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ID PMID Title PublicationDate abstract
19449473 [The network of methotrexate toxicity]. 2009 Jan INTRODUCTION: Methotrexate is a folic acid antagonist recognised as one of the most important DMARD's in the rheumatoid arthritis treatment. Although the indisputable efficacy and the good tolerance profile, the broad toxicity spectrum is very variable with respect both to symptoms and intensity. The side effects vary from malaise and asthenia to pneumonitis or pancytopenia, which can be fatal. OBJECTIVES: To review the adverse effects of methotrexate in the treatment of rheumatoid arthritis. MATERIALS AND METHODS: Literature review, using Medline as a starting point, searching with the keywords "methotrexate", "toxic effects", "adverse effects", "rheumatoid arthritis". The relevant papers and selected references found therein were used. RESULTS: The gastrointestinal symptoms are the most frequent, but myelossupression and pneumonitis are the most feared ones. Elevation of transaminases could indicate hepatic toxicity, placing the risk of cirrhosis. Cutaneous lesions, neurologic symptoms, changes in the bone metabolism, teratogenecity and hyperhomocysteinemia are other examples of the adverse effects of methotrexate. The post-dosing reactions are still not well known. The folate supplementation is important in the prevention of folate metabolism dependent symptoms. The farmacogenomics may help to identify patients in greater risk for multiple side effects. CONCLUSIONS: Knowing and monitoring the methotrexate side effects is extremely important and should be carefully considered in order to prevent both therapeutic withdrawals due to toxicity as well as fatal outcomes.
19067101 Adalimumab response in patients with early versus established rheumatoid arthritis: DE019 2009 Apr In recent years, there has been a shift in the therapeutic approach to rheumatoid arthritis (RA), with emphasis on early therapy. The DE019 trial demonstrated adalimumab efficacy in patients with RA. This subanalysis compares response to adalimumab based on clinical, functional, and radiographic outcomes in patients with early versus established RA. Patients enrolled in the DE019 trial were divided into two groups based on disease duration (3 years=established RA). Data from 407 patients with RA were included, with 78 early (41 adalimumab, 37 placebo) and 329 established (166 adalimumab, 163 placebo) patients. Patients with early disease achieved slightly greater American College of Rheumatology 20 (20% or more improvement or ACR20), 50, and 70 responses of 61%, 46.3%, and 24.4%, respectively, at 52 weeks, compared with those with established disease, with ACR20, 50, and 70 responses of 56%, 37.3%, and 19.9%, respectively. The Health Assessment Questionnaire score improvement between adalimumab and placebo in patients with early disease (0.44) was greater than that for those with established disease (0.25). With adalimumab treatment, there was a statistically significant mean reduction in total Sharp score progression relative to placebo (5.32) in early disease compared with established disease (2.06). While adalimumab is effective for RA of all disease durations, there is a trend toward superior clinical, functional, and radiographic outcomes in patients with early disease.
19043704 Quantification of (R)-[11C]PK11195 binding in rheumatoid arthritis. 2009 Apr PURPOSE: Rheumatoid arthritis (RA) involves migration of macrophages into inflamed areas. (R)-[(11)C]PK11195 binds to peripheral benzodiazepine receptors, expressed on macrophages, and may be used to quantify inflammation using positron emission tomography (PET). This study evaluated methods for the quantification of (R)-[(11)C]PK11195 binding in the knee joints of RA patients. METHODS: Data from six patients with RA were analysed. Dynamic PET scans were acquired in 3-D mode following (R)-[(11)C]PK11195 injection. During scanning arterial radioactivity concentrations were measured to determine the plasma (R)-[(11)C]PK11195 concentrations. Data were analysed using irreversible and reversible one-tissue and two-tissue compartment models and input functions with various types of metabolite correction. Model preferences according to the Akaike information criterion (AIC) and correlations between measures were evaluated. Correlations between distribution volume (V(d)) and standardized uptake values (SUV) were evaluated. RESULTS: AIC indicated optimal performance for a one-tissue reversible compartment model including blood volume. High correlations were observed between V(d) obtained using different input functions (R(2)=0.80-1.00) and between V(d) obtained with one- and two-tissue reversible compartment models (R(2)=0.75-0.94). A high correlation was observed between optimal V(d) and SUV after injection (R(2)=0.73). CONCLUSION: (R)-[(11)C]PK11195 kinetics in the knee were best described by a reversible single-tissue compartment model including blood volume. Applying metabolite corrections did not increase sensitivity. Due to the high correlation with V(d), SUV is a practical alternative for clinical use.
