Rheumatoid Arthritis: Zhang Y

Lovering F, Zhang Y. · Wyeth Research, Cambridge, MA 02140, USA. · Curr Drug Targets CNS Neurol Disord. · Pubmed #15857301 No free full text.

Abstract: Stroke is the third leading cause of death and the leading cause of permanent disability in western countries and the incidence of stroke is expected to increase in the foreseeable future due to the ageing population. The effective treatment of stroke remains challenging due to the complexity and heterogenicity of the disease. Recombinant tissue plasminogen activator (rt-PA) is the only FDA-approved therapy for stroke during the first 3 hr after the disease onset. However the risk of hemorrhage and its narrow therapeutic window has limited its use in clinic. Inflammation has been known to play a crucial role in the induction and development of stroke and tumor necrosis factor-alpha (TNF-alpha) is a central player in the initiation of multiple inflammatory cascades. The recent success of three anti-TNF biologics in the clinic for the treatment of rheumatoid arthritis as well as other inflammatory diseases has further validated TNF159nflammation. TNF-alpha has also been shown to be associated with ischemic stroke. Anti-TNF biologics have been shown to be effective in reducing the disease symptoms in various pre-clinical stroke models. Small molecule TNF inhibitors are highly desirable due to the limitations of protein therapeutics. Tumor necrosis factor-alpha-converting enzyme (TACE) is the major sheddase of TNF-alpha and is essential for the generation of soluble, mature TNF-alpha. Thus TACE appears to be an attractive target for development of oral small molecule TNF-alpha inhibitors. This review summarizes the role of TNF-alpha in stroke and the effect of several TACE/MMP inhibitors in pre-clinical stroke models. The data strongly suggest that TACE/MMP inhibitors have great therapeutic potential and may be valuable alternatives in treating stroke in the clinic.

Zhang Y. · Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA. · Front Biosci. · Pubmed #14977534 No free full text.

Abstract: Tubercle bacillus has remarkable ability to persist in the human host and has caused latent infection in one third of the world population. The current tuberculosis (TB) chemotherapy while effective in killing growing bacilli is largely ineffective in killing persistent or dormant bacilli, leading to prolonged therapy. There is considerable recent interest to study mechanisms of persistence and dormancy in mycobacteria. Meanwhile, there is also confusion about the use of terminology of dormant and persistent bacilli. Different models of mycobacterial persistence have been established. Various mycobacterial factors have recently been identified that may be involved in persistence or dormancy and resuscitation of dormant organisms. The phenotypic resistance to antituberculosis drugs in persistent and dormant bacilli presents a major challenge for effective control of the disease. The host immune system is critical in controlling latent TB infection from reactivation. A recent interesting observation is the reactivation of latent TB infection by anti-TNF-alpha antibody used as a treatment for rheumatoid arthritis and Crohn's disease. The role of psychoneuroendocrinological factors in TB, which is often ignored in the era of modern chemotherapy but could be important for controlling latent infection, is also briefly reviewed. There is recent interest to develop new TB drugs that target persistent and dormant bacilli and also immunotherapeutic agents that enhance chemotherapy and better control latent infection. The complex interaction between the bacteria, drugs, host and the environment underscores the need for a combined approach that incorporates chemotherapy, immunotherapeutic agents, improved socioeconomic, nutritional and even conducive psychological factors for more effective control of TB and latent TB.

Sun Z, Sun Y, Cao J, Wang L, Tian M, Zhang Y, Liu J, Wang P. · Department of Joint Surgery, People's Hospital of Tianjin, Tianjin, 300121, PR China. · Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. · Pubmed #19594004 No free full text.

Abstract: OBJECTIVE: To investigate the causes and the clinical treatment methods of postoperative wound complications following total knee arthroplasty (TKA). METHODS: From June 2005 to August 2008, 486 cases (576 knees, including 314 left knees and 262 right knees) underwent primary TKA using standard midline incision and medial parapatellar arthrotomy. There were 146 males (172 knees) and 340 females (404 knees) aged 51-86 years old (average 61.3 years old). The duration of disease was 3-35 years. Primary diseases included: 138 cases (156 knees) of rheumatoid arthritis, 282 cases (348 knees) of osteoarthritis, 46 cases (49 knees) of traumatic arthritis, 20 cases (23 knees) of pigmented villonodular synovitis. The factors of etiology, deformity correction, duration of tourniquet use and wound drainage were analyzed to determine the cause of postoperative wound complication. RESULTS: Postoperatively, 37 cases (43 knees) had wound complications and the rate of incidence was 7.5%, including 13 cases (15 knees) of aseptic exudation, 3 cases (4 knees) of fat liquefaction, 4 cases (4 knees) of subcutaneous hematoma, 8 cases (9 knees) of flap margin necrosis, 6 cases (7 knees) of superficial infection, 3 cases (4 knees) of red swollen joint with increased skin temperature and deep infection. All 37 patients recoveried after symptomatic treatment. Among those 37 cases, patients with rheumatoid arthritis had a higher incidence rate of wound complication than the patients with other primary diseases (P < 0.05). The incidence rate of patients with deformity correction more than or equal to 20 degree was significantly higher than that of other patients (P < 0.05). The duration of using tourniquet was (86 +/- 15) minutes for patients with wound complication, and (78 +/- 8) minutes for patients without wound complication, indicating there was a significant difference (P < 0.01). Wound complication occurred in 22 knees (5.1%) with autologous blood transfusion absorber, 11 knees (11.5%) with negative pressure attraction, and 10 knees (19.2%) receiving no drainage. The incidence rate of postoperative wound complication in patients without drainage was obviously higher than that in patients with drainage (P < 0.05). CONCLUSION: Patients with rheumatoid arthritis are more likely to have wound complication after TKA. Postoperative wound drainage and short duration of tourniquet application help decrease the incidence of complications. It is necessary to make early definitive diagnosis of postoperative wound complication, and provide proactive treatment.

