI = 14.0-20.2), male sex (OR = 3.0, 95%CI = 2.6-3.5), injected corticosteroid administration (OR = 2.2, 95%CI = 1.6-2.9), obesity (OR = 2.0, 95%CI = 1.2-3.1), rheumatoid arthritis (OR = 1.9, 95%CI = 1.0-3.7), skin or soft tissue infections (OR = 1.5, 95%CI = 0.9-2.3), oral corticosteroids (OR = 1.4, 95%CI = 1.0-1.8), and non-fluoroquinolone antibiotics (OR = 1.2, 95%CI = 1.1-1.5). CONCLUSIONS: The elevation in ATR risk associated with fluoroquinolones was similar in magnitude to that associated with oral corticosteroids or non-fluoroquinolone antibiotics. Trauma and male sex were more strongly associated with ATR, as were obesity and injected corticosteroids.
16319097 VIP down-regulates TLR4 expression and TLR4-mediated chemokine production in human rheumat 2006 May OBJECTIVES: Vasoactive intestinal peptide (VIP) has demonstrated therapeutic effects in arthritis by inhibiting both innate and acquired immune responses. We investigated the potential effects of VIP in the regulation of Toll-like receptor (TLR) expression and function in synovial fibroblasts from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: Cultured fibroblast-like synoviocytes (FLS) were obtained from patients with RA and OA. The effects of VIP on basal or TNF-alpha or lipopolysaccharide (LPS)-induced TLR2, TLR4 and MyD88 expression and its effects on TLR4-mediated CCL2 and CXCL8 chemokine production were studied by reverse transcription-polymerase chain reaction, western blotting and enzyme-linked immunosorbent assay. RESULTS: TLR2, TLR4 and MyD88 mRNA expression was increased in RA FLS compared with OA FLS. The largest increase was observed for TLR4 and there was also overexpression at the protein level in RA FLS. TLR4 and MyD88 mRNA and proteins were induced by LPS and TNF-alpha in RA FLS. VIP down-regulated the induced but not the constitutive expression of TLR4 and MyD88 in RA FLS. VIP treatment decreased CCL2 and CXCL8 chemokine production in response to TLR4 activation with LPS in RA FLS. CONCLUSIONS: We demonstrate that VIP down-regulates LPS and TNF-alpha activation of TLR4 expression and the TLR4 functional response in terms of proinflammatory chemokine production. These studies suggest that the pleiotropic anti-inflammatory actions of VIP involve inhibitory effects on TLR4 expression and signalling.
16310457 Multifocal electroretinographic changes in patients receiving hydroxychloroquine therapy. 2005 Nov PURPOSE: To evaluate the longitudinal changes in multifocal electroretinography (mfERG) in patients receiving hydroxychloroquine and to assess the effects of cumulative hydroxychloroquine dose on mfERG. DESIGN: Prospective cohort study. METHODS: Twenty-four eyes in 12 patients receiving hydroxychloroquine underwent mfERG recordings at baseline and 1 to 2 years later. The first negative (N1) and first positive (P1) response amplitudes and peak latencies were compared with normal controls. Serial changes in the pattern of mfERG abnormalities and in response amplitudes and peak latencies were also compared between eyes in which hydroxychloroquine therapy was continued or stopped. Correlation analyses were performed to assess the effects of a cumulative dose of hydroxychloroquine on mfERG. RESULTS: At baseline, reductions in N1 and P1 response amplitudes were observed in patients receiving hydroxychloroquine compared with controls. At follow-up, in addition to the reductions in N1 and P1 response amplitudes, increases in P1 peak latencies compared with controls were observed. In patients who stopped hydroxychloroquine therapy, there were significant increases in N1 and P1 response amplitudes at follow-up mfERG. CONCLUSIONS: Patients receiving hydroxychloroquine showed a longitudinal decline in retinal function; patients who stopped hydroxychloroquine therapy showed improvement. Although these data are insufficient to demonstrate the sensitivity of mfERG for evaluating early hydroxychloroquine toxicity, the results suggest that serial mfERG assessment may help detect early retinal changes associated with hydroxychloroquine therapy. Further studies with long-term results will be useful in clarifying the value of mfERG in evaluating early retinal toxicity due to hydroxychloroquine.
