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ID PMID Title PublicationDate abstract
17576784 Switching between anti-tumour necrosis factors: trying to get a handle on a complex issue. 2007 Jul The question of switching is not only a question of clinical practice, but has an important scientific dimension as well See linked article, p 893
18574154 Differential function of the NACHT-LRR (NLR) members Nod1 and Nod2 in arthritis. 2008 Jul 1 The pathogenesis of chronic joint inflammation remains unclear, although the involvement of pathogen recognition receptors has been suggested recently. In the present article, we describe the role of two members of the NACHT-LRR (NLR) family, Nod1 (nucleotide-binding oligomerization domain) and Nod2 in a model of acute joint inflammation induced by intraarticular injection of Streptococcus pyogenes cell wall fragments. Here, we show that Nod2 deficiency resulted in reduced joint inflammation and protection against early cartilage damage. In contrast, Nod1 gene-deficient mice developed enhanced joint inflammation with concomitant elevated levels of proinflammatory cytokines and cartilage damage, consistent with a model in which Nod1 controls the inflammatory reaction. To explore whether the different function of Nod1 and Nod2 occurs also in humans, we exposed peripheral blood mononuclear cells (PBMCs) carrying either Nod1ins/del or Nod2fs mutation with SCW fragments in vitro. Production of both TNFalpha and IL-1beta was clearly impaired in PBMCs carrying the Nod2fs compared with PBMCs isolated from healthy controls. In line with results in Nod1 gene-deficient mice, PBMCs from individuals bearing a newly described Nod1 mutation produced enhanced levels of proinflammatory cytokines after 24-h stimulation with SCW fragments. These data indicate that the NLR family members Nod1 and Nod2 have different functions in controlling inflammation, and that intracellular Nod1-Nod2 interactions may determine the severity of arthritis in this experimental model. Whether a distorted balance between the function of Nod1 and/or Nod2 is involved in the pathogenesis of human autoinflammatory or autoimmune disease, such as rheumatoid arthritis, remains to be elucidated.
17530389 Local delivery of indomethacin to arthritis-bearing rats through polymeric micelles based 2007 Oct PURPOSE: Preparation, in vitro and in vivo evaluation of indomethacin-loaded polymeric micelles based on amphiphilic polyphosphazene. METHODS: Amphiphilic polyphosphazenes (PNIPAAm/EAB-PPPs) with poly (N-isopropylacrylamide) (PNIPAAm) and ethyl 4-aminobenzoate (EAB) as side groups were synthesized through thermal ring-opening polymerization and subsequent substitution reactions. Indomethacin (IND) loaded polymeric micelles based on PNIPAAm/EAB-PPPs were prepared by dialysis procedure. In vitro IND release kinetics was investigated in 0.1 M PBS (pH 7.4), while in vivo pharmacokinetics was performed in Sprague-Dawley rats. In vivo pharmacodynamic study was carried out based on two animal models, i.e. carrageenan-induced acute paw edema and complete Freund's adjuvant (CFA) induced ankle arthritis model. RESULTS: Drug loading capacity of micelles based on this type of amphiphilic copolymers was mainly determined by copolymer composition and the chemical structure of drug. In addition to the compatibility between drug and micellar core, hydrogen bonding interaction between drug and hydrophilic corona may significantly influence drug loading as well. In vitro drug release in PBS suggested that there was no significant difference in release rate between micelles based on copolymers with various EAB content. Compared with the rats administered with free IND aqueous solution, IND concentration in rats' plasma showed a prolonged maintenance in experimental group treated with IND-loaded polymeric micelles. In vivo pharmacodynamic study indicated that sustained therapeutic efficacy could be achieved through topical injection of the aqueous solution of IND-loaded micelles. Local delivery of IND can avoid the severe gastrointestinal stimulation, which was frequently associated with oral administration as evidenced by ulceration evaluation. CONCLUSIONS: The promising results of current preliminary study suggest that this type of amphiphilic copolymers could be used as injectable drug carriers for hydrophobic drugs.
