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ID PMID Title PublicationDate abstract
16777581 Ankylosing spondylitis and symptom-modifying vs disease-modifying therapy. 2006 Jun The main objectives of medical therapy in ankylosing spondylitis (AS) are to relieve pain, stiffness and fatigue and to prevent structural damage. The Assessment in Ankylosing Spondylitis Working Group has proposed different domains with specific instruments to assess the efficacy of therapeutic agents classified as symptom-modifying and disease-controlling antirheumatic drugs. Non-steroidal antiinflammatory drugs (NSAIDs) are still the first-line treatment in the management of AS, and they are effective in controlling symptoms such as pain and stiffness and maintaining mobility in many patients. A recent randomized trial suggested that the progression of radiological damage occurs less on continuous use of celecoxib compared with on-demand use. If such findings were confirmed by other studies, the therapeutic value of NSAIDs in AS may extend beyond symptom control. However, for each individual patient, the expected advantages of treatment with NSAIDs should be weighted against any possible gastrointestinal and cardiovascular disadvantages. Disease-modifying antirheumatic drugs (DMARDs) are widely used for second-line therapy in AS, but the evidence for their efficacy is poor. The term 'DMARD' has been borrowed from rheumatoid arthritis, and none of the DMARDs have been shown to prevent or significantly decrease the rate of progression of structural damage which is required to be qualified as a disease-controlling antirheumatic drug for AS. Sulphasalazine is the most extensively studied DMARD and studies suggest some degree of clinical benefit confined to peripheral joint involvement, but no evidence of benefit in axial disease. Methotrexate, which is the gold standard DMARD in rheumatoid arthritis, does not seem to have a substantial therapeutic effect in AS on axial or peripheral joint involvement. Leflunomide appears to exert little beneficial effect, if any, even on peripheral joint involvement. There is also good evidence that local therapy with corticosteroids is effective and may be used in selected patients. Oral corticosteroids may be somewhat effective in relieving the symptoms of AS, but this has not been formally studied. Small studies have reported favourable results with intravenous methylprednisolone pulse therapy, but the effect is temporary. Pamidronate and thalidomide have been used in some preliminary trials but need further studies to assess their potential role in treating AS patients resistant or intolerant to other forms of treatment. Treatment with tumour necrosis factor blockers is not discussed in this review.
19080430 [Abnormal signaling activity of phosphatidylinositol 3-kinase pathway in peripheral blood 2008 Jul 29 OBJECTIVE: To investigate the activity of phosphatidylinositol 3-kinase (PI3K) signal pathway, a cytoplasmic signaling pathway known to play an important role in T cell activation, in peripheral blood T cells from systemic lupus erythematosus (SLE) patients. METHODS: T cells were isolated from the peripheral blood samples of 28 SLE patients, 5 males and 23 females, with RosettSep T cell purification kit. PI3K activity was determined by immunoprecipitation and ELISA, and Western blotting was used to measure the Akt and phosphorylated Akt protein expression. T cell proliferation and cytokine production was examined by MTT test and ELISA respectively. Fifteen healthy adults and 8 active rheumatoid arthritis patients were used as controls. The T cells from the SLE patients and normal controls were treated with 10% normal control serum of SLE serum for 24 h ("rest") and then to detect the P13K and Akt activity. Some T cells from the SLE patients were stimulated with CD3/CD28 mono-antibodies or CD3/CD28 mono-antibodies + LY294002, a specific P13K inhibitor, and then the proliferation and secretion of IL-6 and IL-10 were analyzed. RESULTS: Compared with the healthy controls and rheumatoid arthritis patients, the activity levels of PI3K and Akt in the T cells of peripheral blood from the SLE patients were significantly increased. T cells allowed to "rest" for 24 hours in culture medium showed a reversal of the changes in activity of PI3K and Akt. The activity of PI3K pathway was increased in the T cells from healthy controls when cultured with SLE serum. The proliferation and IL-6 and IL-10 secretion of the T cells from SLE patients cultured with LY294002 were inhibited. The P13K and Akt activity levels of the T cells from SLE patients were not related to SLE disease activity index (SLEDAI). CONCLUSION: The T cells from SLE patients show an abnormal activation of PI3K pathway which may be due, at least in part, to their exposure to relevant serum factors.