Cantaert T, Brouard S, Thurlings RM, Pallier A, Salinas GF, Braud C, Klarenbeek PL, de Vries N, Zhang Y, Soulillou JP, Tak PP, Baeten D. · Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. · Arthritis Rheum. · Pubmed #19565497 No free full text.

Abstract: OBJECTIVE: The association of HLA-DRB1 alleles with anti-citrullinated protein antibodies (ACPAs) in rheumatoid arthritis (RA) suggests the potential involvement of T lymphocytes in ACPA-seropositive disease. The purpose of this study was to investigate this hypothesis by systematic histologic and molecular analyses of synovial T cells in ACPA+ versus ACPA- RA patients. METHODS: Synovial biopsy samples were obtained from 158 RA patients. Inflammation was determined histologically and immunohistochemically. RNA was extracted from peripheral blood mononuclear cells and synovial tissues obtained from 11 ACPA+ RA patients, 7 ACPA- RA patients, and 10 spondylarthritis (SpA) patients (arthritis controls). T lymphocyte clonality was studied by combined quantitative and qualitative T cell receptor CDR3 length distribution (LD) analysis and direct sequencing analysis. RESULTS: ACPA+ and ACPA- RA patients were similar at both the clinical and histologic levels. At the molecular level, however, patients with ACPA+ synovitis displayed a marked elevation of qualitative CDR3 LD alterations as compared with those with ACPA- synovitis and with the SpA controls. These differences in CDR3 LD were not observed in the peripheral blood, indicating a selective recruitment and/or local expansion of T cells in the synovial compartment. The CDR3 LD alterations reflected true monoclonal or oligoclonal expansions, as confirmed by direct sequencing of the T cell receptor. The CDR3 LD alterations in RA synovium did not correlate with B cell clonal expansions but were inversely associated with synovial lymphoid neogenesis. CONCLUSION: The T cell repertoire is specifically restricted in RA patients with ACPA+ synovitis. Whereas the origin and role of these clonal alterations remain to be determined, our data suggest the preferential involvement of T lymphocytes in ACPA-seropositive RA.

Wan Y, Yuan S, Xue X, Li M, Qin X, Zhang C, Wang W, Jiang C, Wu S, Liu Y, Zhu W, Ran Y, Zhang Z, Han W, Zhang Y. · State Key Laboratory of Cancer Biology, Xi'an, People's Republic of China. · Cell Immunol. · Pubmed #19393605 No free full text.

Abstract: Adjuvants are necessary to elicit high titers of antibodies in vaccine-immunization procedures. We previously developed a mouse tumor necrosis factor-alpha (TNF-alpha) autovaccine (mTNF-PADRE) capable of inducing anti-TNF-alpha antibodies. In this study, we investigated the therapeutic effect of adjuvant-free administration of the autovaccine on collagen-type-II-induced rheumatoid arthritis (CIA) in mice. Our results showed that the vaccine could ameliorate the symptoms of CIA in mice. In addition, this study suggests that it is possible to control the antibody levels in mice immunized with mTNF-PADRE without adjuvant.

Tian M, Liu J, Zhang Y, Tian Z, Wang L, Cao J, Sun Y, Sun Z. · Department of Joint Surgery, Tianjin People's Hospital, Tianjin, 300121, P.R. China. · Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. · Pubmed #19192880 No free full text.

Abstract: OBJECTIVE: To summarize and analyze the operation-correlated complications of total knee arthroplasty (TKA) with posterior stabilized prosthesis (PS). METHODS: From October 2000 to October 2007, 707 cases (816 knees) underwent TKA. All the TKA knees were divided equally into former and latter groups according to the operation time (408 knees for each group). In the former group (October 2000 to January 2005, n=350), there were 63 males (84 knees) and 287 females (324 knees), aging (63.5 +/- 7.8) years. A total of 198 left knees affected and 210 right knees affected; 292 single knees affected and 58 both knees affected. There were 304 knees of osteoarthritis, 84 knees of rheumatoid arthritis and 20 knees of other disease. The disease course was (9.3 +/- 5.6) years. The knee range of motion (ROM) was (97.2 +/- 8.7) degrees, the HSS score was 47.4 +/- 12.2. In the latter group (January 2005 to October 2007, n=357), there were 77 males (92 knees) and 280 females (316 knees), aging (62.7 +/- 6.3) years. A total of 221 left knees affected and 187 right knees affected; 306 single knees affected and 51 both knees affected. There were 278 knees of osteoarthritis, 109 knees of rheumatoid arthritis and 21 knees of other disease. The disease course was (8.6 +/- 5.1) years. The knee ROM was (101.1 +/- 10.3) degrees, the HSS score was 49.3 +/- 11.2. We modified the method of lateral patellar retinaculum release and used a new femoral rotational alignment technique in the latter group. The intraoperative and postoperative complications were divided into mild, moderate and severe. The HSS score, ROM and complications of the knee were compared and analyzed statistically during the follow-up. RESULTS: The former group was followed up 5.3 years (1 to 7 years), complications occurred in 278 knees (68.1%), including mild in 136 knees (33.3%), moderate in 135 knees (33.1%) and severe in 7 knees (1.7%). The latter group was followed up 2.1 years (0.5 to 3.5 years), complications occurred in 159 knees (39.0%), including mild in 111 knees (27.2%), moderate in 47 knees (11.5%) and severe in 1 knee (0.2%), and there was significant difference between them (P < 0.001). There was significant difference in increased ROM between the former group (6.0 +/- 3.7) degrees and the latter group (14.4 +/- 4.2) degrees after operation (P < 0.05). There was significant difference in increased HSS score between the former group (36.9 +/- 3.7) and the latter group (44.0 +/- 4.2) after operation (P < 0.05). CONCLUSION: The TKA is a complex operation with innumerable potential complications. To accumulate operative experience and improve surgical skills are the key points to reduce the operation-correlated complications.