20954629 Acetabular center axis: is it the future of hip navigation? 2010 Oct There are 2 distinct methods of cup navigation in total hip arthroplasty. One predicts orientation of the acetabulum through bony landmarks outside the acetabulum (eg, the anterior pelvic plane); its unreliability is well published. The other identifies acetabular center axis (ACA) and is patient-specific method that is independent of pelvic tilt, making it more reliable. Data from readily palpable acetabular registration points were compared with postoperative pelvic computed tomography images in 137 cases. Findings show that ACA software is accurate in determining acetabular/cup version and inclination. Cup center axis should coincide within 4 mm of ACA to minimize impingement and maximize stability without altering preoperative femoral version.
20187936 Akt activity protects rheumatoid synovial fibroblasts from Fas-induced apoptosis by inhibi 2010 INTRODUCTION: Synovial hyperplasia is a main feature of rheumatoid arthritis pathology that leads to cartilage and bone damage in the inflamed joints. Impaired apoptosis of resident synoviocytes is pivotal in this process. Apoptosis resistance seems to involve defects in the extrinsic and intrinsic apoptotic pathways. The aim of this study was to investigate the association of PI3Kinase/Akt and the mitochondrial apoptotic pathway in the resistance of rheumatoid arthritis (RA) fibroblast like synovial cells (FLS) to Fas-mediated apoptosis. METHODS: Apoptosis was assessed by ELISA quantification of nucleosomal release, Hoechst staining and activated caspase-3/7 measure in cultured RA FLS stimulated with anti-Fas antibody. Two Phosphoinositol-3-kinase/protein Kinase B (PI3 Kinase) inhibitors, Wortmannine and LY294002, were used before anti-Fas stimulation. Proapoptotic BH3 interacting domain death agonist (Bid) was suppressed in RA FLS by small interfering RNA (siRNA) transfection. Bid was overexpressed by transfection with the pDsRed2-Bid vector. Phosphorylated Akt, caspase-9, and Bid expression were analysed by western blot. RESULTS: PI3 kinase inhibition sensitizes RA FLS to Fas-induced apoptosis by increasing cleavage of Bid protein. Bid suppression completely abrogated Fas-induced apoptosis and Bid overexpression highly increased apoptotic rate of RA FLS in association with cleavage of caspase-9. CONCLUSIONS: In RA FLS, phosphorylation of Akt protects against Fas-induced apoptosis through inhibition of Bid cleavage. The connection between the extrinsic and the intrinsic apoptotic pathways are critical in this Fas- mediated apoptosis and points to PI3Kinase as potential therapeutic target for RA.
19304525 [Isolation and characterization of human rheumatoid arthritis fibroblast-like synoviocytes 2009 Mar OBJECTIVE: To isolate and characterize human rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLSs). METHODS: The synovial membrane tissues were obtained from 4 RA patients, 1 chondroma patient and 1 healthy subject and FLS were isolated by means of tissue culture. The cell morphology was observed by phase-contrast microscope and the cell surface markers were detected by flow cytometry. RESULTS: The FLSs were successfully cultured from the synovial membrane tissues with good cell homogeneity after the third passage. The FLSs of the 3rd to 7th passages were stable and proliferated actively, followed by slow proliferation and aging since the 8th passage. Flow cytometry showed that the 4th-passage FLSs from the RA patients contained 99.04% CD90(+) cells, 2.73% CD3(+) cells, 0.29% CD3(-)CD19(+) cells, 2.81% CD3(-)CD16(+)CD56(+) cells, 5.89% CD14(+) cells, and 54.17% CD55(+) cells. The presence of interleukin-1 receptor type I (IL-1RI, 158.63-/+20.32 pg/ml) and IL-1beta (4.67-/+0.82 pg/ml) were detected in the cell culture supernatant of the 4th-passage FLSs from the RA patients by enzyme-linked immunosorbent assay ELISA. CONCLUSION: FLSs from RA patients can be effectively culture by means of tissue culture, and the cultured FLSs show high expressions of CD90, IL-1RI and IL-1beta.