17437504 Clustering of inflammatory bowel disease with immune mediated diseases among members of a 2007 Jul BACKGROUND AND AIMS: Previous studies provide evidence that some immune-mediated diseases occur at greater frequency among inflammatory bowel disease (IBD) patients than in the general population. The present study examined the co-occurrence of IBD with common immune-mediated disorders including asthma, psoriasis, type 1 diabetes, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, vitiligo, autoimmune thyroiditis (Grave's and Hashimoto's), and chronic glomerulonephritis. METHODS: We conducted a cross-sectional study among members of the Kaiser Permanente Medical Care Program for the period 1996-2005. A total of 12,601 patients with at least two IBD diagnoses in computerized visit data were ascertained. Four persons without IBD were matched to each IBD patient on age, gender, and length of enrollment. Information on co-occurring diseases was obtained from computerized visit data for 1996-2005. Conditional logistic regression was used to estimate the odds ratio and 95% confidence interval for the association of IBD with immune-mediated disorders after adjusting for smoking. RESULTS: Seventeen percent of the IBD patients and 10% of the persons without IBD had a diagnosis for at least one immune-mediated disease. IBD patients were more likely to have asthma (1.5, 95% CI 1.4-1.6), psoriasis (1.7, 95% CI 1.5-2.0), rheumatoid arthritis (1.9, 95% CI 1.5-2.3), and multiple sclerosis (2.3, 95% CI 1.6-3.3). CONCLUSIONS: Among the immune-mediated diseases we studied, most were more common in IBD patients than in persons without IBD, suggesting that IBD shares common etiologic factors with other immune-mediated diseases.
16859536 Epratuzumab (humanised anti-CD22 antibody) in primary Sjögren's syndrome: an open-label p 2006 This open-label, phase I/II study investigated the safety and efficacy of epratuzumab, a humanised anti-CD22 monoclonal antibody, in the treatment of patients with active primary Sjögren's syndrome (pSS). Sixteen Caucasian patients (14 females/2 males, 33-72 years) were to receive 4 infusions of 360 mg/m2 epratuzumab once every 2 weeks, with 6 months of follow-up. A composite endpoint involving the Schirmer-I test, unstimulated whole salivary flow, fatigue, erythrocyte sedimentation rate (ESR), and immunoglobulin G (IgG) was devised to provide a clinically meaningful assessment of response, defined as a > or = 20% improvement in at least two of the aforementioned parameters, with > or = 20% reduction in ESR and/or IgG considered as a single combined criterion. Fourteen patients received all infusions without significant reactions, 1 patient received 3, and another was discontinued due to a mild acute reaction after receiving a partial infusion. Three patients showed moderately elevated levels of Human anti-human (epratuzumab) antibody not associated with clinical manifestations. B-cell levels had mean reductions of 54% and 39% at 6 and 18 weeks, respectively, but T-cell levels, immunoglobulins, and routine safety laboratory tests did not change significantly. Fifty-three percent achieved a clinical response (at > or = 20% improvement level) at 6 weeks, with 53%, 47%, and 67% responding at 10, 18, and 32 weeks, respectively. Approximately 40%-50% responded at the > or = 30% level, while 10%-45% responded at the > or = 50% level for 10-32 weeks. Additionally, statistically significant improvements were observed in fatigue, and patient and physician global assessments. Further, we determined that pSS patients have a CD22 over-expression in their peripheral B cells, which was downregulated by epratuzumab for at least 12 weeks after the therapy. Thus, epratuzumab appears to be a promising therapy in active pSS, suggesting that further studies be conducted.