17158212 Pregnancy in rheumatology patients exposed to anti-tumour necrosis factor (TNF)-alpha ther 2007 Apr OBJECTIVES: Anti-tumour necrosis factor (TNF)-alpha therapies are considered category B drugs for pregnancy. Although sometimes prescribed to women of reproductive age, data in humans are limited with regard to safety for a developing fetus. The objectives of the present article are to report experience of anti-TNF-alpha use in pregnancy, and review the international literature. METHODS: Since 1999 the present authors have used anti-TNF-alpha (infliximab, etanercept, adalimumab) to treat patients with various chronic rheumatic conditions. All patients were prospectively followed during their treatment time and data were systematically collected. RESULTS: In a group of 442 patients treated with anti-TNF, three women with RA unexpectedly became pregnant One treated with etanercept chose a therapeutic termination at two and a half months, despite of any ultrasound anomaly, and satisfactory fetal growth. The other two patients (one with adalimumab exposure and one with etanercept exposure) delivered healthy infants. The following perinatal complications were observed: prematurity, neonatal jaundice, neonatal urinary Escherichia coli infection and adrenal congenital hyperplasia of probable hereditary origin. CONCLUSIONS: To date, there is no evidence that TNF-alpha antagonists are associated with embryo toxicity, teratogenicity or increased pregnancy loss. However, caution should be taken when anti-TNF agents are used during pregnancy, as human experience is still extremely limited, particularly in patients with rheumatic diseases among whom there are several alarming reports. The potential risk should be balanced against the known risks associated with DMARDs and steroid therapy. Large registries will be necessary before firm conclusions can be drawn.
16232020 Effects of perioperative antiinflammatory and immunomodulating therapy on surgical wound h 2005 Nov Patients with various rheumatologic and inflammatory disease states commonly require drugs known to decrease the inflammatory or autoimmune response for adequate control of their condition. Such drugs include nonsteroidal antiinflammatory drugs (NSAIDs), cyclooxygenase (COX)-2 inhibitors, corticosteroids, disease-modifying antirheumatic drugs (DMARDs), and biologic response modifiers. These drugs affect inflammation and local immune responses, which are necessary for proper wound healing in the perioperative setting, thereby potentially resulting in undesirable postoperative complications. Such complications include wound dehiscence, infection, and impaired collagen synthesis. The end result is delayed healing of soft tissue and bone wounds. The current literature provides insight into the effect of some of these drugs on wound healing. For certain drugs, such as methotrexate, trials have been conducted in humans and direct us on what to do during the perioperative period. Whereas with other drugs, we must rely on either small-animal studies or extrapolation of data from human studies that did not specifically look at wound healing. Unfortunately, no clear consensus exists on the need and optimum time for withholding therapy before surgery. Likewise, clinicians are often uncertain of the appropriate time to resume therapy after the procedure. For those drugs with limited or no data in this setting, the use of pharmacokinetic properties and biologic effects of each drug should be considered individually. In some cases, discontinuation of therapy may be required up to 4 weeks before surgery because of the long half-lives of the drugs. In doing so, patients may experience an exacerbation or worsening of disease. Clinicians must carefully evaluate individual patient risk factors, disease severity, and the pharmacokinetics of available therapies when weighing the risks and benefits of discontinuing therapy in the perioperative setting.
