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ID PMID Title PublicationDate abstract
20506400 Granulin-epithelin precursor binds directly to ADAMTS-7 and ADAMTS-12 and inhibits their d 2010 Jul OBJECTIVE: To determine 1) whether a protein interaction network exists between granulin-epithelin precursor (GEP), ADAMTS-7/ADAMTS-12, and cartilage oligomeric matrix protein (COMP); 2) whether GEP interferes with the interactions between ADAMTS-7/ADAMTS-12 metalloproteinases and COMP substrate, including the cleavage of COMP; 3) whether GEP affects tumor necrosis factor alpha (TNFalpha)-mediated induction of ADAMTS-7/ADAMTS-12 expression and COMP degradation; and 4) whether GEP levels are altered during the progression of arthritis. METHODS: Yeast two-hybrid, in vitro glutathione S-transferase pull-down, and coimmunoprecipitation assays were used to 1) examine the interactions between GEP, ADAMTS-7/ADAMTS-12, and COMP, and 2) map the binding sites required for the interactions between GEP and ADAMTS-7/ADAMTS-12. Immunofluorescence cell staining was performed to visualize the subcellular localization of GEP and ADAMTS-7/ADAMTS-12. An in vitro digestion assay was employed to determine whether GEP inhibits ADAMTS-7/ADAMTS-12-mediated digestion of COMP. The role of GEP in inhibiting TNFalpha-induced ADAMTS-7/ADAMTS-12 expression and COMP degradation in cartilage explants was also analyzed. RESULTS: GEP bound directly to ADAMTS-7 and ADAMTS-12 in vitro and in chondrocytes, and the 4 C-terminal thrombospondin motifs of ADAMTS-7/ADAMTS-12 and each granulin unit of GEP mediated their interactions. Additionally, GEP colocalized with ADAMTS-7 and ADAMTS-12 on the cell surface of chondrocytes. More importantly, GEP inhibited COMP degradation by ADAMTS-7/ADAMTS-12 in a dose-dependent manner through 1) competitive inhibition through direct protein-protein interactions with ADAMTS-7/ADAMTS-12 and COMP, and 2) inhibition of TNFalpha-induced ADAMTS-7/ADAMTS-12 expression. Furthermore, GEP levels were significantly elevated in patients with either osteoarthritis or rheumatoid arthritis. CONCLUSION: Our observations demonstrate a novel protein-protein interaction network between GEP, ADAMTS-7/ADAMTS-12, and COMP. Furthermore, GEP is a novel specific inhibitor of ADAMTS-7/ADAMTS-12-mediated COMP degradation and may play a significant role in preventing the destruction of joint cartilage in arthritis.
20638563 Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid 2010 Jul 17 BACKGROUND: Cyclo-oxygenase (COX)-2-selective non-steroidal anti-inflammatory drugs (NSAIDs) and non-selective NSAIDs plus a proton-pump inhibitor (PPI) have similar upper gastrointestinal outcomes, but risk of clinical outcomes across the entire gastrointestinal tract might be lower with selective drugs than with non-selective drugs. We aimed to compare risk of gastrointestinal events associated with celecoxib versus diclofenac slow release plus omeprazole. METHODS: We undertook a 6-month, double-blind, randomised trial in patients with osteoarthritis or rheumatoid arthritis at increased gastrointestinal risk at 196 centres in 32 countries or territories. Patients tested negative for Helicobacter pylori and were aged 60 years and older or 18 years and older with previous gastroduodenal ulceration. We used a computer-generated randomisation schedule to assign patients in a 1:1 ratio to receive celecoxib 200 mg twice a day or diclofenac slow release 75 mg twice a day plus omeprazole 20 mg once a day. Patients and investigators were masked to treatment allocation. The primary endpoint was a composite of clinically significant upper or lower gastrointestinal events adjudicated by an independent committee. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00141102. FINDINGS: 4484 patients were randomly allocated to treatment (2238 celecoxib; 2246 diclofenac plus omeprazole) and were included in intention-to-treat analyses. 20 (0.9%) patients receiving celecoxib and 81 (3.8%) receiving diclofenac plus omeprazole met criteria for the primary endpoint (hazard ratio 4.3, 95% CI 2.6-7.0; p<0.0001). 114 (6%) patients taking celecoxib versus 167 (8%) taking diclofenac plus omeprazole withdrew early because of gastrointestinal adverse events (p=0.0006). INTERPRETATION: Risk of clinical outcomes throughout the gastrointestinal tract was lower in patients treated with a COX-2-selective NSAID than in those receiving a non-selective NSAID plus a PPI. These findings should encourage review of approaches to reduce risk of NSAID treatment. FUNDING: Pfizer Inc.