18576322 CXCR2-specific chemokines mediate leukotriene B4-dependent recruitment of neutrophils to i 2008 Jul OBJECTIVE: To investigate the mechanism underlying neutrophil migration into the articular cavity in experimental arthritis and, by extension, human inflammatory synovitis. METHODS: Antigen-induced arthritis (AIA) was generated in mice with methylated bovine serum albumin (mBSA). Migration assays and histologic analysis were used to evaluate neutrophil recruitment to knee joints. Levels of inflammatory mediators were measured by enzyme-linked immunosorbent assay. Antibodies and pharmacologic inhibitors were used in vivo to determine the role of specific disease mediators. Samples of synovial tissue and synovial fluid from rheumatoid arthritis (RA) or osteoarthritis patients were evaluated for CXCL1 and CXCL5 expression. RESULTS: High levels of CXCL1, CXCL5, and leukotriene B4 (LTB4) were expressed in the joints of arthritic mice. Confirming their respective functional roles, repertaxin (a CXCR1/CXCR2 receptor antagonist), anti-CXCL1 antibody, anti-CXCL5 antibody, and MK886 (a leukotriene synthesis inhibitor) reduced mBSA-induced neutrophil migration to knee joints. Repertaxin reduced LTB4 production in joint tissue, and neutrophil recruitment induced by CXCL1 or CXCL5 was inhibited by MK886, suggesting a sequential mechanism. Levels of both CXCL1 and CXCL5 were elevated in synovial fluid and were released in vitro by RA synovial tissues. Moreover, RA synovial fluid neutrophils stimulated with CXCL1 or CXCL5 released significant amounts of LTB4. CONCLUSION: Our data implicate CXCL1, CXCL5, and LTB4, acting sequentially, in neutrophil migration in AIA. Elevated levels of CXCL1 and CXCL5 in the synovial compartment of RA patients provide robust comparative data indicating that this mechanism plays a role in inflammatory joint disease. Together, these results suggest that inhibition of CXCL1, CXCL5, or LTB4 may represent a potential therapeutic strategy in RA.
17567894 Demonstration of a novel technique to quantitatively assess inflammatory mediators and cel 2007 Jun 13 BACKGROUND: The inflammation that accompanies the pain and swelling associated with osteo- and rheumatoid arthritis is mediated by complex interactions of inflammatory mediators. Cytokines play a pivotal role in orchestrating many of these processes, including inflammatory cell recruitment, adhesion and activation. In addition, prostaglandins are secreted into the synovial cavity and are involved in perpetuation of local inflammation, vasodilatation and vasoconstriction, and also with bone resorption. Pre-clinical models have been developed in order to correlate to the human disease and principle among these is the adjuvant-induced arthritis model in the rat. METHODS: We have developed a technique to quantitatively assess the contents of synovial fluid samples from rat joints. Two needles joined together are inserted into the knee joint of anaesthetised rats and connected to a Watson-Marlow perfusion pump. Sterile saline is infused and withdrawn at 100 microl min-1 until a 250 microl sample is collected. RESULTS: Our results demonstrate up to 125 fold increases in synovial IL1alpha and IL1beta concentrations, approximately 30 fold increases in levels of IL6 and IL10 and a 200-300 fold elevation in synovial concentrations of TNFalpha during FCA-induced experimental arthritis. Finally, this novel technique has demonstrated a dose-response relationship between FCA and the total cell counts of synovial perfusates. CONCLUSION: In summary, this new technique provides a robust method for quantifying inflammatory mediators and cells from the synovial cavity itself, thereby detailing the inflammatory processes from within the capsule and excluding those processes occurring in other tissues surrounding the entire articulation.