Yu L, Ao M, Wan J, Zhang Y. · School of Life Science and Technology, Huazhong University of Science and Technology, 430074 Wuhan, PR China. · Fitoterapia. · Pubmed #18672035 No free full text.

Abstract: The root of Tripterygium wilfordii (TWH) is a traditional Chinese herb used to treat the immune-related diseases such as rheumatoid arthritis, whereas the leaf and twig of TWH was considered useless and discarded. We performed a study on the anti-inflammatory effects on the leaf and twig portion agent using carrageenan- and adjuvant-induced paw edema in rats. They showed a marked inhibitory effect on edema in both models of inflammation in rats, at the dose of 50, 100 and 200 mg/kg, especially on secondary immunological arthritis. Based on this study, we confirmed that the leaf and twig of TWH is a potentially useful drug suitable for further evaluation for rheumatoid arthritis and can replace root of TWH.

Allaire S, Wolfe F, Niu J, Zhang Y, Zhang B, LaValley M. · Clinical Epidemiology Research and Training Unit, Boston University, 715 Albany Street, Boston, MA 02118, USA. · Arthritis Rheum. · Pubmed #18668597 No free full text.

Abstract: OBJECTIVE: To examine the role of anti-tumor necrosis factor (anti-TNF) agents in predicting work disability in subjects with rheumatoid arthritis (RA). METHODS: We studied 953 subjects with rheumatologist-diagnosed RA from a US cohort using a nested, matched, case-control approach. Subjects provided data on medication usage and employment every 6 months for 18 months, were employed at baseline, and were age <65 years at last followup. Cases were subjects who were not employed at followup (n = 231) and were matched approximately 3:1 by time of entry into the cohort to 722 controls who were employed at followup. Risk of any employment loss, or loss attributed to RA, at followup as predicted by use of an anti-TNF agent at baseline was computed using conditional logistic regression. Stratification on possible confounding factors and recursive partitioning analyses were also conducted. RESULTS: Subjects' mean age was 51 years, 82% were female, 92% were white, and 72% had more than a high school education. Nearly half (48%) used an anti-TNF agent at baseline; characteristics of anti-TNF agent users were similar to nonusers. In the main analyses, anti-TNF use did not protect against any or RA-attributed employment loss (odds ratio [95% confidence interval] 1.1 [0.7-1.6] versus 0.9 [0.5-1.5]). However, a protective effect was found for users with disease duration <11 years (odds ratio [95% confidence interval] 0.5 [0.2-0.9]). In recursive partitioning analyses, age, RA global severity, and functional limitation played a much greater role in determining employment loss than anti-TNF agent use. CONCLUSION: Anti-TNF agent use did not protect against work disability in the main analyses. In stratified analyses, their use was protective among subjects with shorter RA duration, whereas in nonparametric analyses, age and disease factors were the prominent predictors of work disability.

Cantaert T, Kolln J, Timmer T, van der Pouw Kraan TC, Vandooren B, Thurlings RM, Cañete JD, Catrina AI, Out T, Verweij CL, Zhang Y, Tak PP, Baeten D. · Clinical Immunology and Rheumatology, Department of Experimental Immunology, Academic Medical Center/University of Amsterdam, The Netherlands. · J Immunol. · Pubmed #18566445 links to  free full text

Abstract: B lymphocyte autoimmunity plays a crucial role in the pathogenesis of rheumatoid arthritis. The local production of autoantibodies and the presence of ectopic lymphoid neogenesis in the rheumatoid synovium suggest that these dedicated microenvironments resembling canonical lymphoid follicles may regulate the initiation and maturation of B cell autoimmunity. In this study, we assessed experimentally the relevance of ectopic lymphoid neogenesis for B cell autoimmunity by a detailed structural, molecular, and serological analysis of seropositive and seronegative human synovitis. We demonstrate that synovial lymphoid neogenesis is a reversible process associated with inflammation which is neither restricted to nor preferentially associated with autoantibody positive rheumatic conditions. Despite the abundant expression of key chemokines and cytokines required for full differentiation toward germinal center reactions, synovial lymphoid neogenesis in rheumatoid arthritis only occasionally progresses toward fully differentiated follicles. In agreement with that observation, we could not detect Ag-driven clonal expansion and affinity maturation of B lymphocytes. Furthermore, ectopic lymphoid neogenesis is not directly associated with local production of anti-citrullinated protein Abs and rheumatoid factor in the rheumatoid joint. Therefore, we conclude that synovial lymphoid neogenesis is not a major determinant of these rheumatoid arthritis-specific autoantibody responses.

Du F, Wang L, Zhang Y, Jiang W, Sheng H, Cao Q, Wu J, Shen B, Shen T, Zhang JZ, Bao C, Li D, Li N. · Shanghai Institute of Immunology, Institute of Medical Sciences, Jiao Tong University School of Medicine, Shanghai, China. · Clin Immunol. · Pubmed #18501677 No free full text.