15208177 Results from a nationwide postmarketing cohort study of patients in Sweden treated with et 2005 Feb OBJECTIVES: To describe a nationwide system for postmarketing follow up of new antirheumatic drugs in Sweden, and to analyse safety and effectiveness in an etanercept treated patient cohort. METHODS: Etanercept became available in Sweden for prescribing on a named patient basis in 1999. All patients treated were included in a follow up of intensified adverse event reporting and recording of clinical outcome during 24 months, according to the EULAR core set. RESULTS: The mean (SD) disease activity score (DAS 28) value at inclusion among 820 patients recruited on a named patient basis during year 1 was 5.99 (1.19). After two years, 21% (n = 172) of these patients had discontinued the treatment. Of the remaining 648 patients, 68% (n = 442) responded to the treatment. However, in 55% of the responders, the disease activity was intermediate or high (mean DAS 28, 3.37 (1.20)). In all, 540 adverse events were reported in 421 adverse drug reaction (ADR) reports, in 294 patients. The events in 80 reports (19%) were serious. Twenty two per cent of the events were infections, of which 24% (n = 29) were serious. The incidence of serious adverse events remained constant over time. CONCLUSIONS: At start of etanercept treatment, patients had high disease activity. Activity remained high in a large proportion of the responding patients. Although serious ADRs occurred during late phases of treatment, no unexpected safety problems arose. No specific indicators of ADR risk were found. The monitoring system that was established may be useful in future postmarketing surveillance.
16912945 Antirheumatic drugs and the risk of tuberculosis. 2006 Sep 15 BACKGROUND: We aimed to quantify the rate of Mycobacterium tuberculosis disease (TB) among a cohort of patients with rheumatoid arthritis (RA) and to assess whether the independent use of disease-modifying antirheumatic drugs (DMARDs) is associated with the risk of developing TB. METHODS: The study was performed using the PharMetrics Patient-Centric database (PharMetrics). The cohort consisted of all subjects with > or =1 occurrence of a diagnosis of RA during an inpatient or outpatient visit during the period of September 1998 through December 2003. Conditional logistic regression was used in a nested case-control analysis to estimate the rate ratio (RR) of TB with any use of biological or traditional DMARDs during the year before the index date. We also assessed the interaction between DMARDs and the current use of corticosteroids. RESULTS: The cohort consisted of 112,300 patients with RA. A total of 386 cases of TB were identified, which resulted in an overall rate of 2.19 cases per 1000 person-years. The adjusted RR of TB for biological DMARD use is 1.5 (95% CI, 1.1-1.9). Use of traditional DMARDs was also independently associated with TB (RR, 1.2; 95% CI, 1.0-1.5). RRs of developing TB disease with the use of biological or traditional DMARD were lower among current users of corticosteroids than among noncurrent users of corticosteroids. CONCLUSION: We found that the use of biological and traditional DMARDs is associated with an increased risk of developing TB in patients with RA, mainly among noncurrent users of corticosteroids.
16385498 Anti-tumor necrosis factor therapy increases synovial osteoprotegerin expression in rheuma 2006 Jan OBJECTIVE: Treatment of rheumatoid arthritis (RA) with tumor necrosis factor (TNF)-blocking agents, including etanercept and infliximab, has resulted in reductions in the radiographic progression of RA. However, the exact mechanism by which this protection occurs has not been determined. In order to add to such knowledge, we investigated the effect of anti-TNF therapy on the expression of osteoprotegerin (OPG) and receptor activator of NF-kappaB ligand (RANKL) in synovial tissue. METHODS: The expression of OPG and RANKL in synovial biopsy specimens was evaluated by immunohistochemistry. Serial synovial biopsy specimens were obtained from 18 patients with RA, before and after treatment with etanercept (9 patients) or infliximab (9 patients). Biopsy specimens were evaluated by double-blind semiquantitative analysis and image analysis. The in vitro effect of TNF antagonists on the RANKL/OPG expression in osteoblasts and endothelial cells was evaluated by Western blotting. Statistical analysis was performed using Wilcoxon's signed rank test, followed by the Bonferroni correction for multiple comparisons of paired samples. The results of in vitro experiments were evaluated by one-way analysis of variance, with Tukey's post hoc test. RESULTS: Treatment with both infliximab and etanercept increased the expression of OPG in synovial tissue. After 8 weeks of treatment, neither infliximab nor etanercept influenced RANKL expression. In both groups of patients, the RANKL:OPG ratio decreased following therapy. In vitro, both of the TNF antagonists mimicked the in vivo effect, inducing a decrease in the RANKL:OPG ratio in TNF-primed osteoblasts and endothelial cells. CONCLUSION: Therapy with TNF antagonists in RA modulates the OPG/RANKL system, a potential mechanism that could explain the retardation of radiographic damage observed following anti-TNF therapy.