17485663 Agalactosylated IgG antibodies depend on cellular Fc receptors for in vivo activity. 2007 May 15 IgG antibodies are glycoproteins containing a branched sugar moiety attached to the asparagine 297 residue in the antibody constant region (Fc). This glycan is essential for maintaining a functional Fc structure, which is a prerequisite for antibody-mediated effector functions, such as the interaction with cellular Fc receptors or the complement component C1q. Variations in the composition of the sugar moiety can dramatically influence antibody activity. Moreover, humans and mice with autoimmune disorders, such as rheumatoid arthritis, have altered IgG glycosylation patterns with increased levels of antibodies lacking terminal sialic acid and galactose residues (IgG-G0). There is great interest in understanding whether this altered glycosylation pattern influences antibody-mediated effector functions. In vitro studies have suggested that IgG-G0 antibodies gain the capacity to activate the complement pathway via mannose-binding lectin (MBL), which could contribute to antibody-mediated inflammation. We have analyzed the activity of IgG-G0 antibodies in mice with a genetic deletion of MBL (MBL-null mice) and demonstrate that IgG-G0 antibodies are unimpaired in MBL-null mice. In contrast, the activity of these antibody glycovariants is fully dependent on the presence of activating Fc receptors.
17311556 Emerging roles of cysteine cathepsins in disease and their potential as drug targets. 2007 The general view on cysteine cathepsins, which were long believed to be primarily involved in intracellular protein turnover, has dramatically changed in last 10 to 15 years. The discovery of new cathepsins, such as cathepsins K, V, X, F and O, and their tissue distribution suggested that at least some of them are involved in very specific cellular processes. Moreover, gene ablation experiments revealed that cathepsins play a vital role in numerous physiological processes, such as antigen processing and presentation, bone remodelling, prohormone processing and wound healing. Their involvement in several pathologies, including osteoporosis, rheumatoid arthritis, osteoarthritis, bronchial asthma and cancer have also been confirmed and today several of them have been validated as relevant targets for therapies. Compounds targeting cathepsins S and K are already in clinical evaluation, whereas others are in experimental phases. The cathepsin K inhibitor AAE-581 (balicatib) as the most advanced of them passed Phase II clinical trials in 2005. In this review, we discuss the current view on cathepsins as an emerging group of targets for several diseases and the development of cathepsin K and S inhibitors for treatment of osteoporosis and various immune disorders.
18562982 Psychiatric diagnosis in children and adolescents with obesity-related health conditions. 2008 Aug OBJECTIVE: Childhood obesity is linked with a number of problematic health conditions. While data suggest that children who are obese are at increased risk of psychosocial distress relative to nonobese peers, there are limited data outlining the rates of psychiatric diagnoses in children with obesity-related health conditions such as type 2 diabetes and the metabolic syndrome. METHODS: This study used Medicaid claims data from the State of Florida to compare the rates of psychiatric diagnoses for children with obesity-related health conditions, aged 5 to 18 years, to those of children with comparison chronic health conditions. RESULTS: Overall, 35% of children with an obesity-related diagnosis had a psychiatric diagnosis. While controlling for age, gender, and race, youths with type 2 diabetes, the metabolic syndrome, and dyslipidemia had higher rates of International Classification of Disease, Ninth Revision (ICD-9) psychiatric diagnoses than children with cystic fibrosis, sickle cell disease, and juvenile rheumatoid arthritis (p < .001), but similar to those of children with asthma. Non-Hispanic white children with an obesity-related health condition had greater odds of receiving a psychiatric diagnosis than African American (odds ratio [OR] = 0.54, p < .001) or Hispanic (OR = 0.41, p < .001) children. Males and females differed in rates of externalizing and internalizing diagnoses. CONCLUSIONS: The data suggest that children with an obesity-related health condition have higher rates of internalizing and externalizing mental health conditions relative to children with other chronic health conditions. Prospective, longitudinal research is needed to further confirm these findings and examine factors that affect this association and potential impacts on the health care system.