Abstract: Rheumatoid arthritis (RA) is characterized by persistent Th1 cell infiltration and production of inflammatory cytokines in the location of joint lesion. It is known that infiltrated Th1 cells in the synovial fluid (SF) of RA patients are resistant to apoptosis. Here we demonstrate that Th1 cells accumulated in patient SF expressed a high level of GADD45 beta (Growth Arrest and DNA Damage-inducible 45 beta) which further inhibited Th1 cell apoptosis. Interestingly, in vitro culture of T cells with SF from RA patients increased GADD45 beta expression in Th1 cells and inhibited their apoptosis. Silencing of GADD45 beta by RNAi abolished the anti-apoptotic effect of RA SF, which was accompanied by down-regulation of Bcl-2 and up-regulation of Bax. Further analysis showed that TNF-alpha and IL-12 in RA SF could stimulate GADD45 beta expression in Th1 cells and inhibit their apoptosis. Taken together, our results suggest a novel mechanism by which specific cytokines in the RA SF elevate GADD45 beta expression in local Th1 cells and subsequently leading to the enhanced T cell survival.

Gierse J, Nickols M, Leahy K, Warner J, Zhang Y, Cortes-Burgos L, Carter J, Seibert K, Masferrer J. · Pfizer Global Research and Development, 700 Chesterfield Village Parkway N., Chesterfield, Missouri 63198, United States. · Eur J Pharmacol. · Pubmed #18457826 No free full text.

Abstract: A new class of selective cyclooxygenase-2 (COX-2) inhibitors has been identified by high throughput screening. Structurally distinct from previously described selective COX-2 inhibitors, these benzopyrans contain a carboxylic acid function and CF3 functionality. The compound SC-75,416 is a representative of this class. A range if in vitro and in vivo tests were employed to characterize its potency and selectivity. Using human recombinant enzymes, this compound displays a concentration that provides 50% inhibition (IC50) of 0.25 microM for COX-2 and 49.6 microM for COX-1. A mutation of the side pocket residues in COX-2 to COX-1 had little effect on potency suggesting that these inhibitors bind in a unique manner in COX-2 distinct from COX-2 inhibiting diaryl heterocycles. Using rheumatoid arthritic synovial cells stimulated with interleukin-1beta (IL-1beta) and washed platelets the compound displayed IC50 of 3 nM and 400 nM respectively. Potency and selectivity was maintained but predictably right shifted in whole blood with IC50 of 1.4 microM for lipopolysaccharide (LPS) stimulated induction of COX-2 and >200 microM for inhibition of platelet thromboxane production. SC-75,416 is 89% bioavailable and its in vivo half life is sufficient for once a day dosing. In the rat air pouch model of inflammation, the compound inhibited PGE2 production with an effective dose that provides 50% inhibition (ED50) of 0.4 mg/kg, while sparing gastric prostaglandin E2 (PGE2) production with an ED50 of 26.5 mg/kg. In a model of acute inflammation and pain caused by carrageenan injection into the rat paw, the compound reduced edema and hyperalgesia with ED50s of 2.7 and 4 mg/kg respectively. In a chronic model of arthritis the compound demonstrated an ED50 of 0.081 mg/kg and an ED(80) of 0.38 mg/kg. In a model of neuropathic pain, SC-75,416 had good efficacy. This compound's unique chemical structure and effect on COX enzyme binding and activity as well as its potency and selectivity may prove useful in treating pain and inflammation.

Xue X, Feng G, Li M, Qin X, Wu S, Zhang C, You Y, Wang W, Jiang C, Liu Y, Zhu W, Ran Y, Zhang Z, Yan Z, Han W, Zhang Y. · Biotechnology Center of The Fourth Military Medical University, 17 Changle West Road, 710032 Xi'an, People's Republic of China. · Vaccine. · Pubmed #18440104 No free full text.

Abstract: The B-lymphocyte stimulator (BLyS) is implicated in various pathophysiological processes. The overexpression of BLyS has been observed in some human diseases, including systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, and multiple sclerosis. This feature suggests that BLyS may be a therapeutic target for some human autoimmune diseases. We developed a therapeutic vaccine by coupling a tetanus toxoid T-helper cell epitope with the C-terminal of BLyS (TT-BLyS). This vaccine can induce high titers of neutralizing antibodies against BLyS in an animal model; the antibody has markedly protective effects on experimental autoimmune encephalomyelitis in rats, which is induced by inoculation of spinal cord homogenate. Our data suggest that the BLyS autovaccine may be a useful candidate for the treatment of some autoimmune diseases associated with the production of BLyS.

Zhang Y, Guo F, Jiang C. · National Laboratory of Medical Molecular Biology, Dept. of Biochemistry & Molecular Biology, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 5 dongdansantiao, Beijing, Peoples Republic of China. · J Drug Target. · Pubmed #18172821 No free full text.