18287112 A pilot study of combination anti-cytokine and anti-lymphocyte biological therapy in rheum 2008 Apr BACKGROUND: Immunological tolerance in humans using anti-T-cell monoclonal antibodies (mAbs) may be hampered by a pro-inflammatory microenvironment. All clinical trials of such therapies in rheumatoid arthritis (RA), however, have selected patients with active disease at baseline. Concurrent neutralization of inflammation with a TNFalpha antagonist should maximize the potential of anti-T-cell mAbs to induce tolerance in RA. AIM: To evaluate the safety of combining a TNFalpha antagonist and CD4 mAb in RA. DESIGN: An iterative pilot study focused on the safety of such combination therapy. METHODS: Eight poor prognosis, seropositive RA patients were treated with combined CD4 and TNFalpha blockade. Prolonged CD4 blockade was achieved with a humanized mAb, and TNFalpha blockade with a p55 TNF receptor fusion protein. RESULTS: There was a low incidence of classical first-dose reactions to the CD4 mAb, possibly reflecting concomitant TNFalpha blockade. An unusual anaphylactoid reaction was seen, however, and one patient developed a probable allergic reaction after several infusions. Skin rashes were common, as previously reported with CD4 mAb monotherapy. No serious infections were documented during follow-up, despite CD4+ lymphopenia in some patients. Most patients appeared to demonstrate improved RA disease control after the study. After 17-49 months after therapy, one patient was in remission, one remained off disease modifying anti-rheumatic drugs and five had stable disease, three on previously ineffective doses of methotrexate. CONCLUSION: We report, for the first time in man, immunotherapy with a combination of an anti-cytokine and an anti-T-cell reagent. We witnessed an unusual first-dose reaction but there were no significant infectious complications.
18821683 Highly sensitive B cell analysis predicts response to rituximab therapy in rheumatoid arth 2008 Oct OBJECTIVE: In rheumatoid arthritis (RA), B cell depletion occurs in all patients treated with rituximab, but the clinical responses to rituximab are variable. A highly sensitive assay was used to test the hypothesis that B cell depletion is variable, and that incomplete depletion leads to a poorer outcome. METHODS: Sixty patients with active RA unresponsive to anti-tumor necrosis factor agents received two 1-gram infusions of rituximab. B cell numbers were measured by highly sensitive flow cytometry before and after each infusion and at 3-month intervals thereafter. A reduction in B cell levels below 0.0001x10(9)/liter was defined as complete depletion (compared with 0.05x10(9)/liter by conventional cytometry). Clinical responses were measured using the European League Against Rheumatism (EULAR) criteria. RESULTS: At 6 months, 92% of patients had a moderate-to-good clinical response according to the EULAR criteria. B cells were detected in 63% of patients after the first infusion of rituximab (median level 0.0009x10(9)/liter [range<0.0001-0.0015x10(9)/liter), and these patients had poorer clinical outcomes than patients with complete depletion. At 9 months, 82% of patients with complete depletion had a moderate-to- good EULAR response, compared with 43% of those with partial depletion (P=0.01). At 12 months, 59% of complete responders had a moderate-to-good EULAR response, compared with 21% of those with partial depletion (P=0.01). Patients in whom B cells were depleted only after the second infusion did no better than those in whom depletion was never complete and had poorer clinical outcomes than those in whom depletion was initially complete. CONCLUSION: This study is the first to show, using a highly sensitive analysis, that rituximab therapy is associated with variable diminution in B cell numbers. A lack of complete depletion of B cells after 1 infusion was associated with a poorer outcome.