20532936 Functional analysis of the p53 codon 72 polymorphism in black South Africans with rheumato 2010 Oct The p53 tumor-suppressor protein plays an integral role in apoptosis. Perturbations in peripheral lymphocyte (PL) apoptosis may be associated with rheumatoid arthritis (RA). Polymorphisms at codon 72 of p53 (arginine (Arg72) to proline transition) confers differences in mitochondrial translocation and apoptosis inducing capabilities of p53 in vitro. We examined associations of this polymorphism with PL apoptosis, mitochondrial depolarization, and clinical markers of disease activity in a cohort of black South African RA patients. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. PL apoptosis was measured using the annexin-V assay and mitochondrial membrane potential with the JC-1 assay. Clinical and laboratory parameters were recorded for all patients. Statistical differences in these parameters were investigated according to genotype. Genotype distribution did not differ significantly between RA patients and controls (Arg/Arg, Arg/Pro, Pro/Pro: 12%, 46%, and 42% versus 3%, 34%, and 63%), despite significantly higher frequency of the Arg72 allele in patients (p = 0.0406). There was no significant difference in PL apoptosis and mitochondrial depolarization based on p53 codon 72 genotype. In addition, clinical markers of disease activity were not significantly different between genotypes. We conclude that p53 codon 72 genotype does not influence PL apoptosis or mitochondrial depolarization and is not associated with clinical markers of disease in RA.
19278814 [Indications of anakinra]. 2009 May The efficacy of anakinra on both RA-related symptoms and structural damage has been demonstrated in several randomized controlled trials. However, its interest seems limited with regards to other biologic agents. Anakinra seems promising in the treatment of childhood or adult onset Still disease, after the failure of both high dose steroids and methotrexate. The efficacy of anakinra is dramatic in several hereditary auto-inflammatory syndromes. Anakinra could be an interesting drug for the treatment of neutrophilic dermatosis or relapsing chondritis, refractory to conventional agents. Injection site reactions and infections are the 2 main anakinra-related side effects.
19428978 Association between C-reactive protein and depressive symptoms in women with rheumatoid ar 2009 May Converging lines of evidence support an association between systemic inflammation and depressive symptoms. Neuroimmune pathways may account for the high prevalence of depression in individuals with inflammatory conditions such as rheumatoid arthritis (RA). However, this relationship is complicated by factors linked to both inflammatory disease activity and mood, such as pain and physical disability. The goal of this cross-sectional study was to examine the relationship between C-reactive protein (CRP) and depressive symptoms among 173 women with RA. Somatic symptoms of depression and circulating CRP were significantly associated in regression analyses adjusted for body mass index (beta=.19, p<.05), but this relationship was attenuated when pain and disability were included as covariates (beta=.09, p=.24). CRP was not significantly associated with negative mood symptoms of depression. Findings suggest that depression in the context of RA may result from the overlap of somatic depressive and RA symptoms rather than neuroimmune pathways.