17269145 Folate coupled poly(ethyleneglycol) conjugates of anionic poly(amidoamine) dendrimer for i 2007 Jul Folate receptor is overexpressed on the activated (but not quiescent) macrophages in both animal models and human patients with naturally occurring rheumatoid arthritis. The aim of this study was to prepare folate targeted poly(ethylene glycol) (PEG) conjugates of anionic dendrimer (G3.5 PAMAM) as targeted drug delivery systems to inflammation and to investigate its biodistribution pattern in arthritic rats. Folate-PEG-PAMAM conjugates, with different degrees of substitution were synthesized by a two-step reaction through a carbodiimide-mediated coupling reaction and loaded with indomethacin. Folate-PEG conjugation increased the drug loading efficiency by 10- to 20-fold and the in vitro release profile indicated controlled release of drug. The plasma pharmacokinetic parameters indicated an increased AUC, circulatory half-life and mean residence time for the folate-PEG conjugates. The tissue distribution studies revealed significantly lesser uptake by stomach for the folate-PEG conjugates, thereby limiting gastric-related side effect. The time-averaged relative drug exposure (r(e)) of the drug in paw for the folate-PEG conjugates ranged from 1.81 to 2.37. The overall drug targeting efficiency (T(e)) was highest for folate-PEG conjugate (3.44) when compared to native dendrimer (1.72). The folate-PEG-PAMAM conjugates are the ideal choice for targeted delivery of antiarthritic drugs to inflammation with reduced side-effects and higher targeting efficiency.
16406545 Retrospective case review of pediatric patients with uveitis treated with infliximab. 2006 Feb PURPOSE: To assess the response and adverse events associated with infliximab treatment for refractory, noninfectious pediatric uveitis. DESIGN: Retrospective noncomparative case series of pediatric patients with refractory uveitis treated with infliximab. PARTICIPANTS: Six patients were identified. Diagnoses of the participants included idiopathic uveitis (n = 1), juvenile rheumatoid arthritis with uveitis (n = 3), idiopathic retinal vasculitis with uveitis (n = 1), and bilateral pars planitis, with vitreitis and papillitis of the left eye (n = 1). Uveitis developed in the patients (5 female, 1 male) at a mean age of 9.0 years (+/-5.0 years; range, 0.9-14.8 years). All patients had bilateral eye involvement. These patients were refractory to or dependent on topical steroids (n = 4), oral prednisone (n = 3), or both, and were also refractory to the following therapies: methotrexate (n = 6), cyclosporine (n = 3), mycophenolate mofetil (n = 3), etanercept (n = 3), and daclizumab (n = 1). INTERVENTION: All patients initially received infliximab at doses between 5 and 10 mg/kg at 2- to 4-week intervals, and then were maintained at 4- to 8-week intervals at doses of 5 to 18 mg/kg. Mean follow-up time on treatment has been 48.1 weeks (+/-14.9 weeks; range, 32-74 weeks). MAIN OUTCOME MEASURES: Primary outcome measures included the quantitative measurement of the amount of ocular inflammation in different locations within the eye. Patients were monitored for infusion reactions as well as other potential side effects. The children's clinical status, complete blood counts, and liver function panels were monitored by pediatric rheumatologists every 6 weeks. RESULTS: All 6 patients showed reduction in their intraocular inflammation after infliximab therapy was initiated. Furthermore, control of ocular inflammation was achieved while receiving infliximab therapy. Topical and systemic corticosteroids were able to be discontinued in all patients except for 1 patient, who is currently weaning off prednisone. The only adverse reactions seen were the development of vitreous hemorrhage in 1 patient and a case of transient upper respiratory infusion reaction. No patient has had to discontinue treatment. CONCLUSIONS: Infliximab seems to be an effective agent for the treatment of refractory pediatric uveitis without apparent serious toxicity in this series of patients.
17470266 Increased serum levels of macrophage migration inhibitory factor in patients with primary 2007 The objective of this study was to analyse levels of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) in patients with primary Sjögren's syndrome (pSS) and to examine associations of MIF with clinical, serological and immunological variables. MIF was determined by ELISA in the sera of 76 patients with pSS. Further relevant cytokines (IL-1, IL-6, IL-10, IFN-gamma and TNF-alpha) secreted by peripheral blood mononuclear cells (PBMC) were determined by ELISPOT assay. Lymphocytes and monocytes were examined flow-cytometrically for the expression of activation markers. Results were correlated with clinical and laboratory findings as well as with the HLA-DR genotype. Healthy age- and sex-matched volunteers served as controls. We found that MIF was increased in patients with pSS compared with healthy controls (p < 0.01). In particular, increased levels of MIF were associated with hypergammaglobulinemia. Further, we found a negative correlation of MIF levels with the number of IL-10-secreting PBMC in pSS patients (r = -0.389, p < 0.01). Our data indicate that MIF might participate in the pathogenesis of primary Sjögren's syndrome. MIF may contribute to B-cell hyperactivity indicated by hypergammaglobulinemia. The inverse relationship of IL-10 and MIF suggests that IL-10 works as an antagonist of MIF in pSS.