Abstract: AIM: To discover compounds or proteins that can efficiently bind the glucocorticoid receptor (GR) and trigger the transcription of target genes, resulting in clinical improvement of diseases such as rheumatoid arthritis, asthma, inflammatory bowel disease, a high-throughput drug screening cell model using green fluorescent protein 4 (GFP4) as a marker expressed in response to GR activation has been established and evaluated. METHODS: Eight repeats of the glucocorticoid response element (GRE) were cloned into the Peak12SxSynGFP4 vector, and the resulting recombinant plasmid Peak12GRE8 x SxSynGFP4 was stably transfected into the 293E cells. The stable and sensitive cell line 293E/GRE8 x /GFP4 was selected by dexamethasone (DEX) using fluorescent microscopy and fluorescence-activated cell sorting. DEX induction and phorbol myristate acetate (PMA) inhibition of the green fluorescence intensity of the cell line were tested. RESULTS: The expression of GFP4 in the cell line was under the control of GRE, up-regulated by DEX treatment and down-regulated by phorbol myristate acetate (PMA). The up-regulation of the GFP4 expression was DEX concentration-dependent, with an EC(50) at approximately 5 x 10(- 8) M. The down-regulation of the GFP4 expression was phorbol myristate acetate (PMA) concentration-dependent, with an IC(50) at approximately 3 x 10(- 6) gl - 1. The expression of GFP4 was effectively activated when cells were treated with triamcinolone acetonide. CONCLUSION: This drug screening cell line can be used for GR-targeted high-throughput drug screening for the treatment of inflammatory diseases.

Krueger K, Lino L, Dore R, Radominski S, Zhang Y, Kaur A, Simpson R, Curtis S. · Praxiszentrum St. Bonifatius, Munchen, Germany. · Ann Rheum Dis. · Pubmed #17965424 No free full text.

Abstract: OBJECTIVE: A randomised, double-blind study to compare the gastrointestinal (GI) tolerability, safety and efficacy of etoricoxib and diclofenac in patients with rheumatoid arthritis (RA). PATIENTS AND METHODS: A total of 4086 patients (mean age 60.8 years) diagnosed with RA were enrolled and received etoricoxib 90 mg daily (n = 2032) or diclofenac 75 mg twice daily (n = 2054). Use of gastroprotective agents and low-dose aspirin was allowed. The prespecified primary end point consisted of the cumulative rate of patient discontinuations due to clinical and laboratory GI adverse experiences (AEs). General safety was also assessed, including adjudicated thrombotic cardiovascular event data. Efficacy was evaluated using the Patient Global Assessment of Disease Status (PGADS; 0-4 point scale). RESULTS: Mean (SD; maximum) duration of treatment was 19.3 (10.3; 32.9) and 19.1 (10.4; 33.1) months in the etoricoxib and diclofenac groups, respectively. The cumulative discontinuation rate due to GI AEs was significantly lower with etoricoxib than diclofenac (5.2 vs 8.5 events per 100 patient-years, respectively; hazard ratio 0.62 (95% CI: 0.47, 0.81; p<or=0.001)). The incidence of discontinuations for hypertension-related and oedema-related AEs were significantly higher with etoricoxib (2.5% and 1.1% respectively) compared with diclofenac (1.5% and 0.4% respectively; p<0.001 for hypertension and p<0.01 for oedema). Etoricoxib and diclofenac treatment resulted in similar efficacy (PGADS mean changes from baseline -0.62 vs -0.58, respectively). CONCLUSIONS: Etoricoxib 90 mg demonstrated a significantly lower risk for discontinuing treatment due to GI AEs compared with diclofenac 150 mg. Discontinuations from renovascular AEs, although less common than discontinuations from GI AEs, were significantly higher with etoricoxib.

Wu R, Shovman O, Zhang Y, Gilburd B, Zandman-Goddard G, Shoenfeld Y. · Pathway Diagnostics Inc., Malibu, CA, USA. · Clin Rev Allergy Immunol. · Pubmed #17426360 No free full text.

Abstract: To investigate the prevalence of anti-third generation cyclic citrullinated peptide antibodies (anti-CCP3) in patients with systemic connective tissue diseases, we assembled a training set consisting of 115 patients with rheumatoid arthritis (RA), 52 with Calcinosis, Raynaud's phenomenon, oesophageal dysmotility, sclerodactyly, telangiectasia (CREST) syndrome, 21 with scleroderma, 20 with ankylosing spondylitis, 18 with reactive arthritis, 25 with juvenile rheumatoid arthritis (RA), 51 with osteoarthritis, 26 with mixed connective tissue disease, 23 with primary Sjogren's syndrome, 74 with systemic lupus erythematosus, 49 with Polymyalgia rheumatica, and 39 with polymyositis/dermatomyositis. The commercial enzyme-linked immunosorbent assay (ELISA) was used to detect anti-CCP antibodies, including anti-CCP2 (regular, second generation of CCP antigen) and anti-CCP3 (third generation of CCP antigen) in disease-related specimens and normal controls. These serum samples were also evaluated for anti-centomere antibodies by anti-centromere ELISA kit. The higher frequencies of anti-CCP3 and anti-CCP2 were detected in 75.6 and 70.4% patients with RA, respectively. At the same time, anti-CCP3 (not anti-CCP2) was significantly increased in samples isolated from patients with CREST syndrome. The clinical sensitivity of IgG anti-CCP3 for the patients with CREST syndrome was 29% (15 of 52) and the specificity was 96% (384 of 397), with the exception of the RA group. The anti-centromere antibodies were significantly higher in patients with CREST only. The results of our study suggest that compared to anti-CCP2 assay, the new anti-CCP3 assay can enhance the clinical sensitivity for diagnosis of RA and, as an associate marker combined with anticentromere, can distinguish CREST syndrome from other systemic connective tissue diseases, especially RA. The clinical specificity of anti-CCP3 was lower than anti-CCP2 assay in diagnosis of RA because of the crossreaction to the patients with CREST syndrome.