19192274 Antirheumatic drug response signatures in human chondrocytes: potential molecular targets 2009 INTRODUCTION: Rheumatoid arthritis (RA) leads to progressive destruction of articular cartilage. This study aimed to disclose major mechanisms of antirheumatic drug action on human chondrocytes and to reveal marker and pharmacological target genes that are involved in cartilage dysfunction and regeneration. METHODS: An interactive in vitro cultivation system composed of human chondrocyte alginate cultures and conditioned supernatant of SV40 T-antigen immortalised human synovial fibroblasts was used. Chondrocyte alginate cultures were stimulated with supernatant of RA synovial fibroblasts, of healthy donor synovial fibroblasts, and of RA synovial fibroblasts that have been antirheumatically treated with disease-modifying antirheumatic drugs (DMARDs) (azathioprine, gold sodium thiomalate, chloroquine phosphate, and methotrexate), nonsteroidal anti-inflammatory drugs (NSAIDs) (piroxicam and diclofenac), or steroidal anti-inflammatory drugs (SAIDs) (methylprednisolone and prednisolone). Chondrocyte gene expression profile was analysed using microarrays. Real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay were performed for validation of microarray data. RESULTS: Genome-wide expression analysis revealed 110 RA-related genes in human chondrocytes: expression of catabolic mediators (inflammation, cytokines/chemokines, and matrix degradation) was induced, and expression of anabolic mediators (matrix synthesis and proliferation/differentiation) was repressed. Potential marker genes to define and influence cartilage/chondrocyte integrity and regeneration were determined and include already established genes (COX-2, CXCR-4, IL-1RN, IL-6/8, MMP-10/12, and TLR-2) and novel genes (ADORA2A, BCL2-A1, CTGF, CXCR-7, CYR-61, HSD11B-1, IL-23A, MARCKS, MXRA-5, NDUFA4L2, NR4A3, SMS, STS, TNFAIP-2, and TXNIP). Antirheumatic treatment with SAIDs showed complete and strong reversion of RA-related gene expression in human chondrocytes, whereas treatment with NSAIDs and the DMARD chloroquine phosphate had only moderate to minor effects. Treatment with the DMARDs azathioprine, gold sodium thiomalate, and methotrexate efficiently reverted chondrocyte RA-related gene expression toward the 'healthy' level. Pathways of cytokine-cytokine receptor interaction, transforming growth factor-beta/Toll-like receptor/Jak-STAT (signal transducer and activator of transcription) signalling and extracellular matrix receptor interaction were targeted by antirheumatics. CONCLUSIONS: Our findings indicate that RA-relevant stimuli result in the molecular activation of catabolic and inflammatory processes in human chondrocytes that are reverted by antirheumatic treatment. Candidate genes that evolved in this study for new therapeutic approaches include suppression of specific immune responses (COX-2, IL-23A, and IL-6) and activation of cartilage regeneration (CTGF and CYR-61).
20039397 Immunization responses in rheumatoid arthritis patients treated with rituximab: results fr 2010 Jan OBJECTIVE: To examine immunization responses in patients with rheumatoid arthritis (RA) treated with rituximab and to investigate the effects of rituximab-induced CD20+ B cell depletion on immune responses to tetanus toxoid (T cell-dependent antigen), pneumococcal polysaccharide (T cell-independent antigen), and keyhole limpet hemocyanin (KLH) (neoantigen) and on delayed-type hypersensitivity (DTH). METHODS: In a controlled trial, we enrolled 103 patients with active RA receiving a stable dose of methotrexate (MTX). Tetanus toxoid, pneumococcal polysaccharide, and KLH vaccines as well as a Candida albicans skin test were administered to 1 group of patients receiving rituximab plus MTX (called rituximab-treated patients) for 36 weeks and to 1 group of patients receiving MTX alone for 12 weeks. The primary end point was the proportion of patients with a >or=4-fold rise in antitetanus IgG levels. Antitetanus, antipneumococcal, and anti-KLH serum IgG levels were measured prior to and 4 weeks following vaccine administration. The DTH response to C albicans was measured 2-3 days following placement. RESULTS: Responses to tetanus toxoid vaccine (>or=4-fold rise) were similar in both groups (39.1% of rituximab-treated patients and 42.3% of patients treated with MTX alone). The ability to maintain a positive DTH response to the C albicans skin test was comparable in both groups (77.4% of rituximab-treated patients and 70% of patients treated with MTX alone), showing no effect of rituximab treatment. Rituximab-treated patients had decreased responses to pneumococcal polysaccharide vaccine (57% of patients had a 2-fold rise in titer in response to >or=1 serotype, compared with 82% of patients treated with MTX alone) and to KLH vaccine (47% of patients had detectable anti-KLH IgG, compared with 93% of patients treated with MTX alone). CONCLUSION: Recall responses to the T cell-dependent protein antigen tetanus toxoid as well as DTH responses were preserved in rituximab-treated RA patients 24 weeks after treatment. Responses to neoantigen (KLH) and T cell-independent responses to pneumococcal vaccine were decreased, but many patients were able to mount responses. These data suggest that polysaccharide and primary immunizations should be administered prior to rituximab infusions to maximize responses.