18227362 Progressive preclinical interstitial lung disease in rheumatoid arthritis. 2008 Jan 28 BACKGROUND: Early detection and treatment for interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA) may ameliorate disease progression. The objective of this study was to identify asymptomatic lung disease and potential therapeutic targets in patients having RA and preclinical ILD (RA-ILD). METHODS: Sixty-four adults with RA and 10 adults with RA and pulmonary fibrosis (RAPF) were referred to the National Institutes of Health, Bethesda, Maryland, and underwent high-resolution computed tomography (HRCT) and pulmonary physiology testing. Proteins capable of modulating fibrosis were quantified in alveolar fluid. RESULTS: Twenty-one of 64 patients (33%) having RA without dyspnea or cough had preclinical ILD identified by HRCT. Compared with patients without lung disease, patients with RA-ILD had statistically significantly longer histories of cigarette smoking (P< .001), increased frequencies of crackles (P= .02), higher alveolar-arterial oxygen gradients (P= .004), and higher HRCT scores (P< .001). The HRCT abnormalities progressed in 12 of 21 patients (57%) with RA-ILD. The alveolar concentrations of platelet-derived growth factor-AB and platelet-derived growth factor-BB were statistically significantly higher in patients having RA-ILD (mean [SE], 497.3 [78.6] and 1473 [264] pg/mL, respectively) than in patients having RA without ILD (mean [SE], 24.9 [42.4] and 792.7 [195.0] pg/mL, respectively) (P< .001 and P=.047, respectively). The concentrations of interferon gamma and transforming growth factor beta(2) were statistically significantly lower in patients having RAPF (mean [SE], 5.59 [1.11] pg/mL and 0.94 [0.46] ng/mL, respectively) than in patients having RA without ILD (mean [SE], 14.1 [1.9] pg/mL and 2.30 [0.39] ng/mL, respectively) (P=.001 and P=.006, respectively) or with preclinical ILD (mean [SD], 11.4 [2.6] pg/mL and 3.63 [0.66] ng/mL, respectively) (P=.04 and P=.007, respectively). Compared with patients having stable RA-ILD, patients having progressive RA-ILD had statistically significantly higher frequencies of treatment using methotrexate and higher alveolar concentrations of interferon gamma and transforming growth factor beta(1) (P=.046, P=.04, and P=.04, respectively). CONCLUSIONS: Asymptomatic preclinical ILD, which is detectable by HRCT, may be prevalent and progressive among patients having RA. Cigarette smoking seems to be associated with preclinical ILD in patients having RA, and treatment using methotrexate may be a risk factor for progression of preclinical ILD. Quantification of alveolar proteins indicates that potential pathogenic mechanisms seem to differ in patients having RA-ILD and symptomatic RAPF.
18313425 Elevated plasma homocysteine and low vitamin B-6 status in nonsupplementing older women wi 2008 Mar OBJECTIVE: The purpose of this study was to determine if nonsupplementing older women (aged >or=55 years) with rheumatoid arthritis had higher plasma homocysteine and lower B-vitamin status compared to healthy controls. Elevated plasma homocysteine, a risk factor for cardiovascular disease, may help explain why individuals with rheumatoid arthritis have an increased risk of cardiovascular disease. METHODS: Older, free-living women were classified as rheumatoid arthritis (n=18) or healthy control (n=33). Participants were not using B-vitamin supplements. Fasting blood samples were measured for pyridoxal 5'phosphate (PLP) (the metabolically active coenzyme form of vitamin B-6), folate, red blood cell folate, vitamin B-12, transcobalamin II, homocysteine, C-reactive protein, and lipid concentrations. Participants completed 7-day weighed food records, the Stanford Health Assessment Questionnaire (HAQ), and a visual analog pain scale. RESULTS: PLP concentrations were lower in the rheumatoid arthritis vs healthy control participants (4.93+/-3.85 vs 11.35+/-7.11 ng/mL [20+/-16 vs 46+/-29 nmol/L]; P<0.01) whereas plasma homocysteine was higher in the rheumatoid arthritis group (1.63+/-0.74 vs 1.15+/-0.38 mg/L [12.1+/-5.5 vs 8.5+/-2.8 micromol/L]; P=0.02). Red blood cell folate concentrations were lower in the rheumatoid arthritis vs healthy control participants [414+/-141 vs 525+/-172 ng/mL [938+/-320 vs 1,190+/-390 nmol/L]; P=0.02). No significant differences were found for plasma folate, vitamin B-12, and transcobalamin II. An inverse correlation was found between PLP concentrations and the HAQ disability index (r=-0.37; P<0.01). A positive correlation was found between homocysteine concentrations and the HAQ disability index (r=0.36; P=0.01). Total cholesterol and low-density lipoprotein cholesterol levels were lower in the rheumatoid arthritis group (cholesterol 191+/-43 vs 218+/-33 mg/dL [4.95+/-1.11 vs 5.65+/-0.85 mmol/L]; P=0.02; low-density lipoprotein cholesterol 110+/-36 vs 137+/-29 mg/dL [2.85+/-0.93 vs 3.55+/-0.75 mmol/L]; P<0.01). No significant differences were seen between groups for protein (g/day), fat (g/day), cholesterol (mg/day), folate (microg/day), vitamin B-12 (microg/day), and vitamin B-6 (mg/day) dietary intakes. CONCLUSIONS: Poor vitamin B-6 status and elevated plasma homocysteine concentrations were seen in older women with rheumatoid arthritis compared to healthy controls and may contribute to their increased risk of cardiovascular disease.