Wang Q, Zhang Y, Hall JP, Lin LL, Raut U, Mollova N, Green N, Cuozzo J, Chesley S, Xu X, Levin JI, Patel VS. · Department of Discovery Pharmacokinetics, Wyeth Research, 1 Burtt Road, Andover, MA 01810, USA. <> · J Pharmacol Toxicol Methods. · Pubmed #17391989 No free full text.

Abstract: INTRODUCTION: Tumor necrosis factor-alpha (TNFalpha) participates in many inflammatory processes. TNFalpha modulators show beneficial effects for the treatment of many diseases including rheumatoid arthritis. The purpose of this study was to validate a rat pharmacokinetic/pharmacodynamic (PK/PD) model for rapid assessment of drug candidates that intended to interrupt TNFalpha synthesis or release. METHODS: Rats received intravenous (IV) or oral administrations of test article or dose vehicle, followed by LPS challenge. Plasma levels of test article and TNFalpha were determined. The areas under the concentration-time curves (AUC(drug) and AUC(TNFalpha)) were calculated. The overall percentage of inhibition on TNFalpha release in vivo was calculated by comparing AUC(TNFalpha) of the test article treated group against that for the vehicle control group. RESULTS: The dosing vehicles tested in this study did not increase plasma TNFalpha level. At IV dose of up to 100 microg/kg, LPS did not alter the pharmacokinetics of the compound tested. Using a selective TNFalpha converting enzyme (TACE) inhibitor as model compound, this PK/PD model demonstrated its ability to correlate plasma test article concentration with its biological activity of lowering the LPS-induced TNFalpha plasma levels in vivo. DISCUSSION: A rat PK/PD model for evaluation of the effect of drug candidates on LPS-induced TNFalpha synthesis and/or release has been investigated. This model provides integrated information on pharmacokinetics and in vivo potency of the test articles.

Zhu L, Ji F, Wang Y, Zhang Y, Liu Q, Zhang JZ, Matsushima K, Cao Q, Zhang Y. · Joint Immunology Laboratory, Institute of Health Sciences and Shanghai Institute of Immunology, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, 225 South Chongqing Road, Shanghai 200225, China. · J Immunol. · Pubmed #17114500 links to  free full text

Abstract: A hallmark of T cell-mediated autoimmunity is the persistence of autoreactive T cells. However, it remains to elucidate the manner in which synovial T cells are sustained in patients with rheumatoid arthritis (RA). We found that dendritic cells (DC) and tissues from the synovial joints of RA patients expressed higher levels of IDO than DC from healthy donors. Interestingly, T cells derived from the joint synovial fluid (SF) of RA patients proliferated in response to either autologous or allogeneic IDO-positive DC, an outcome that was not affected by the addition of IDO inhibitor 1-methyl-D-tryptophan (1-MT). In contrast, addition of 1-MT to the culture stimulated with allogeneic or autologous IDO-positive DC significantly enhanced the proliferation of T cells derived from peripheral blood of healthy donors or from peripheral blood of RA patients. Furthermore, we found that functionally active tryptophanyl-tRNA-synthetase (TTS) was significantly elevated in T cells derived from the SF of RA patients, leading to enhanced storage of tryptophan in T cells and to subsequent resistance to IDO-mediated deprivation of tryptophan. The RA SF enhancement of TTS expression in T cells was blocked by mAb to IFN-gamma and TNF-alpha. These results suggest that the resistance of T cells to IDO-mediated deprivation of tryptophan represents a mechanism by which autoreactive T cells are sustained in vivo in RA patients. Specifically, blocking of the up-regulation of TTS expression in T cells presents an avenue for development of a novel therapeutic approach to treatment of RA.

Zhu L, Ji F, Wang Y, Zhang Y, Liu Q, Zhang JZ, Matsushima K, Cao Q, Zhang Y. · Joint Immunology Laboratory, Institute of Health Sciences and Shanghai Institute of Immunology, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, 225 South Chongqing Road, Shanghai 200225, China. · J Immunol. · Pubmed #17114500 links to  free full text

Abstract: A hallmark of T cell-mediated autoimmunity is the persistence of autoreactive T cells. However, it remains to elucidate the manner in which synovial T cells are sustained in patients with rheumatoid arthritis (RA). We found that dendritic cells (DC) and tissues from the synovial joints of RA patients expressed higher levels of IDO than DC from healthy donors. Interestingly, T cells derived from the joint synovial fluid (SF) of RA patients proliferated in response to either autologous or allogeneic IDO-positive DC, an outcome that was not affected by the addition of IDO inhibitor 1-methyl-D-tryptophan (1-MT). In contrast, addition of 1-MT to the culture stimulated with allogeneic or autologous IDO-positive DC significantly enhanced the proliferation of T cells derived from peripheral blood of healthy donors or from peripheral blood of RA patients. Furthermore, we found that functionally active tryptophanyl-tRNA-synthetase (TTS) was significantly elevated in T cells derived from the SF of RA patients, leading to enhanced storage of tryptophan in T cells and to subsequent resistance to IDO-mediated deprivation of tryptophan. The RA SF enhancement of TTS expression in T cells was blocked by mAb to IFN-gamma and TNF-alpha. These results suggest that the resistance of T cells to IDO-mediated deprivation of tryptophan represents a mechanism by which autoreactive T cells are sustained in vivo in RA patients. Specifically, blocking of the up-regulation of TTS expression in T cells presents an avenue for development of a novel therapeutic approach to treatment of RA.

Zhou X, Zhao X, Tang L, Zhang Y, Ruan H, Pi H, Qiu J, Wu J. · Faculty of Pharmaceutical Sciences, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. · J Ethnopharmacol. · Pubmed #17113740 No free full text.