20001765 A more active treatment has profound effects on the health status of rheumatoid arthritis 2010 May OBJECTIVE: Population-based studies on the trends and effects of modern antirheumatic treatment are scarce. The aim of this study was to examine trends in treatment, health-related quality of life (HRQL), and disease outcome in a population-based register of patients with rheumatoid arthritis (RA) in Malmö, Sweden. METHODS: A continuously updated population-based RA register was established in the city of Malmö, southern Sweden, in 1997. Self-completed postal questionnaires issued in 1997, 2002, and 2005 were used to collect information on demographics, medication, and health status. Cross-sectional comparisons were made between data from 1997, 2002, and 2005. RESULTS: Between 1997 and 2005, the proportion of patients treated with any disease-modifying anti-rheumatic drug (DMARD) including biologics increased substantially (from 52% to 87%), as well as the proportion treated with methotrexate (from 23% to 52%) and biologics (almost exclusively tumour necrosis factor inhibitors) (from 0% to 20%). Twelve per cent of RA patients received biologics 5 years from disease onset in 2005. In parallel with changes in treatment, mean Health Assessment Questionnaire (HAQ) scores (1.19 vs. 0.89) and all Short Form 36 (SF-36) subscales improved from 1997 to 2005 (non-overlapping confidence intervals). CONCLUSION: Between 1997 and 2005, there was a substantial increase in the use of DMARDs, which was accompanied by improved mean HAQ and SF-36 scores in cross-sectional comparisons. These results support the concept that more intensive treatment with DMARDs and biologics can have profound effects on the overall health status in RA patients at the population level.
19788740 Synovial tissues concentrate secreted APRIL. 2009 INTRODUCTION: A proliferation-inducing ligand (APRIL) from the TNF family, owing to its role in the generation and survival of plasma cells (PCs), is currently targeted for rheumatoid arthritis (RA) treatment. However, little is known about APRIL expression in RA lesions, hampering our understanding of the way APRIL may modulate this autoimmune disease. METHODS: We performed immunological staining of human normal, non-RA and RA synovial tissues with a pair of antibodies specifically recognizing APRIL-producing cells and secreted APRIL. RESULTS: We detected significant amounts of secreted APRIL in normal synovium mostly concentrated around blood vessels and at the lining layer, but no cells producing APRIL. Meanwhile, we observed that blood neutrophils constitutively secrete APRIL, indicating that blood APRIL may diffuse into the synovium via its fenestrated vessels. Synovium from non-RA and RA patients retained similarly secreted APRIL, but in this case APRIL-producing cells, including neutrophils and macrophages, were present in the tissue. Notably, PCs--when present in RA synovium--accumulated in areas of APRIL retention, spreading from blood vessels towards the lining layer. CONCLUSIONS: PCs accumulate in synovial zones rich in secreted APRIL, consistent with a pro-survival role of APRIL for PCs in RA. The concentration of APRIL by normal synovium indicates that this tissue may constitute a proper environment for PCs even before RA onset.