16736521 Immunohistochemical analysis of hip arthritis in ankylosing spondylitis: evaluation of the 2006 Jun OBJECTIVE: Previous histopathologic and magnetic resonance imaging studies suggest that the subchondral bone marrow might be the primary site of inflammation in patients with ankylosing spondylitis (AS) and that this might be reflected by inflammation found in hip joints. The aim of this study was to conduct an immunohistologic assessment of the bone-cartilage interface and subchondral bone marrow in AS patients with hip arthritis. METHODS: We collected femoral heads from patients with AS, osteoarthritis (OA), and rheumatoid arthritis (RA) who were undergoing hip replacement. The subchondral bone marrow and bone-cartilage interface were assessed immunohistochemically by evaluating infiltrating T cells, microvessel density, and osteoclasts. Areas of the femoral head surface with and without cartilage were assessed separately. RESULTS: At sites with surface cartilage, we found subchondral infiltration of CD3+ T cell aggregates at significantly higher numbers in AS patients as compared with OA patients, but not RA patients. At sites of complete cartilage destruction, the frequency of CD3+ T cell aggregates was significantly reduced as compared with sites with cartilage on the surface in AS patients, but not in RA patients. Similar differences were found for CD4+ and CD8+ T cells. Only at sites with surface cartilage, but not those without, angiogenesis and osteoclastic foci in the subchondral bone marrow in AS patients were significantly increased as compared with RA patients and with OA patients. CONCLUSION: These findings suggest that the subchondral bone marrow and bone-cartilage interface are primary sites of inflammation in AS and that cartilage might be necessary for the induction of inflammation.
17029568 The impact of glycosylation on the biological function and structure of human immunoglobul 2007 Immunoglobulins are the major secretory products of the adaptive immune system. Each is characterized by a distinctive set of glycoforms that reflects the wide variation in the number, type, and location of their oligosaccharides. In a given physiological state, glycoform populations are reproducible; therefore, disease-associated alterations provide diagnostic biomarkers (e.g., for rheumatoid arthritis) and contribute to disease pathogenesis. The oligosaccharides provide important recognition epitopes that engage with lectins, endowing the immunoglobulins with an expanded functional repertoire. The sugars play specific structural roles, maintaining and modulating effector functions that are physiologically relevant and can be manipulated to optimize the properties of therapeutic antibodies. New molecular models of all the immunoglobulins are included to provide a basis for informed and critical discussion. The models were constructed by combining glycan sequencing data with oligosaccharide linkage and dynamics information from the Glycobiology Institute experimental database and protein structural data from "The Protein Data Bank."
18794857 Rheumatoid arthritis susceptibility loci at chromosomes 10p15, 12q13 and 22q13. 2008 Oct The WTCCC study identified 49 SNPs putatively associated with rheumatoid arthritis at P = 1 x 10(-4) - 1 x 10(-5) (tier 3). Here we show that three of these SNPs, mapping to chromosome 10p15 (rs4750316), 12q13 (rs1678542) and 22q13 (rs3218253), are also associated (trend P = 4 x 10(-5), P = 4 x 10(-4) and P = 4 x 10(-4), respectively) in a validation study of 4,106 individuals with rheumatoid arthritis and an expanded reference group of 11,238 subjects, confirming them as true susceptibility loci in individuals of European ancestry.