18668586 Inhibition of experimental Sjögren's syndrome through immunization with HSP60 and its pep 2008 Aug OBJECTIVE: To investigate a potential immunomodulatory effect of the 60-kd heat-shock protein (Hsp60) on experimental spontaneous Sjögren's syndrome (SS). METHODS: Seven-week-old nonobese diabetic (NOD) mice were immunized with eukaryotic Hsp60 or an Hsp60-derived peptide (amino acid residue [aa] 437-460). At 21 weeks of age, nondiabetic mice were investigated for salivary gland inflammation, exocrine function, and extraglandular disease manifestations. In addition, biomarker profiles comprising 87 analytes in serum and 75 in saliva were analyzed. RESULTS: In mice immunized with Hsp60 and aa 437-460, SS-related histopathologic features were significantly reduced compared with NOD controls. In addition, 50% of Hsp60-injected mice and 33% of aa 437-460-injected mice retained normal exocrine function. Both treatments induced similar changes in biomarker profiles. Notably, levels of circulating interferon-gamma-inducible 10-kd protein (IP-10) and eotaxin were decreased significantly after treatment. Anti-type 3 muscarinic acetylcholine receptor (anti-M3R) IgG1, interleukin-10, and leptin discriminated best between the different treatment groups. Successful prevention of hyposalivation was accompanied by quantitative alterations in 36 biomarkers, of which 19 mediators of inflammation declined to levels comparable with those found in BALB/c mice. Low secreted vascular endothelial growth factor A was the most accurate predictor of successful prevention of hyposalivation. Low salivary granulocyte chemotactic protein 2 was identified as the best predictor of normal secretory function across the strains. CONCLUSION: Immunization with Hsp60 and its peptide aa 437-460 led to inhibition of SS in NOD mice. Comprehensive analyses revealed specific biomarker signatures capable of predicting treatment group and treatment outcome. Molecules involved in inflammatory chemotaxis, neovascularization, and regulatory pathways caused the differences displayed by the biomarker profiles.
18508410 Demonstration of autoantibody binding to muscarinic acetylcholine receptors in the salivar 2008 Aug A significant pathogenetic role of antimuscarinic acetylcholine receptor-3 (anti-m3AChR) autoantibodies in primary Sjögren's syndrome (pSS) has been suggested. However, the binding of these antibodies to the receptors in the target tissues has not yet been demonstrated. In this study, the binding characteristics of pSS sera and anti-m3AChR-monospecific sera affinity-purified from pSS patients to labial salivary gland samples from healthy subjects were studied with light- and electron microscopy. Furthermore, the ultrastructural localisation of in vivo deposited antibodies in pSS salivary glands was also investigated. Light microscopic immunohistochemistry revealed the binding of the anti-m3AChR-specific sera to the membrane of acinar cells. Similar reaction end-products were observed in the pSS salivary gland epithelial cell membranes. With electron microscopy, the autoantibody binding was observed to be localised to the junctions of epithelial cell membranes with nerve endings, both in normal and pSS glands. The results indicate that anti-m3AChR antibodies bind to the receptors in the salivary glands.