20213805 Anti-citrullinated protein antibodies bind surface-expressed citrullinated Grp78 on monocy 2010 May OBJECTIVE: Anti-citrullinated protein antibodies (ACPAs), which are the most specific autoantibody marker in patients with rheumatoid arthritis (RA), correlate with disease activity; however, the role of ACPAs in RA pathogenesis has not been elucidated. We hypothesized that ACPAs may directly stimulate mononuclear cells to produce inflammatory cytokines. Thus, we identified cognate antigens of ACPAs on monocyte/macrophages and examined their immunopathologic roles in the pathogenesis of RA. METHODS: ACPAs were purified from pooled ACPA-positive RA sera by cyclic citrullinated peptide-conjugated affinity column. After coculture of U937 cells with ACPAs, the tumor necrosis factor alpha (TNFalpha) production and NF-kappaB DNA binding activity of the cells were measured by enzyme-linked immunosorbent assay. The cognate antigens of ACPAs on the U937 cell surface were probed by ACPAs, and the reactive bands were examined via proteomic analysis. RESULTS: ACPAs specifically enhanced TNFalpha production and increased the DNA-binding activity of NF-kappaB in U937 cells. Proteomic analysis revealed that Grp78 protein (72 kd) was one of the cognate antigens of ACPAs. The truncated form of cell surface-expressed Grp78 (55 kd) on U937 cells contained citrulline capable of binding with ACPAs. After citrullination, glutathione S-transferase-tagged recombinant Grp78 (97.52 kd) became a 72-kd fragment and bound with ACPAs. ACPAs also bound to human monocytes and lymphocytes to promote TNFalpha production. CONCLUSION: We clearly demonstrated that ACPAs enhance NF-kappaB activity and TNFalpha production in monocyte/macrophages via binding to surface-expressed citrullinated Grp78.
20097033 Five Duraloc locking ring failures. 2010 Oct We report on 5 cases that underwent revision for locking ring failure in the Duraloc product line (DePuy, Warsaw, Ind). All liner retrievals showed signs of posterior neck/liner impingement and superior edge loading or significant wear. In these cases, we believe superior head migration and neck/liner impingement due to cup anteversion contributed to these locking ring failures. More research is needed to determine the incidence of this complication. Patients with locking ring failures should be closely monitored. Full cup revision, face-changing liners, or cementing liners into well-fixed cups are all options to correct suboptimal cup positioning.
20108489 Anti-cyclic citrullinated peptide antibodies--activity markers in rheumatoid arthritis. 2009 Jan BACKGROUND: Immunological abnormalities in rheumatoid arthritis (RA) imply several antibodies, among which anti-cyclic cytrullinated peptide antibodies (anti-CCP) have the highest sensitivity and specificity. Their diagnostic and prognostic value in RA is well known, although their value as markers of the disease activity has not been established yet. OBJECTIVES: The aim of this study is to evaluate the correlation between anti-CCP antibodies and RA activity which eventually leads to the best treatment of choice. PATIENTS AND METHODS: 217 consecutive patients hospitalized in the Department of Internal Medicine and Rheumatology, "Sf Maria" Clinical Hospital between 01.01-31.06 2007 were retrospectively studied. They were divided into two groups: group A-111 patients with RA (ACR criteria fulfilled) and group B-106 patients with other rheumatic diseases. The following parameters taken out of the patients files were studied: parameters of the clinical activity of disease (C reactive protein, fibrinogen), rheumatoid factor (RF) and anti-CCP antibodies. Disease activity score (DAS) using 4 variables (number of tender joints, number of swollen joints, erythrocyte sedimentation rate and assessement of the disease activity) was also studied. Data were processed with SPSS program using linear functions, Pearson correlation coefficient and Hi2 test of interdependency. RESULTS: The sensitivity of anti-CCP antibodies in patients with RA was 56.75%. The specificity of anti-CCP antibodies in patients with RA was 90.56%. Low seric levels of anti-CCP antibodies were also found in patients without RA, but with other conditions like: osteoarthritis, viral polyarthritis, infectious myositis and Still disease; moderate to high seric levels were found in patients with psoriatic arthritis. Significant correlations were found between anti-CCP antibodies and DAS (r = 0.437), between anti-CCP and fibrinogen (r = 0.32) between anti-CCP antibodies and C reactive protein (r = 0.237) as well as between anti-CCP and RF (r = 0.38). CONCLUSIONS: Anti-CCP antibodies are highly specific but moderately sensitive for RA, their highest frequencies and seric levels being found in seropositive RA. Anti-CCP can be used in patients with RA not only as a diagnostic marker but also as a reliable test for assessing the activity of the disease.