18370440 Rheumatoid arthritis: strategies in the management of patients showing an inadequate respo 2008 The introduction of medications that target specific proinflammatory cytokines has revolutionized the management of patients with rheumatoid arthritis. The agents that antagonize the effects of tumour necrosis factor (TNF)-alpha -- infliximab, etanercept and adalimumab -- have consistently shown very good efficacy for controlling the clinical and radiographic manifestations of the disease. However, it has become apparent that some patients will receive no clinical benefit, gradually lose the effect over time or experience adverse effects with the TNFalpha antagonists. The management of these patients is challenging and there are no clear guidelines. The concomitant administration of a disease-modifying antirheumatic drug, such as methotrexate, has been shown to improve outcomes. Optimization of the methotrexate or TNFalpha antagonist dose may lead to improved responses, as demonstrated in some dose escalation studies. Switching to another TNFalpha antagonist is a step that is supported by small, mostly uncontrolled studies. Finally, the T-cell co-stimulation antagonist abatacept, as well as the B-cell depleting agent rituximab, are also available for use in patients who have had an inadequate response or intolerance to the TNFalpha antagonists.Genotypic studies have identified TNF and TNF receptor polymorphisms that appear to predict independently whether a patient will respond to a TNFalpha antagonist, but genotyping is not available for routine use in clinical practice. Until such tools for predicting response are widely available, the management of patients with poor responses to TNFalpha antagonists will have to depend upon the wishes of the patient regarding medication dosage schedules and adverse effect profiles, as well as how comfortable the treating physician is with the available biological medications. In this article, we review the current data and construct an algorithm to help guide clinicians in the management of patients with inadequate responses to the TNFalpha antagonists.
18311806 Induction of macrophage secretion of tumor necrosis factor alpha through Fcgamma receptor 2008 Mar OBJECTIVE: Macrophage-derived tumor necrosis factor alpha (TNFalpha) is a dominant mediator of synovitis in rheumatoid arthritis (RA). This study was undertaken to assess whether and how immune complexes (ICs) formed by the interaction of disease-specific autoantibodies to citrullinated proteins (ACPAs) with their main synovial target antigen, citrullinated fibrin, contribute to TNFalpha production by macrophages. METHODS: An in vitro human model was developed in which monocyte-derived macrophages were stimulated with ACPA-containing ICs that were generated by capturing ACPAs from RA sera on immobilized citrullinated fibrinogen. Cellular activation was evaluated by TNFalpha assay in culture supernatants. Selective blockade of IC interactions with the 3 classes of Fcgamma receptors (FcgammaR) was used to assess the contribution of each receptor to macrophage activation. In addition, 2 citrullinated fibrin-derived peptides bearing major ACPA epitopes were tested for their capacity to inhibit formation of macrophage-activating ACPA-containing ICs. RESULTS: ACPA-containing ICs induced a dose-dependent TNFalpha secretion by macrophages from 14 of 20 healthy donors. The macrophage response was systematically higher than that of the paired monocyte precursors. TNFalpha secretion was not reduced by blockade of FcgammaRI or FcgammaRIII, but was strongly repressed when interaction of ICs with FcgammaRII was prevented. The 2 citrullinated peptides significantly inhibited ACPA reactivity to citrullinated fibrinogen and, when tested together, almost completely abolished formation of macrophage-activating ICs, thereby diminishing the secreted TNFalpha levels. CONCLUSION: Our model demonstrates the inflammatory potential of ACPA-containing ICs via engagement of FcgammaRIIa at the surface of macrophages, strongly supporting their pathophysiologic involvement. Continuing dissection of these molecular pathways could open the way to new therapeutic approaches in patients with RA.
18050191 Type IV collagen alpha-chain composition in synovial lining from trauma patients and patie 2007 Dec OBJECTIVE: Normal synovial lining is composed of macrophage-like type A and fibroblast-like type B lining cells. This sheet-like structure lacks a basement membrane, but its intercellular substance contains some basement membrane components, including type IV collagen. We undertook this study to determine the alpha-chain composition of type IV collagen in normal and arthritic synovial lining, using monoclonal alpha-chain antibodies. METHODS: Samples were analyzed using avidin-biotin-peroxidase complex staining for the presence of collagen alpha1/2(IV), alpha3(IV), alpha4(IV), alpha5(IV), alpha6(IV), matrix metalloproteinase 2 (MMP-2), and MMP-9, and the enzyme activity was detected using gelatin zymography. Double immunofluorescence was performed for type IV collagen/MMP-9 and type IV collagen/CD68. Synovial fibroblasts were studied using quantitative reverse transcriptase-polymerase chain reaction. RESULTS: In mildly inflamed synovium from 5 trauma patients, alpha1/2(IV) chains were strongly stained, but alpha5(IV) and alpha6(IV) chains were weakly stained. Coding messenger RNA was shown in cultured synovial fibroblasts. Basement membranes of blood vessels contained all alpha(IV) chains and served as useful positive sample controls. In the synovial lining from 5 patients with rheumatoid arthritis (RA), all alpha-chains were absent/very weakly stained. This was coupled with numerous type A lining cells containing MMP-9 (type IV collagenase), also found in synovial fluid. CONCLUSION: Synovial lining has a unique and very limited alpha-chain composition, different from that of the vascular basement membrane, which contains all alpha-chains. This special composition and lack of nidogen are probably of relevance for the bidirectional translining diffusion. Such tentative alpha-chain-dependent adhesive and transport-regulating properties seem to be deranged in RA, probably in part due to type IV collagenases produced in the lining and/or released by transmigrating or synovial fluid neutrophils.