20346242 Renal safety of initial combination versus single DMARD therapy in patients with early rhe 2010 Jan OBJECTIVE: To evaluate the renal safety of traditional disease-modifying antirheumatic drugs (DMARDs) in early rheumatoid arthritis (RA). METHODS: One hundred and ninety-five DMARD-naïve patients with recent-onset RA were randomised to receive combination DMARD therapy (n=97) starting with sulfasalazine, methotrexate, hydroxychloroquine, and prednisolone (COMBI) or monotherapy (n=98), initially with sulfasalazine, with or without prednisolone (SINGLE). After two years, the choice and dosing of DMARDs and prednisolone were not restricted, but the treatment was still targeted to achieve or maintain remission. Urinalysis, serum creatinine and glomerular filtration rate (GFR; estimated according to the Cockcroft-Gault formula [eGFRCG]) were analysed at baseline and at months 6, 9, 12, 18, 24 and thereafter yearly up to 11 years. RESULTS: The cumulative incidence of repeated (>or=3 times) abnormal renal findings during the 11-year follow-up period were as follows (COMBI versus SINGLE; p-values adjusted for age and sex): proteinuria (dipstick positive) 4.8% (95%CI 1.8-12.2) vs. 5.3% (95%CI 2.0-13.7, p=0.93), haematuria (dipstick positive) 14.1% (95%CI 8.0-24.2) vs. 22.1 % (95%CI 14.5-33.0, p=0.14), raised serum creatinine (>or=100 micromol/l in females and >or=115 micromol/l in males) 4.4% (95%CI 1.7-11.4) vs. 6.7% (3.0-14.3, p=0.87) and eGFRGC<60 ml/min/1.73 m2 11.9% (95%CI 6.8-20.5) vs. 10.5% (95%CI 5.8-18.7, p=0.85). CONCLUSION: Initial remission targeted therapy with the FIN-RACo DMARD combination in early RA is safe for kidneys and does not induce more short- or long-term renal complications compared to traditional therapy with a single DMARD.
19634020 Total ankle prostheses in rheumatoid arthropathy: Outcome in 52 patients followed for 1-9 2009 Aug BACKGROUND AND PURPOSE: The first generations of total ankle replacements (TARs) showed a high rate of early failure. In the last decades, much progress has been made in the development of TARs, with the newer generation showing better results. We evaluated TARs implanted with rheumatoid arthritis (RA) or juvenile inflammatory arthritis (JIA) as indication. PATIENTS AND METHODS: 58 total ankle prostheses (Buechel-Pappas and STAR type) were implanted in patients with RA (n = 53) or JIA (n = 5) in 54 patients (4 bilateral). After a mean followup of 2.7 (1-9) years, all patients were reviewed by two orthopedic surgeons who were not the surgeons who performed the operation. Standard AP and lateral radiographs were taken and a Kofoed ankle score was obtained; this is a clinical score ranging from 0-100 and consists of sub-scores for pain, disability, and range of motion. RESULTS: 2 patients died of unrelated causes. Of the 52 patients who were alive (56 prostheses), 51 implants were still in place and showed no signs of loosening on the most recent radiographs. The mean Kofoed score at follow-up was 73 points (SD 16, range 21-92). 4 patients showed a poor result (score < 50) with persistent pain for which no obvious reason could be found. 5 implants were removed, 4 because of infection and 1 because of aseptic loosening. INTERPRETATION: Medium-term results of the STAR and BP types of TAR in RA were satisfactory. The main reason for failure of the implant was infection.