17223657 Safety and efficacy of leflunomide in primary Sjögren's syndrome: a phase II pilot study. 2007 Aug BACKGROUND: For invalidating symptoms in primary Sjögren's syndrome (pSS), there is still a need for easy-to-administer, cost-effective and well-tolerated systemic treatment. Leflunomide (LEF) is structurally unrelated to other immunomodulatory drugs and might be efficacious in pSS, given its characteristic immunoregulatory modes of action. OBJECTIVE: To investigate the safety and efficacy of LEF in pSS in a phase II open-label pilot study. METHODS: 15 patients with pSS with early and active disease received LEF 20 mg once daily for 24 weeks. Tolerability, safety and efficacy of LEF were evaluated every 8 weeks. Additional safety visits were performed every fortnight. RESULTS: Mild gastrointestinal discomfort (including diarrhoea) and hair loss were mainly reported. Five patients developed lupus-like skin lesions on the face, arms or trunk, responding well to topical corticosteroids, nevertheless causing the withdrawal of one patient. Two patients with pre-existing hypertension had to increase dosages of anti-hypertensive drugs. Increased levels of alanine aminotransferase normalised after dose reduction in two patients. A decrease in general fatigue and an increase in physical functioning were observed after 24 weeks. Serum IgG levels decreased from 8 weeks onwards. Schirmer test values increased, not reaching statistical significance, whereas sialometry values did not change. In four of five repeated biopsies, the lymphocytic focus score decreased at the rate of 1 focus/4 mm(2). A remarkable amelioration of leucocytoclastic vasculitis was observed in three patients. CONCLUSIONS: Although the safety profile seems fairly acceptable, the observed indications for efficacy were modest and may be doubtful in justifying a randomised controlled trial of LEF in pSS.
16948117 Identification of fibronectin neoepitopes present in human osteoarthritic cartilage. 2006 Sep OBJECTIVE: Fibronectin fragments are present at high concentrations in the cartilage of patients with rheumatoid arthritis and patients with osteoarthritis (OA) and have been shown to promote cartilage catabolism in human cartilage cultures, suggesting that fibronectin fragments participate in the initiation and progression of arthritic disease. This study was undertaken to 1) identify the major fibronectin fragments in human OA cartilage and confirm their ability to elicit cartilage catabolism, 2) identify the cleavage sites in fibronectin and generate the corresponding neoepitope antibodies, and 3) explore the utility of fibronectin neoepitopes as biomarkers. METHODS: Fibronectin fragments were purified from human OA cartilage using affinity chromatography; their N-termini were then identified by sequencing. Bovine nasal cartilage was treated with affinity-purified fibronectin fragments and assayed for aggrecan breakdown by monitoring the release of glycosaminoglycans and the aggrecan neoepitope 1771AGEG. Fibronectin neoepitopes were detected by Western blotting in cytokine-treated media of human cartilage explants, and by immunohistochemical analyses of human OA cartilage. RESULTS: Multiple fibronectin fragments were isolated from human OA cartilage, and all contained the N-terminus 272VYQP. These fragments induced aggrecanase-mediated cartilage catabolism in bovine cartilage explants. Fibronectin fragments with the N-terminus 272VYQP and fragments with the C-terminus VRAA271 were detected following cytokine treatment of human cartilage extracts. These neoepitopes localized with areas of aggrecan loss in OA cartilage. CONCLUSION: Human OA cartilage contains fibronectin fragments with catabolic activity and a major cleavage site within fibronectin. This study is the first to characterize fibronectin neoepitopes in OA cartilage, suggesting that they may represent a novel biomarker of arthritis.
16937151 Bilateral total knee replacement under a single anaesthetic, using a cementless implant is 2007 Mar Bilateral knee replacement under single anaesthetic is not a common procedure. There is a general agreement that this is associated with greater morbidity and mortality. However, there is a suggestion in literature that using a cementless implant could reduce this risk. We wanted to make a prospective comparison of safety and clinical results, between unilateral and bilateral cementless knee replacements performed under a single anaesthetic. A prospective non-randomised matched cohort study on 87 consecutive patients who had bilateral simultaneous/sequential knee replacement and 174 consecutive patients who had unilateral knee replacement between the period of 1997 and 2002 were included in this study. All patients had a cementless mobile-bearing implant. All patients had an independent objective assessment at follow-up. There was no significant difference between the two groups in terms of age, sex, primary diagnosis (osteoarthritis or rheumatoid arthritis), co-morbidity, ASA grade, average range of motion and average American knee society score and post-operative surgical complications. There was one early death in the bilateral group, and three in the unilateral group. The clinical results of bilateral group were as good as the unilateral group. Our study showed that in terms of postoperative medical and surgical complications, bilateral simultaneous/sequential knee replacement using a cementless mobile-bearing implant is as safe as a unilateral knee replacement. With careful patient selection, bilateral knee replacement under a single anaesthetic would be a suitable option for patients who present with bilateral symptomatic arthritis of the knee.