16649193 LIGHT (TNFSF14), a novel mediator of bone resorption, is elevated in rheumatoid arthritis. 2006 May OBJECTIVE: Human osteoclast formation from mononuclear phagocyte precursors involves interactions between tumor necrosis factor (TNF) ligand superfamily members and their receptors. LIGHT is a transmembrane protein expressed and shed from the surface of activated T cells. Since activated T cells have been implicated in osteoclastogenesis in rheumatoid arthritis (RA), this study sought to determine whether LIGHT can regulate RANKL/cytokine-induced osteoclast formation, to identify the mechanism by which LIGHT influences osteoclastogenesis, and to investigate the presence of LIGHT in the serum of RA patients. METHODS: The effect of LIGHT on human and murine osteoclast formation was assessed in the presence and absence of neutralizing reagents to known osteoclastogenic factors. Serum levels of LIGHT in RA patients were measured by enzyme-linked immunosorbent assay. RESULTS: In the presence and absence of RANKL, LIGHT induced osteoclast formation from both human peripheral blood mononuclear cells and murine macrophage precursors, in a dose-dependent manner, whereas no inhibition was observed by adding osteoprotegerin, RANK:Fc, TNFalpha, or interleukin-8 or by blocking the LIGHT receptors herpesvirus entry mediator or lymphotoxin beta receptor. However, formation of osteoclasts was significantly decreased by the soluble decoy receptor for LIGHT, DcR3, and by blocking antibodies to the p75 component of the TNF receptor. A significant increase in LIGHT levels in the serum of RA patients compared with normal controls was also noted. CONCLUSION: Our results indicate that LIGHT promotes RANKL-mediated osteoclastogenesis and that it can induce osteoclast formation by a mechanism independent of RANKL. The increased concentration of LIGHT in patients with RA raises the possibility that LIGHT may play a role in immunopathogenic conditions that are associated with localized or systemic bone loss.
19083617 The results of utilizing proximal tibial bone graft in reconstructive procedures of the fo 2008 BACKGROUND: The proximal tibia is becoming a popular site for harvesting autogenous bone graft. Reports on the use of the proximal tibia for bone graft have focused on donor-site morbidity. The purpose of this study is to determine the clinical rate of bony healing following the use of proximal tibial bone graft in foot and ankle procedures. METHODS: This study is a retrospective review of consecutive patients who underwent proximal tibial bone grafting as an adjunct to a foot and ankle reconstructive procedure. Patients undergoing this combination of procedures at a single institution over a 2-year period were eligible for inclusion. RESULTS: There were no fractures of the donor site or need to prolong non-weightbearing status beyond that required for the primary operation. Twenty-three of the 25 arthrodesis procedures healed completely. Three fracture cases also healed completely. CONCLUSIONS: Our findings expand on prior studies by demonstrating the efficacy of proximal tibia bone graft in achieving bony healing in foot and ankle procedures with a union rate of 93%.