Abstract: Impatiens pritzellii Hook. f. var. hupehensis Hook. f. (Balsaminaceae) has been well-known and widely used in China as an anti-rheumatoid arthritis (anti-RA) herb. In this present study, mice with collagen-induced arthritis (CIA) have been treated with the methanol (MeOH) extract (0.56, 1.12, 1.68 and 2.24 g/kg body weight) and the n-butanol (BuOH) fraction (0.13, 0.27, 0.40 and 0.53 g/kg body weight) of the rhizomes of Impatiens pritzellii orally for 3 weeks. The progression of CIA was evaluated by macroscopic scoring. Administration of the MeOH extract at dose of 1.12 g/kg and the BuOH fraction at 0.53 g/kg suppressed the development of CIA in mice significantly. The spleen and thymus indexes were measured and the levels of IgG, IL-10, INF-gamma and IL-18 in the serum of CIA mice were examined after the treatment of the MeOH extract (1.12 and 1.68 g/kg body weight) and the BuOH fraction (0.40 and 0.53 g/kg body weight). Administration of the MeOH extract and the BuOH fraction of Impatiens pritzellii decreased the spleen and thymus indexes, down-regulated the levels of IgG, INF-gamma, IL-18, and up-regulated the concentration of IL-10 in the serum of mice with CIA. From the results, it was concluded that administration of Impatiens pritzellii had obviously therapeutic effects on RA including immunomodulatory activity. Moreover, the BuOH fraction exerted the activity of anti-RA of Impatiens pritzellii.

Li H, Luo W, Zeng Q, Lin Z, Luo H, Zhang Y. · Shantou University Medical College, Central Laboratory, Shantou, Guangdong 515041, China. · J Chromatogr B Analyt Technol Biomed Life Sci. · Pubmed #16890029 No free full text.

Abstract: Methotrexate (MTX) has been widely used at low dose for the treatment of different diseases including rheumatoid arthritis. MTX might be present in plasma in free form, and in blood cells in methotrexate polyglutamate (MTXPG). A rapid and sensitive HPLC method was developed for the determination of plasma MTX level, whole-blood MTX level, and whole-blood total MTX (MTX+MTXPG) level. To determine plasma MTX level or whole-blood MTX level, a 0.2-ml aliquot of plasma or whole blood (after a freeze-thaw cycle to break blood cells) was well mixed with 0.8 ml methanol and centrifuged. To determine whole-blood total MTX level, a 0.1-ml aliquot of whole blood (after a freeze-thaw cycle) was mixed with 80 microl ascorbic acid (114 mM) and incubated at 37 degrees C for 2h to enzymatically convert the MTXPG to MTX. Then 20 microl NaOH solution (0.5M) and 0.8 ml methanol were added and mixed well. After centrifugation, a 0.5-ml aliquot of the supernatant was evaporated to dryness and re-dissolved in 0.2 ml hydrochloric acid (10mM). Methylene chloride (0.2 ml) was added and mixed well. After centrifugation, the top aqueous layer was injected to HPLC for analysis. After the MTX was eluted from the HPLC column, it was electrochemically oxidized and detected by a fluorescence detector. Recoveries of spiked MTX at ppb (ng/ml) level were between 87.9 and 118% with within-day relative standard deviation less than 5.2% and day-to-day relative standard deviation less than 9.8%. The limit of detection (LOD) and limit of quantitation (LOQ) of the described method were 1.2 and 2.6 ng/ml, respectively.

Wang XY, Zhang Y, Xu JY, Qiu DW, Huang LQ. · Institute of Chinese Materia Medica, China Academy of Chinese Medical Science, Beijing. · Zhongguo Zhong Yao Za Zhi. · Pubmed #16711432 No free full text.

Abstract: OBJECTIVE: To observe the antiarthritic effects and the possible mechanism of total saponins of Psammruosilene tunicoids (TSPT) against rheumatoid arthritis (RA). METHOD: After establishing AA rat model, the TSPT'S antiarthritic effects and mechanism against RA were studied through observing the changes of ankle swelling, arthritis index and levels of IL-1beta and TNF-alpha after medication. RESULT: TSPT could effectively inhibits articular swelling, decrease arthritis index and regulate down the content of IL-1beta and TNF-alpha in the inflammatory tissue soak of AA rats. CONCLUSION: TSPT has good antiarthritic effects and the possible mechanism may be related to its down-regulation of IL-1beta and TNF-alpha.

Chen L, Wang H, Zhao Z, Zhang Y, Huang G. · Department of Forensic Medicine and Pathology, Shanghai Medical Center, Fudan University, Shanghai 200032, China. · Am J Chin Med. · Pubmed #16355451 No free full text.

Abstract: In China, the ethylacetate extract of the herb Tripterygium wilfordii Hook f (TWEE), containing the major active ingredient triptolide, is often used with favorable effect on rheumatoid arthritis patients, in alternation with the use of prednisone. The mechanism of this therapeutic effect, however, has not been completely delineated. In this study, we studied how TWEE and prednisone affect the pituitary and adrenal glands in rats. Thirty normal male Sprague-Dawley rats (ten per group) were randomly assigned to receive: (1) TWEE (25 mg/kg, twice a day), (2) prednisone (2 mg/kg, twice a day), or (3) vehicle (control) (0.5% sodium carboxymethyl cellulose 1 ml, twice a day), orally for 30 days. Pituitary and trunk blood were collected on day 31. Adrenocorticotropic hormone (ACTH) expression in the pituitary gland was assessed morphologically by immunohistochemical techniques. Plasma ACTH concentrations and serum corticosterone concentrations were quantitatively measured by radioimmunoassay. We found that TWEE significantly increased plasma ACTH concentration and serum corticosterone concentration and dramatically increased the number of ACTH-positive cells in the pituitary. Our findings indicate that TWEE can promote the synthesis and secretion of ACTH cells--in the pars distalis of the rat pituitary gland and the production of corticosterone in the zone fasciculata of the adrenal cortex. Our results indicate that TWEE has a cortical hormone-like function and can promote adrenal cortex function by activating the hypothalamus-pituitary-adrenal axis.