21226309 [Case of pulmonary cryptococcosis which developed in a patient receiving abatacept therapy 2010 Dec A 59-year-old woman who had been receiving abatacept therapy for rheumatoid arthritis was noted to have multiple nodules in both lungs on routine chest X-ray films. Chest computed tomography (CT) revealed multiple nodules with small cavities in both lung fields. The Cryptococcus neoformans antigen was detected from her serum and bronchial lavage fluids, indicating a diagnosis of pulmonary cryptococcosis. Abatacept was discontinued, and antifungal treatment with fluconazole was started. The lung nodules gradually shrank, and the cavities disappeared. To the best of our knowledge, we describe the first case of pulmonary cryptococcosis associated with abatacept therapy.
19740335 Peripheral blood T4 cell surface CCR5 density as a marker of activity in rheumatoid arthri 2009 Sep The chemokine (C-C motif) receptor CCR5 and its ligand CCL5 play key roles in the intra-articular recruitment of peripheral blood mononuclear cells (PBMC) in rheumatoid arthritis (RA). Therefore, using quantitative cytofluorometry, we followed T4 cell surface CCR5 density in 27 subjects with RA before and after treatment with the anti-CD20 monoclonal antibody rituximab. We observed low T4 cell surface CCR5 densities before treatment, which correlated positively with disease activity, as determined using a disease activity score evaluated on 28 joints (DAS 28), and negatively with CCL5 mRNA concentrations in PBMC, contrasting with a high proportion of intracellular CCR5 molecules, a pattern compatible with ligand-induced CCR5 internalization. At 3 months post-treatment, CCL5 mRNA expression in PBMC declined, whereas T4 cell surface CCR5 densities increased proportionally to the decrease in DAS 28. Thus, peripheral blood T4 cell surface CCR5 density is a good surrogate marker of RA activity and of the efficiency of anti-CD20 therapy.
19879729 Seven years of chronological changes of serum chromium levels after Metasul metal-on-metal 2010 Dec Although many authors have reported the serum concentrations of metal ions in patients who had metal-on-metal coupling prostheses, most of the studies were not longitudinal, and the follow-up periods were short. We evaluated the longitudinal changes of serum chromium levels in 44 patients who had undergone unilateral metal-on-metal total hip arthroplasty for a minimum of 7 years postoperatively. Although there was a consistent increase in the mean serum chromium level until 3 years after implantation, there was little difference in the levels from years 3 to 7 postoperatively. Although the serum chromium concentration was low throughout postoperative follow-up for 7 years in about 25% of patients, the serum chromium level stayed high or showed gradual elevation in 16.3% of our patients.
19198909 Obstructive sleep apnoea and periodontitis: a novel association? 2009 Aug PURPOSE: Since both obstructive sleep apnoea (OSA) and periodontitis are associated with systemic inflammation and cardiovascular morbidity, we questioned whether there may be an association between these two disorders. MATERIALS AND METHODS: A standard periodontal examination was undertaken in a group of 66 (54 men and 12 women) treatment-naïve patients diagnosed with OSA [apnoea-hypopnoea index (AHI) >5/h] to derive a number of quantitative variables which could then be used to determine the prevalence of periodontitis in a group of patients. RESULTS: The prevalence of periodontitis in our study group was 77-79%, depending on the definition used. This was almost four times that of historical controls derived from a recent national survey. When sleep-related variables were compared against periodontal variables, significant correlations were found between periodontal clinical attachment level and total sleep time. CONCLUSION: Our pilot study suggests that OSA is associated with periodontitis. Further research is needed to elucidate the nature of this association.
20090771 Supervised machine learning and logistic regression identifies novel epistatic risk factor 2010 Apr Investigating genetic interactions (epistasis) has proven difficult despite the recent advances of both laboratory methods and statistical developments. With no 'best' statistical approach available, combining several analytical methods may be optimal for detecting epistatic interactions. Using a multi-stage analysis that incorporated supervised machine learning and methods of association testing, we investigated epistatic interactions with a well-established genetic factor (PTPN22 1858T) in a complex autoimmune disease (rheumatoid arthritis (RA)). Our analysis consisted of four principal stages: Stage I (data reduction)-identifying candidate chromosomal regions in 292 affected sibling pairs, by predicting PTPN22 concordance using multipoint identity-by-descent probabilities and a supervised machine learning algorithm (Random Forests); Stage II (extension analysis)-testing detailed genetic data within candidate chromosomal regions for epistasis with PTPN22 1858T in 677 cases and 750 controls using logistic regression; Stage III (replication analysis)-confirmation of epistatic interactions in 947 cases and 1756 controls; Stage IV (combined analysis)-a pooled analysis including all 1624 RA cases and 2506 control subjects for final estimates of effect size. A total of seven replicating epistatic interactions were identified. SNP variants within CDH13, MYO3A, CEP72 and near WFDC1 showed significant evidence for interaction with PTPN22, affecting susceptibility to RA.