19333923 In vitro spontaneous osteoclastogenesis of human peripheral blood mononuclear cells is not 2009 Apr OBJECTIVE: In vitro spontaneous osteoclastogenesis from peripheral blood mononuclear cells (PBMCs) is increased in diseases with excessive bone loss. The purpose of this study was to reassess the role of T lymphocytes in this process. METHODS: Fresh or cryopreserved PBMCs obtained from healthy subjects and from patients with rheumatoid arthritis, psoriatic arthritis, and non-psoriatic spondylarthritis were cultured at high density and stained for tartrate-resistant acid phosphatase (TRAP). Resorption of mineralized matrix was assessed by a dentin disc assay. CD14+ monocytes and CD3+ T cells were selected using magnetically labeled antibodies. RESULTS: Numerous multinucleated, TRAP+, dentin-resorbing osteoclasts developed spontaneously from fresh PBMCs from healthy individuals. This process was abrogated by T cell depletion and was restored by exogenous macrophage colony-stimulating factor (M-CSF) and RANKL, indicating the important role of T cells in spontaneous osteoclastogenesis in vitro. Using physiologic freezing and thawing as a model for the activation of PBMCs, spontaneous osteoclastogenesis was significantly increased in cryopreserved versus fresh cells. Under these conditions, spontaneous osteoclastogenesis was not dependent on T lymphocytes, since it was not influenced by T cell depletion and persisted in purified CD14+ cell cultures supplemented with M-CSF and RANKL. In contrast to studies with fresh PBMCs, spontaneous osteoclastogenesis under these conditions did not appear to be clearly different between healthy subjects and patients with arthritis. CONCLUSION: Spontaneous osteoclastogenesis in vitro is dependent on T lymphocytes or on the direct activation of monocytic cells, depending on the test conditions. This variability warrants better validation of the relevance of this functional test for in vivo osteoclastogenesis.
19652889 Heterogeneous pathogenic processes of thrombotic microangiopathies in patients with connec 2009 Aug To clarify the pathogenic processes of thrombotic microangiopathies (TMAs) in patients with connective tissue disease (CTD), we analysed clinical characteristics and plasma ADAMTS13 levels in 127 patients with CTD-TMAs, including patients with systemic lupus erythematosus (SLE), systemic sclerosis, polymyositis/dermatomyositis, and rheumatoid arthritis (RA), and 64 patients with acquired idiopathic thrombotic thrombocytopenic purpura (ai-TTP). Plasma levels of ADAMTS13 activity, antigen, and inhibitors were determined by enzyme immunoassays. IgG type anti-ADAMTS13 antibodies were also detected by immunoblots using purified ADAMTS13. ADAMTS13 activity was significantly decreased in CTD-TMAs, regardless of the underlying disease, but the frequency of severe deficiency (defined as <0.5% of normal) was lower in CTD-TMA patients than in ai-TTP patients (16.5% vs. 70.3%, p < 0.01). Severe deficiency of ADAMTS13 activity was predominantly detected in patients with RA- and SLE-TMAs, and was closely associated with the presence of anti-ADAMTS13 IgG antibodies. CTD-TMA patients with severe deficiency of ADAMTS13 activity appeared to have lower platelet counts and better therapeutic outcomes. At least two phenotypic TMAs occur in patients with CTDs: a minor population with deficient ADAMTS13 activity caused by neutralising autoantibodies, and a major population with normal or moderately reduced activity. Classifying CTD-TMAs by ADAMTS13 activity may be useful in predicting the clinical course and therapeutic outcomes, as patients with moderately reduced activity are likely to have more prominent renal impairment and poor prognoses.