Zhang Y, Huang W, Zhong B. · Department of Vertebra Disease, Zhuhai Municipal People's Hospital, Zhuhai Guangdong 519000, P R China. · Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. · Pubmed #16130385 No free full text.

Abstract: OBJECTIVE: To investigate the clinical application and curative effect of isoionic microtrauma arthroscope on treatment of knee arthropathy. METHODS: From May 2003 to November 2004, 52 cases of knee joint injury were cured by using isoionic microtrauma arthroscope, including 30 cases of knee osteoarthritis, 10 cases of meniscus injury, 5 cases of knee-cap dislocation, 5 cases of laxity of anterior cruciate ligation and 2 cases of rheumatoid arthritis. In accordance with Lysholm criterion for knee joint function, the scores were 35.5 +/- 4.9 before operation. RESULTS: All of these patients were followed up for 2-17 months. The scores of knee joint function was 86.4 +/- 5.3 after operation, and there was significant difference (P < 0.001). CONCLUSION: Isoionic microtrauma arthroscope is characterized by low-temperature hemoagglutination, crimping, boiling, cutting and hemostasis, which makes knee joint arthroscope operation easier-to-do, miner histological scathe and lighter side effect; so it is favourable for functional recovery and its curative effect is satisfactory.

Wu HX, Zhang Y, Zhu YL. · Department of Rheumatology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China. · Zhonghua Yi Xue Za Zhi. · Pubmed #15949333 No free full text.

Abstract: OBJECTIVE: To explore the role of several chemokines in rheumatoid arthritis (RA) and their clinical significance. METHOD: ELISA was used to detect the serum levels of interleukin (IL)-8, interferon-gamma inducible protein (IP)-10, and RANTES in 58 active RA patients, 29 clinically remissive RA patients, 21 osteoarthritis (OA) patients, and 30 healthy volunteers. Clinical data of these patients were compared between different groups. RESULTS: The serum levels of IL-8, IP-10 and RANTES in the active RA patients were significantly higher than those of the healthy controls and OA patients. The serum level of IP-10 of the active patients was higher than that of the clinically remissive patients. The index IL-8/IP-10 x RANTES/IP-10 of the active patients was higher than that of the healthy controls (P = 0.01). The serum RANTES level was positively correlated with erythrocyte sedimentation rate, C-reactive protein, platelet count, and numbers of swollen joints, and was negatively correlated with the hemoglobin level. The serum level of IP-10 was negatively correlated with X-ray image grade of hand and wrist joints. CONCLUSION: The serum levels of IL-8, IP-10 and RANTES significantly increase in active RA. The level of RANTES may be a useful additional marker for disease activity and the level of IP-10 can be used as an index of prognosis.

Zhang Y, Hegen M, Xu J, Keith JC, Jin G, Du X, Cummons T, Sheppard BJ, Sun L, Zhu Y, Rao VR, Wang Q, Xu W, Cowling R, Nickerson-Nutter CL, Gibbons J, Skotnicki J, Lin LL, Levin J. · Department of Inflammation, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA. · Int Immunopharmacol. · Pubmed #15531300 No free full text.

Abstract: TNF-alpha converting enzyme (TACE) is a validated therapeutic target for the development of oral tumor necrosis factor-alpha (TNF-alpha) inhibitors. Here we report the pre-clinical results and characterization of a selective and potent TACE inhibitor, (2R, 3S)-2-([[4-(2-butynyloxy)phenyl]sulfonyl]amino)-N,3-dihydroxybutanamide (TMI-2), in various in vitro and in vivo assays. TMI-2 is a potent TACE inhibitor in an enzymatic FRET assay (IC50=2 nM). It is more than 250-fold selective over MMP-1, -7, -9, -14, and ADAM-10 in vitro. In cell-based assays and human whole blood, TMI-2 inhibits lipopolysaccharide (LPS)-induced TNF secretion with IC50s<1 uM. Importantly, TMI-2 inhibits the spontaneous release of TNF-alpha in human synovium tissue explants of rheumatoid arthritis patients with an IC50 of 0.8 microM. In vivo, TMI-2 potently inhibits LPS-induced TNF-alpha production in mice (ED50=3 mg/kg). In the adjuvant-induced arthritis (AIA) model in rats, treatment with TMI-2 at 30 mg/kg and 100 mg/kg p.o. b.i.d. was highly effective in reducing joint arthritis scores. In a semi-therapeutic collagen-induced arthritis (CIA) model in mice, TMI-2 is highly effective in reducing disease severity scores after oral treatment at 100 mg/kg twice per day. In summary, TMI-2 is a potent and selective TACE inhibitor that inhibits TNF-alpha production and reduces the arthritis scores in pre-clinical models. TMI-2 represents a novel class of TACE inhibitors that may be effective and beneficial in the treatment of rheumatoid arthritis as well as other TNF-mediated inflammatory autoimmune diseases.