20390114 [How to prescribe physical exercise in rheumatology]. 2010 Jan Physical exercise, aiming to improve range of movement, muscle strength and physical well being, lately substituted the immobilization previously prescribed in rheumatic diseases. International guidelines, recommendations of Scientific Societies, and structured reviews regard physical exercise as of pivotal importance in treating rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, fibromyalgia syndrome, osteoporosis, and to be considered in connective tissue diseases. Therapeutic exercise should: aim to improve firstly local symptoms and then general health; respect the pain threshold; be a part of a treatment including pharmacological therapies and other rehabilitation techniques, be administered by skilled physiotherapist under the guide of a rheumatologist, be different according to different diseases, disease phases and patient expectations.
19165421 Macular sensitivity changes for detection of chloroquine toxicity in asymptomatic patient. 2010 Apr PURPOSE: To describe the efficacy of microperimetry (MP-1) in detecting early retinal toxicity as a result of chronic use of chloroquine and in monitoring the changes in macular sensitivity in an asymptomatic patient with best-corrected visual acuity of 20/20 bilaterally. METHODS: A 60-year-old woman presented for routine ocular examination with a medical history of severe rheumatoid arthritis, for which she had been receiving 3 mg chloroquine (CQ) per kilogram for the past 17 years. The patient was asymptomatic with best-corrected visual acuity of 20/20 bilaterally. RESULTS: Microperimeter showed loss of sensitivity in the macular region with a dense scotoma within the central 12 degrees (2.80 +/- 4.7 dB right eye and 2.84 +/- 4.7 dB left eye). CQ treatment was discontinued and substituted by Plaquenil. CONCLUSIONS: Chloroquine retinal toxicity can be recognized in a subclincal form by the presence of early changes in macular sensitivity, detected by MP-1.
20829370 Steady-state generation of mucosal IgA+ plasmablasts is not abrogated by B-cell depletion 2010 Dec 9 The anti-CD20 antibody rituximab depletes human B cells from peripheral blood, but it remains controversial to what extent tissue-resident B cells are affected. In representative patients with rheumatoid arthritis, we here demonstrate that recently activated presumably short-lived plasmablasts expressing HLA-DR(high) and Ki-67 continuously circulate in peripheral blood after B-cell depletion by rituximab at 26%-119% of their initial numbers. They circulate independent of splenectomy, express immunoglobulin A (IgA), β₇ integrin, and C-C motif receptor 10 (CCR10) and migrate along CCL28 gradients in vitro, suggesting their mucosal origin. These plasmablasts express somatically hypermutated V(H) gene rearrangements and spontaneously secrete IgA, exhibiting binding to microbial antigens. Notably, IgA(+) plasmablasts and plasma cells were identified in the lamina propria of patients treated with rituximab during peripheral B-cell depletion. Although a relation of these "steady state"-like plasmablasts with rheumatoid arthritis activity could not be found, their persistence during B-cell depletion indicates that their precursors, that is, B cells resident in the mucosa are not deleted by this treatment. These data suggest that a population of mucosal B cells is self-sufficient in adult humans and not replenished by CD20(+) B cells immigrating from blood, lymphoid tissue, or bone marrow, that is, B cells depleted by rituximab.