16542849 Anti-TNF therapies in the management of acute and chronic uveitis. 2006 Feb 21 Patients with anterior uveitis may be treated with topical therapy alone but patients with posterior uveitis and those with sight threatening complications of anterior uveitis usually require systemic treatment especially if the disease is bilateral. The mainstay of treatment is corticosteroids and additional immunosuppressive agents such as cyclosporin and mycophenolate are used when necessary. There remains a significant cohort of patients in whom this therapy is either not tolerated or is ineffective. The use of the anti-tumour necrosis factor (TNF) antibodies has been very successful in controlling other immune-mediated disorders such as rheumatoid arthritis and has subsequently been extended to use in other arthritidies and other disorders such as psoriasis and Crohn's disease. TNF is known to play a key role in ocular inflammation as shown by animal studies and its detection in the ocular fluids of inflamed eyes in man. In some disorders all types of anti-TNF antibodies have similar efficacy but that does not appear to be the case with uveitis where infliximab is at present looking to be more effective than etanercept. The data on the use of anti-TNF drugs in uveitis is presented together with new data on its role as a steroid sparing agent.
18662248 Follicular dendritic cells confirm lymphoid organization in the minor salivary glands of p 2008 Oct BACKGROUND: Sjögren's syndrome (SS) is an autoimmune chronic inflammatory disorder affecting the salivary and lacrimal glands. The aim of this study was to explore immunophenotypic features of chronic inflammatory reactions in the minor salivary glands in patients with primary SS (pSS). METHODS: Formalin-fixed, paraffin-embedded labial minor salivary gland tissue sections from randomly selected patients with pSS (n = 60) were investigated for the expression of CD21, CD23, CD35 and IgD by immunohistochemistry. RESULTS: Based on the distribution and staining pattern of CD21, CD23, CD35 and IgD in lymphoid aggregates, several stages of chronic inflammatory reactions were observed. In 12/60 (20%) patients, lymphoid infiltrates with germinal centre (GC)-like features such as extensive networks of CD21-, CD23- and CD35-positive cells were observed in the minor salivary gland tissue. Smaller networks and /or focal infiltrates with scattered CD21(+), CD23(+) and CD35(+) cells were observed in the remaining 48/60 (80 %) cases. When dividing patients according to the presence (GC+) or the absence (GC-) of GC in the minor salivary glands, the mean focus score was significantly higher in the GC+ patients (P < 0.05). Double staining of the minor salivary glands revealed focal infiltrates with follicular dentritic cell networks and B cells resembling normal GCs in tonsillar tissue. CONCLUSION: A particular cellular profile was demonstrated in a sub-group of patients with pSS and could be linked to serological aberrations. These findings warrant further prospective studies.
18062353 The therapy of Sjogren's syndrome: a review. 2007 Sep The Sjogren's syndrome (SS) is an chronic inflammatory autoimmune disease of the exocrine glands as well as of internal apparatus. The therapy of exocrinopathy is represented by parasympathomimetic drugs such as pilocarpine and cevimeline. The therapy of systemic manifestations, actually is represented by the inhibitors of TNF alfa, as well as leflunomide, methotrexate and cyclosporine-A, but the results are quite insufficient and disappointed. In order to the involvement of B-cell function in the pathogenesis of SS, one of the most important option in the future should be specific inhibitors of that cells.