17362502 The identification and characterization of a novel protein, c19orf10, in the synovium. 2007 Joint inflammation and destruction have been linked to the deregulation of the highly synthetic fibroblast-like synoviocytes (FLSs), and much of our current understanding of the mechanisms that underlie synovitis has been collected from studies of FLSs. During a proteomic analysis of FLS cells, we identified a novel protein, c19orf10 (chromosome 19 open reading frame 10), that was produced in significant amounts by these cells. The present study provides a partial characterization of c19orf10 in FLSs, synovial fluid, and the synovium. Murine monoclonal and chicken polyclonal antibodies were produced against recombinant human c19orf10 protein and used to examine the distribution of c19orf10 in cultured FLSs and in synovial tissue sections from patients with rheumatoid arthritis or osteoarthritis. The intracellular staining pattern of c19orf10 is consistent with localization in the endoplasmic reticulum/Golgi distribution. Sections of rheumatoid arthritis and osteoarthritis synovia expressed similar patterns of c19orf10 distribution with perivascular and synovial lining staining. Double-staining in situ analysis suggests that fibroblast-like synovial cells produced c19orf10, whereas macrophages, B cells, or T cells produced little or none of this protein. There is evidence of secretion into the vascular space and the extracellular matrix surrounding the synovial lining. A competitive enzyme-linked immunosorbent assay confirmed the presence of microgram levels of c19orf10 in the synovial fluids of patients with one of various arthropathies. Collectively, these results suggest that c19orf10 is an FLS-derived protein that is secreted into the synovial fluid. However, the significance of this protein in synovial biology remains to be determined. The absence of known structural motifs or domains and its relatively late evolutionary appearance raise interesting questions about its function.
17537677 Inflammation and bone erosion are suppressed in models of rheumatoid arthritis following t 2007 Sep Spleen tyrosine kinase (Syk), a key mediator of immunoreceptor signaling in inflammatory cells, is essential for immune complex-mediated signal transduction initiated by activated receptors for immunoglobulin G. In collagen-induced arthritis, R788/R406, a novel and potent small molecule Syk inhibitor suppressed clinical arthritis, bone erosions, pannus formation, and synovitis. Serum anti-collagen type II antibody levels were unaltered, while the half-life of exogenous antibody was extended when co-administered with R406. Expression of the targeted kinase (Syk) in synovial tissue correlated with the joint level of inflammatory cell infiltrates and was virtually undetectable in treated rats. Syk inhibition suppressed synovial cytokines and cartilage oligomeric matrix protein (COMP) in serum, suggesting a sensitive and reliable biomarker for R406 activity. These results highlight the role of activating Fcgamma receptors in inflammatory synovitis and suggest that interruption of the signaling cascade with a novel Syk inhibitor may be a useful addition to immunosuppressive disease-modifying anti-rheumatic drugs currently used in the treatment of human autoimmune diseases such as rheumatoid arthritis.
17530711 Fluvastatin reverses endothelial dysfunction and increased vascular oxidative stress in ra 2007 Jun OBJECTIVE: To investigate the effect of statins on vascular dysfunction in rat adjuvant-induced arthritis (AIA). METHODS: Fluvastatin (5 mg/kg/day) was administered orally to rats with AIA, for 21 days after the onset of arthritis. The vasodilatory response to acetylcholine of aortic rings isolated from rats with AIA that were not treated or were treated with fluvastatin and from normal rats was determined. The amounts of 4-hydroxy-2-nonenal (HNE) and nitrotyrosine in aortas were measured by Western blotting. In vitro and in situ superoxide production in aortas was evaluated based on fluorogenic oxidation of dihydroethidium to ethidium. Expression of NAD(P)H components and endothelial nitric oxide synthase (eNOS) in aortas was examined by real-time reverse transcriptase-polymerase chain reaction and Western blotting. Serum levels of tetrahydrobiopterin, a critical eNOS cofactor, were determined by high-performance liquid chromatography. RESULTS: Fluvastatin reversed endothelial dysfunction in AIA without affecting the clinical severity of arthritis or serum cholesterol concentration. Fluvastatin reduced the amounts of HNE and nitrotyrosine in the aorta, and the levels of superoxide expressed in endothelial cells and smooth muscle cells in the tissue, in rats with AIA. NADH- or L-arginine-induced superoxide production was not observed in the aortic samples from fluvastatin-treated rats with AIA. Fluvastatin decreased the levels of expression of messenger RNA for p22phox, a NAD(P)H oxidase component, in the aortas of rats with AIA, but did not affect the expression of eNOS. Serum levels of tetrahydrobiopterin were significantly reduced in rats with AIA, and were increased by administration of fluvastatin. CONCLUSION: Our findings demonstrate that fluvastatin has potent vascular protective effects in AIA and provide additional scientific rationale for the use of statins to reduce cardiovascular mortality in patients with rheumatoid arthritis.