20709179 Chemokine profile of synovial fluid from normal, osteoarthritis and rheumatoid arthritis p 2010 Nov OBJECTIVE: The microfracture technique activates mesenchymal progenitors that enter the cartilage defect and form cartilage repair tissue. Synovial fluid (SF) has been shown to stimulate the migration of subchondral progenitors. The aim of our study was to determine the chemokine profile of SF from normal, rheumatoid arthritis (RA) and osteoarthritis (OA) donors and evaluate the chemotactic effect of selected chemokines on human subchondral progenitor cells. METHOD: Chemokine levels of SF were analyzed using human chemokine antibody membrane arrays. The chemotactic potential of selected chemokines on human mesenchymal progenitors derived from subchondral cortico-spongious bone was tested using 96-well chemotaxis assays. Chemokine receptor expression of subchondral progenitors was assessed by real-time gene expression analysis and immuno-histochemistry. RESULTS: Chemokine antibody array analysis showed that SF contains a broad range of chemokines. Ten chemokines that showed significantly reduced levels in RA or OA compared to normal SF or robustly high levels in all SF tested were used for further chemotactic analysis. Chemotaxis assays showed that the chemokines MDC/CCL22, CTACK/CCL27, ENA78/CXCL5 and SDF1α/CXCL12 significantly inhibited migration of progenitors, while TECK/CCL25, IP10/CXCL10 and Lymphotactin/XCL1 effectively stimulated cell migration. MCP1/CCL2, Eotaxin2/CCL24 and NAP2/CXCL7 showed no chemotactic effect on subchondral progenitors. Gene expression and immuno-histochemical analysis of corresponding chemokine receptors document presence of low levels of chemokine receptors in subchondral progenitors, with the CXCL10 receptor CXCR3 showing the highest expression level. CONCLUSION: These results suggest that SF contains chemokines that may contribute to the recruitment of human mesenchymal progenitors from the subchondral bone in microfracture.
19489653 Golimumab: in the treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing s 2009 Golimumab is a human anti-tumor necrosis factor (TNF) monoclonal antibody that acts principally by targeting and neutralizing TNF to prevent inflammation and destruction of cartilage and bone. Large, randomized, double-blind trials in patients with rheumatoid arthritis who were methotrexate-naïve (GO-BEFORE) or -experienced (GO-FORWARD) have shown that golimumab 50 or 100 mg every 4 weeks, in combination with methotrexate, was more effective than methotrexate alone for improving signs and symptoms of arthritis at weeks 14 and/or 24, according to American College of Rheumatology (ACR) criteria. In patients with active rheumatoid arthritis despite previous treatment with anti-TNF agents (GO-AFTER), golimumab 50 or 100 mg every 4 weeks was more effective than placebo for improving ACR responses at weeks 14 and 24; most patients in the study received concomitant methotrexate. In patients with psoriatic arthritis in the GO-REVEAL study, significantly more golimumab than placebo recipients achieved a >or=20% improvement in ACR criteria at week 14. Golimumab was also superior to placebo for improving the signs and symptoms of ankylosing spondylitis in the GO-RAISE study; significantly more golimumab than placebo recipients achieved a >or=20% improvement in the Assessment in Ankylosing Spondylitis (ASAS) criteria at week 14. In the five phase III trials in patients with rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis, there was no clear evidence of improved ACR or ASAS responses with the 100 mg dosage compared with the 50 mg dosage of golimumab. The tolerability profile of golimumab was generally consistent with that of other anti-TNF agents.
20542963 Targeting pathophysiological rhythms: prednisone chronotherapy shows sustained efficacy in 2010 Jul OBJECTIVE: This 9-month open-label extension of the Circadian Administration of Prednisone in Rheumatoid Arthritis Study (CAPRA 1) investigated the long-term safety and efficacy of prednisone chronotherapy with a novel modified-release (MR) prednisone for up to 12 months. METHODS: Of 288 patients with rheumatoid arthritis originally randomised to MR or immediate-release (IR) prednisone, 249 continued with prednisone chronotherapy (2-10 mg/day) in the 9-month open-label extension. Duration of morning stiffness of the joints (MS), disease activity scores (DAS28), American College of Rheumatology (ACR20) responses and plasma levels of interleukin 6 (IL-6) were assessed. Safety was analysed from adverse event reports and laboratory investigations. RESULTS: During the 3-month double-blind phase, patients in the MR group achieved a reduction in MS of 33.1% while no change was observed in the IR group. After 6 months of treatment, MS was reduced in the IR/MR group by 54% and in the MR/MR group by 56%. MS reduction after 12 months was 45% (IR/MR group) and 55% (MR/MR group). Plasma levels of IL-6 declined on MR treatment. DAS28 was reduced from 5.8 to 4.8 (MR/MR group) and 4.9 (IR/MR group), respectively. 37% of the 219 patients who completed the 12-month study achieved improvement according to the ACR20 criteria. Adverse events did not differ from the known profile of low-dose prednisone. CONCLUSIONS: Prednisone chronotherapy with the MR tablet was safe and well tolerated and provided a sustained improvement which resulted in a better benefit to risk ratio of low-dose glucocorticoid treatment for at least 12 months.