15974986 Advances in the treatment of autoimmune diseases; cellular activity, type-1/type-2 cytokin 2005 Autoimmune diseases are many, have an overall prevalence of about 3% of the world population, affecting more women than men, and their incidence is influenced by genetics and the environment. It is currently thought that the immune response of a genetically predisposed individual to an environmental pathogen, under the influence of inadequate or non-functional immunoregulatory mechanisms, can lead to the development of an autoimmune disease. Advances in the treatment of autoimmune diseases follow a better understanding of the abnormalities in the cellular activity pathways and the resulting, often permanent, imbalance of the pro- and anti-inflammatory cytokine expression profiles. Over the past few years, there has been a dramatic change in the therapeutic regimens employed in autoimmune diseases, with soluble receptors, monoclonal antibodies and molecular mimetics enhancing or gradually replacing conventional immunosuppressive therapies. New biologicals have been developed, targeting defined pathways of the adaptive immune response. One approach towards the therapeutic management of autoimmune diseases involves the design and use of peptide analogs of disease-associated epitopes to be used as immunomodulatory drugs. Peptides can target cell-functions directly, by interfering with the formation of the tri-molecular complex MHC-Peptide-TCR, and/or they can target soluble mediators such as cytokines or their receptors, eventually replacing monoclonal antibody therapies. This review offers an update on the treatment modalities of certain prototypic autoimmune diseases, based on the current knowledge of disease pathogenesis, with emphasis on cell activation and cytokine expression profiles.
16698443 How NKG2D ligands trigger autoimmunity? 2006 Mar The function of NK and CD8 T cells in the elimination of infected, transformed, or stressed cells occurs together with tolerance to self, a property that is essential to prevent autoimmunity. Inappropriate expression of NK receptor ligands, leading to activation of autoreactive effector cells, might therefore trigger or exacerbate autoimmunity. We review here some recent data on the activating receptor NKG2D and its MIC ligand, which are indicative of their detrimental roles in some autoimmune disorders.
16086759 Adverse cutaneous reactions to anakinra in patients with rheumatoid arthritis: clinicopath 2005 Aug BACKGROUND: Anakinra, a recombinant human form of interleukin-1 receptor antagonist, is used to treat patients with active rheumatoid arthritis (RA). OBJECTIVES: To report five patients with cutaneous adverse drug reactions due to anakinra and to evaluate the histopathological and immunohistochemical findings with the aim of understanding the possible mechanisms involved. METHODS: Five patients of a series of 10 patients with RA undergoing treatment with anakinra in a clinical trial presented inflammatory lesions at the anakinra injection sites. In each case, clinical features were recorded and skin biopsy specimens were obtained. In one patient sequential biopsy specimens were obtained from skin lesions at different stages of development. Tissue sections of the biopsy specimens were stained with haematoxylin and eosin and May-Grünwald-Giemsa, and were immunoreacted with antibodies to leucocyte common antigen, CD68, CD3, CD45RO, CD20 and CD45RA. RESULTS: The onset of reaction was within the first month of treatment and appeared as well-defined erythema and oedema involving the injection sites. In two patients the treatment had to be discontinued because of the skin reaction, and in one patient it was associated with systemic involvement. All biopsy specimens exhibited marked dermal oedema and a lichenoid dermal infiltrate composed mainly of lymphomononuclear cells with prominent populations of eosinophils and large CD68+ dermal macrophages and an increase in the number of mast cells, which were spindle shaped in a significant proportion. CONCLUSIONS: Cutaneous toxicity is a frequent, usually well-tolerated complication of treatment with anakinra in patients with RA, although in some cases it can be associated with systemic involvement. The most relevant histopathological findings include dermal oedema and a lichenoid, perivascular and periadnexal predominantly lymphomononuclear infiltrate, with many eosinophils and the presence of enlarged CD68+ macrophages. These findings resemble those seen in skin reactions in patients receiving chemotherapy and colony-stimulating factors. We also found an increase in mast cell numbers that could be a specific effect of anakinra.