16079165 Anti-TNF antibody treatment improves glucocorticoid induced insulin-like growth factor 1 ( 2006 Mar BACKGROUND: Insulin-like growth factor 1 (IGF1) is an important determinant of muscle mass because it promotes growth and suppresses protein degradation. IGF1 is decreased in rheumatoid arthritis and juvenile idiopathic arthritis because its synthesis is inhibited by inflammation. In parallel, glucocorticoids induce IGF1 resistance and add to muscle degradation. OBJECTIVE: To investigate the influence of anti-tumour necrosis factor antibody treatment (anti-TNF) with adalimumab on levels of myoglobin (degradation marker) and IGF1 in patients with rheumatoid arthritis with and without prednisolone treatment. METHODS: Subcutaneous adalimumab was given to 32 patients with longstanding rheumatoid arthritis (16 with and 16 without prednisolone) in a longitudinal study. IGF1, IGF1 binding protein 1 (IGFBP-1), IGFBP-3, and myoglobin were measured by enzyme linked immunosorbent assay. RESULTS: Rheumatoid patients had normal serum myoglobin. Patients on prednisolone had higher myoglobin than patients not receiving prednisolone, indicating increased muscle degradation. On treatment with anti-TNF, myoglobin levels did not change in either patient group. Serum IGF1 was increased in patients with v without prednisolone, indicating IGF1 resistance (mean (SEM): 221 (23) v 122 (14) microg/l, p<0.001). Adalimumab treatment decreased the raised IGF1 levels in patients with prednisolone, so that after 12 weeks of treatment they reached the level of patients without prednisolone. Serum IGFBP-1 and IGFBP-3 did not differ in the two groups, and anti-TNF did not change these concentrations. CONCLUSIONS: Anti-TNF antibody treatment over 12 weeks improved glucocorticoid induced IGF1 resistance without influencing myoglobin and IGF1 binding proteins. Thus, in rheumatoid patients on glucocorticoids with generally decreased muscle mass anti-TNF treatment with adalimumab has favourable effects.
17350489 Prescription rheumatology practices among Mexican specialists. 2007 Apr BACKGROUND: We undertook this study to describe prescription practices and the degree of disease control in a large sample of patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) treated by rheumatologists in Mexico. METHODS: Board-certified Mexican rheumatologists across the country were asked to assess consecutive RA and AS patients; 1208 patients completed a self-administered questionnaire with information on demographics, disease duration, co-morbidity, treatment, pain, disability and a validated Spanish version of instruments to measure physical function and quality of life. RESULTS: Of the 1096 RA patients, 88.1% were treated with nonsteroidal anti-inflammatory drugs (NSAIDs), 1020 (93.3%) with disease-modifying anti-rheumatic drugs (DMARDs), 365 (33.4%) with steroids, and 70 (6.4%) with biological agents. Their mean Health Assessment Questionnaire Disability Index (HAQ-Di) score was 1.21+/-0.80, Disease Activity Index, 28 joint count (DAS 28) 3.9+/-1.29, and Rheumatoid Arthritis Disease Activity Index (RADAI), 3.94+/-2.01. Regarding the 112 AS patients, 110 (98.2%) received NSAIDs, 90 (80.4%) were on DMARDs, 11 (9.8%) took steroids, and 11 (9.8%) received biological agents, their functional status shown as Bath Ankylosing Spondylitis Functional Index (BASFI) score of 4.4+/-2.5. Among the 1110 DMARD users, only 64 received one drug, and a great proportion used two or more DMARDs; 81 subjects (16.2%) were on biological agents, in any combination. RA patients more commonly used methotrexate, 791 (72%) cases, and hydroxychloroquine. Taking into account their diagnosis, the combination most prescribed was NSAIDs plus DMARDs in 660 subjects (54.7%). CONCLUSIONS: DMARDs in combination with other drug are the most frequently prescribed therapeutic scheme for RA and AS patients. These schemes used for both conditions by Mexican rheumatologists are in line with current international recommendations.