19277666 IL-6/sIL-6R trans-signalling, but not TNF-alpha induced angiogenesis in a HUVEC and synovi 2009 Oct Angiogenesis in synovia is a characteristic of RA patients. We examined whether IL-6 or TNF-alpha induce tubule formation in a co-culture system of fibroblast-like synovial cells from RA patients (RA-FLS) and human umbilical vein endothelial cells (HUVEC). The effects of IL-6 and TNF-alpha on the expression of angiogenic factors in RA-FLS and HUVEC, and the proliferation of HUVEC were also studied. IL-6 + sIL-6R induced tubule formation, whereas IL-6 alone did not. IL-6/sIL-6R-induced tubule formation was completely suppressed by the addition of either anti-IL-6R or anti-VEGF antibody. TNF-alpha did not induce tubule formation. On the contrary, it decreased CD31-positive area compared with the control. IL-6 + sIL-6R augmented VEGF production in RA-FLS, whereas IL-6 alone did not. Anti-IL-6R antibody suppressed IL-6/sIL-6R-induced VEGF production, but not spontaneous VEGF production. In contrast, TNF-alpha did not induce VEGF production from RA-FLS and HUVEC. IL-6 + sIL-6R stimulation of RA-FLS strongly induced mRNA expression of VEGF, but not of other angiogenic factors, such as EGF, bFGF, TGF-beta, IL-1, TNF-alpha and IL-8. Neither IL-6 nor IL-6/sIL-6R promoted HUVEC proliferation, whereas TNF-alpha significantly inhibited VEGF-induced HUVEC proliferation. In conclusion, IL-6/sIL-6R complex showed angiogenic activity via the production of VEGF from RA-FLS, but TNF-alpha was anti-angiogenic in our experimental system.
20483045 Public healthcare attendance associates with enhanced conventional and non-conventional at 2010 Mar OBJECTIVES: To assess whether public healthcare attendance associates with altered atherosclerotic cardiovascular disease risk in established rheumatoid arthritis (RA). METHODS: We determined disparities in major conventional (hypertension, dyslipidemia, smoking and diabetes), other conventional (underweight, obesity, metabolic syndrome, chronic kidney disease, alcohol use, tension, depression and body height) and non-conventional (current and cumulative inflammation markers) cardiovascular risk factors between 424 consecutive public and 202 private healthcare patients in mixed regression models. RESULTS: Eighty-one percent of public healthcare patients were black (67%) or caucasian (14%) and 83% of private healthcare cases were caucasian. Seventy percent of the patients had > or = 1 major conventional risk factor. After adjustment for age, gender, ethnic origin and statin use when appropriate, public healthcare attendance associated with the prevalence of hypertension (odds ratio (OR) [95%CI]=1.72 [1.03, 2.85]), having > or = 1 major conventional risk factor (OR [95%CI]=1.83 [1.09, 3.07]) and an increased mean (SD) number of such risk factors (p=0.03), metabolic syndrome frequency (OR [95%CI]=1.90 [1.07, 3.40]), alcohol use (OR [95%CI]=0.07 [0.03, 0.18]), shorter stature (p<0.0001), higher tension (p=0.02) and depression score (p<0.0001) and higher inflammatory markers including the disease activity score in 28 joints (p=0.005), C-reactive protein concentration (p=0.0006), Health Assessment Questionnaire disability index (p<0.0001), and number of deformed joints (p<0.0001). In sensitivity analyses performed in caucasian Africans, public healthcare attendance associated with increased frequencies of each major conventional risk factor (OR=2.06 to 3.69) and higher other conventional and non-conventional mediated cardiovascular risk. CONCLUSIONS: Public healthcare patients with established RA experience markedly enhanced conventional and non-conventional cardiovascular risk burdens.