16806997 The cleavage of biglycan by aggrecanases. 2006 Nov OBJECTIVE: Aggrecanase-1 [a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4] and aggrecanase-2 (ADAMTS-5) have been named for their ability to degrade the proteoglycan aggrecan. While this may be the preferred substrate for these enzymes, they are also able to degrade other proteins. The aim of this work was to determine whether the aggrecanases could degrade biglycan and decorin. METHODS: Biglycan, decorin and aggrecan were purified from human and bovine cartilage and subjected to degradation by recombinant aggrecanase-1 or aggrecanase-2. In vitro degradation was assessed by sodium dodecyl sulfate/polyacrylamide gel electrophoresis (SDS/PAGE) and immunoblotting, and the cleavage site in biglycan was determined by N-terminal amino acid sequencing. SDS/PAGE and immunoblotting were also used to assess in situ degradation in both normal and arthritic human articular cartilage. RESULTS: Both aggrecanase-1 and aggrecanase-2 are able to cleave bovine and human biglycan at a site within their central leucine-rich repeat regions. Cleavage occurs at an asparagine-cysteine bond within the fifth leucine-rich repeat. In contrast, the closely related proteoglycan decorin is not a substrate for the aggrecanases. Analysis of human articular cartilage from osteoarthritic (OA) and rheumatoid arthritic (RA) joints showed that a biglycan degradation product of equivalent size is present in the extracellular matrix. No equivalent degradation product was, however, detectable in normal adult human articular cartilage. CONCLUSION: Biglycan, which is structurally unrelated to aggrecan, can act as a substrate for aggrecanase-1 and aggrecanase-2, and these proteinases may account for at least part of the biglycan degradation that is present in arthritic cartilage.
15887283 A comparative study of endothelial cell markers expressed in chronically inflamed human ti 2005 Jul Endothelial cells play a central role in chronic inflammation: for example, they express adhesion molecules and present chemokines leading to enhanced leukocyte recruitment into tissues. Numerous markers of endothelial cells have been reported but there has been a lack of comparative data on their specificity. The present study compared the specificity of seven endothelial cell markers in the rheumatoid synovium and the colon of patients with Crohn's disease. These markers were: the sulphated epitope MECA-79, the Duffy antigen receptor for chemokines (DARC), von Willebrand factor, CD31 (PECAM-1), CD34, CD105 (endoglin) and CD146. MECA-79, DARC and von Willebrand factor showed a specific endothelial cell distribution. MECA-79, which recognizes sulphated ligands for leukocyte adhesion receptor L-selectin (CD62L), was selective for a subset of venules in highly inflamed tissue and was present in rheumatoid but not control osteoarthritic synovia. DARC was also specific for venules but had a more widespread distribution than MECA-79, and was present in rheumatoid and control synovia. The other markers all labelled endothelial cells in venules, arterioles and capillaries. However, they also localized to other cell types. For example, CD34 stained fibroblasts, CD146 was expressed by the pericytes and smooth muscle cells of vessel walls and CD31 and CD105 labelled a broad range of cell types.