20039425 Rapid and sustained improvement in bone and cartilage turnover markers with the anti-inter 2010 Jan OBJECTIVE: To investigate the effects of tocilizumab (TCZ) added to a stable dosage of methotrexate (MTX) on biochemical markers of bone and cartilage metabolism in patients in the multicenter double-blind, placebo-controlled OPTION (Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders) study who have moderate-to-severe rheumatoid arthritis (RA) and an inadequate response to MTX. METHODS: Included in this study were 416 of the 623 patients with active RA enrolled in the OPTION study. Patients were randomized to receive TCZ (4 mg/kg or 8 mg/kg) or placebo intravenously every 4 weeks, with MTX continued at the stable prestudy doses (10-25 mg for 20 weeks, with a final followup at week 24). Serum biochemical markers of bone formation (osteocalcin, N-terminal propeptide of type I collagen [PINP]), bone resorption (C-terminal crosslinking telopeptide of type I collagen [CTX-I] and C-terminal crosslinking telopeptide of type I collagen generated by matrix metalloproteinases [ICTP]), cartilage metabolism (N-terminal propeptide of type IIA collagen [PIIANP]), collagen helical peptide [HELIX-II]), and matrix metalloproteinase 3 (MMP-3) were measured at baseline and at weeks 4, 16, and 24. RESULTS: TCZ induced marked dose-dependent reductions in PIIANP, HELIX-II, and MMP-3 levels at week 4 that were maintained until week 24, an effect associated with increased levels of bone formation markers that were significant as compared with placebo only for PINP and only at 4 weeks (P < 0.01 for both TCZ doses). TCZ induced significant decreases in the bone degradation markers CTX-I and ICTP, providing initial evidence of a beneficial effect on bone turnover. TCZ-treated patients who met the American College of Rheumatology 50% improvement criteria (achieved an ACR50 response) or achieved clinical remission (as determined by a Disease Activity Score in 28 joints <2.6) at week 24 had greater reductions in ICTP, HELIX-II, and MMP-3 levels as compared with ACR50 nonresponders. CONCLUSION: TCZ combined with MTX reduces systemic bone resorption, cartilage turnover, and proteolytic enzyme MMP-3 levels, which provides evidence of a limitation of joint damage and possible beneficial effects on skeletal structure in patients with established moderate-to-severe RA.
19841745 Potential role of decoy B7-H4 in the pathogenesis of rheumatoid arthritis: a mouse model i 2009 Oct BACKGROUND: A pathogenic hallmark of rheumatoid arthritis (RA) is persistent inflammatory responses in target tissues and organs. Immune responses mediated by T cells and autoantibodies are known to play pivotal roles. A possible interpretation for this observation is a loss of negative regulation of autoimmune responses. Here we sought to investigate whether B7-H4, a cell surface inhibitory molecule of the B7-CD28 signaling pathway, may play a role in the pathogenesis of RA. METHODS AND FINDINGS: In a cross-sectional study of a clinical convenience sample using monoclonal antibodies against human B7-H4 molecules, we detected high levels of the soluble form of B7-H4 (sH4) in the sera of 65% of patients with RA (n = 68) versus only 13% of healthy donors (n = 24). Elevated sH4 was associated with an increased disease severity score (DAS28) in a cross-sectional analysis. In a mouse model of RA, transgenic expression of sH4 or genetic deletion of B7-H4 accelerated the progression of collagen-induced arthritis, accompanied by enhanced T and B cell-mediated autoimmune responses as well as increased activity of neutrophils. Expression in vivo of an agonist, a B7-H4-immunoglobulin Fc fusion protein, profoundly suppressed disease progression in the mouse model. CONCLUSIONS: Our findings in mice indicate that sH4 acts as a decoy molecule to block the inhibitory functions of cell-surface B7-H4, leading to exacerbation of collagen-induced arthritis. If the preliminary correlation between sH4 levels and disease activity in patients with RA can be confirmed to reflect a similar mechanism, these findings suggest a novel target for treatment approaches. Please see later in the article for the Editors' Summary.