19193011 Pyrido[2,3-d]pyrimidin-5-ones: a novel class of antiinflammatory macrophage colony-stimula 2009 Feb 26 A series of pyrido[2,3-d]pyrimidin-5-ones has been synthesized and evaluated as inhibitors of the kinase domain of macrophage colony-stimulating factor-1 receptor (FMS). FMS inhibitors may be useful in treating rheumatoid arthritis and other chronic inflammatory diseases. Structure-based optimization of the lead amide analogue 10 led to hydroxamate analogue 37, which possessed excellent potency and an improved pharmacokinetic profile. During the chronic phase of streptococcal cell wall-induced arthritis in rats, compound 37 (10, 3, and 1 mg/kg) was highly effective at reversing established joint swelling. In an adjuvant-induced arthritis model in rats, 37 prevented joint swelling partially at 10 mg/kg. In this model, osteoclastogenesis and bone erosion were prevented by low doses (1 or 0.33 mg/kg) that had minimal impact on inflammation. These data underscore the potential of FMS inhibitors to prevent erosions and reduce symptoms in rheumatoid arthritis.
19714643 TRAF1 polymorphisms associated with rheumatoid arthritis susceptibility in Asians and in C 2009 Sep OBJECTIVE: Recent genome-wide association scans and replication studies of European populations have disclosed several single-nucleotide polymorphisms (SNPs) associated with rheumatoid arthritis (RA) susceptibility. The aim of this study was to evaluate the RA-associated loci by genotyping previously reported SNPs and additional tag SNPs in a Korean population. METHODS: A total of 1,316 unrelated RA patients and 1,006 controls were genotyped for 12 SNPs identified in genome-wide scans and for 12 additional tag SNPs in IL2RB, OLIG3-TNFAIP3, PTPN22, and TRAF1-C5, and the findings were statistically compared. RESULTS: None of the SNPs tested was associated with RA susceptibility, except rs7021206 in TRAF1 intron 3 (P = 0.0032) and, among the SNPs previously reported, rs6457617 in HLA (P = 4.6 x 10(-35)). The association of rs7021206 was positive in patients who were seropositive for rheumatoid factor (P = 0.0051) or for anti-cyclic citrullinated peptide autoantibodies (P = 0.0062). However, Korean patients were negative for the association of rs3761847 in the TRAF1-C5 intergenic region previously reported in Caucasians. Linkage disequilibrium between rs3761847 and rs7021206 was not as high in Koreans (r(2) = 0.37) as in Caucasians (r(2) = 0.67), which explains the lack of association of rs3761847 in Koreans. Accordingly, RA susceptibility was localized to an extended haplotype marked by rs7021206 rather than rs3761847, and SNPs highly correlated with rs7021206 (r(2) > or = 0.81) extended from rs1953126 in the PHF19-TRAF1 intergenic region to rs2900180 in the TRAF1-C5 intergenic region, spanning 66 kb. CONCLUSION: Our results demonstrate that within and around TRAF1, excluding PHF19 and C5, SNPs highly correlated with rs7021206, but not those correlated with rs3761847, are associated with RA in both Asians and Caucasians and are possibly correlated with causative variations.
20472506 Enhanced suppressive function of regulatory T cells from patients with immune-mediated dis 2010 Sep Recent studies and our current data demonstrated the deficits in the numbers and/or functions of the CD4(+)CD25(+)Foxp3(+) Treg cells in the patients with autoimmune diseases, indicating that restoration of Treg cells in these patients could be a potential therapeutic approach. Here, we demonstrated that CD4(+)CD25(+)Foxp3(+) Treg cells can be purified, activated and expanded from peripheral blood of patients with immune-mediated diseases, to a similar degree to those from healthy donors. Within 3weeks, Treg cells from most patients could be expanded ex vivo 100-2000 fold and maintained their phenotypic characteristics. Furthermore, ex vivo expanded Treg cells displayed potent and enhanced in vitro suppressive activities inhibiting T effector cell proliferation compared to Treg cells freshly purified from the same patients. The expanded Treg cells with enhanced biological function may provide an opportunity to restore the proper balance of immunity and tolerance, suggesting the potential of using Treg cell therapy for treatment of immune-mediated diseases.