Rheumatoid Arthritis: Liu L

Xu M, Liu L, Qi C, Deng B, Cai X. · School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region, PR China. · Planta Med. · Pubmed #18683125 No free full text.

Abstract: Sinomenine (SIN), an alkaloid isolated from CAULIS SINOMENII, has been used in the treatment of rheumatoid arthritis (RA) clinically. This study aimed to systematically evaluate the efficacy and safety of SIN by a comparison between SIN and non-steroidal anti-inflammatory drugs (NSAIDs). Forty-three electronic databases were systematically searched. The quality of eligible trials was assessed by Jadad's scale. Revman 5.0 software was used for data syntheses and meta-analyses. The results showed that (i) of the 121 potential studies identified, 10 clinical trials involving 1185 patients met the inclusion criteria; (ii) improved patients and rheumatoid factor disappearance patients after SIN treatments were significantly more than those treated by NSAIDs ( P < 0.00001 and P = 0.008); (iii) compared with NSAIDs, SIN was more effective in amelioration of morning stiffness ( P < 0.00001), painful joints ( P = 0.03), and erythrocyte sedimentation rate ( P < 0.00001), but there was no significant difference between the two remedies in the treatment of swollen joints, grip strength, and C-reactive protein ( P > 0.05); and (iv) adverse events occurred less frequently in the digestive system during SIN treatment than during NSAID treatment ( P = 0.0003) but occurred more frequently in the dermatomucosal system with SIN treatment ( P = 0.03), while adverse events of the nervous system were similar for both treatments ( P = 0.31). In conclusion, SIN may be a valuable remedy to treat RA clinically, although current evidence needs to be further verified by more high-quality trials.

Huang GZ, Li L, Liu L. · Department of Forensic Pathology, Tongji Medical College of Huazhong University of Sciences and Technology, Wuhan. · Zhongguo Zhong Xi Yi Jie He Za Zhi. · Pubmed #19382482 No free full text.

Abstract: The Tripterygium preparation, a Chinese herbal medicine, has been widely used to treat various autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Its significant clinical effects have received a great praise and attention by the public health in China, but its toxicity also definitely exists, with the therapeutic dosage approaching the minimal toxic dosage. In order to provide reference for the safe use of Tripterygium preparation in clinical practice, the pathological changes of 4 autopsy cases by Tripterygium poisoning were reported in this paper. In them, 2 cases died of acute cardiogenic shock caused by myocardial damage, showing hydropic degeneration of the myocardial cells, even with obvious contraction band necrosis in the papillary muscles; the other 2 died of severe acute renal failure due to severe acute toxic nephrosis; cerebral edema and gastrointestinal inflammatory changes were found in all cases. The authors suggested that careful dosage control is the key step to prevent Tripterygium intoxication during the medical treatments; directly using the crude Tripterygium in clinics should be prohibited; and the Tripterygium preparation used should be produced by the pharmaceutical companies regulated by the government.

Zhou H, Wong YF, Wang J, Cai X, Liu L. · School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon Tong, Hong Kong, China. · Biochem Biophys Res Commun. · Pubmed #18782565 No free full text.

Abstract: Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease that results in progressive joint destruction and substantial morbidity. The stem of the Chinese medicinal plant, Sinomenium acutum Rehder & Wilson (Family Menispermaceae), has been used to treat various rheumatic and arthritic diseases, of which the major bioactive component is sinomenine. We investigated the nature and molecular mechanisms of the anti-arthritic effect of sinomenine on collagen-induced arthritis in female Wistar rats. The results showed that sinomenine markedly suppressed the incidence and disease progression of established CIA, showing as dramatic reduction of paw swelling, ESR, and arthritic scores. Sinomenine suppressed the production of proinflammatory cytokines IL-1beta and IL-6 in serum, inhibited the protein expressions and activities of MMP-2 and MMP-9, and elevated the protein expressions and activities of TIMP-1 and TIMP-3 in rat paw tissues.

Jung J, Zhong M, Liu L, Fan R. · Department of Medical and Molecular Genetics, Indiana University, School of Medicine, Indianapolis, Indiana, USA. · Genet Epidemiol. · Pubmed #18278817 No free full text.

Abstract: In this paper, bivariate/multivariate variance component models are proposed for high-resolution combined linkage and association mapping of quantitative trait loci (QTL), based on combinations of pedigree and population data. Suppose that a quantitative trait locus is located in a chromosome region that exerts pleiotropic effects on multiple quantitative traits. In the region, multiple markers such as single nucleotide polymorphisms are typed. Two regression models, "genotype effect model" and "additive effect model", are proposed to model the association between the markers and the trait locus. The linkage information, i.e., recombination fractions between the QTL and the markers, is modeled in the variance and covariance matrix. By analytical formulae, we show that the "genotype effect model" can be used to model the additive and dominant effects simultaneously; the "additive effect model" only takes care of additive effect. Based on the two models, F-test statistics are proposed to test association between the QTL and markers. By analytical power analysis, we show that bivariate models can be more powerful than univariate models. For moderate-sized samples, the proposed models lead to correct type I error rates; and so the models are reasonably robust. As a practical example, the method is applied to analyze the genetic inheritance of rheumatoid arthritis for the data of The North American Rheumatoid Arthritis Consortium, Problem 2, Genetic Analysis Workshop 15, which confirms the advantage of the proposed bivariate models.

Yang Q, Biernacka JM, Chen MH, Houwing-Duistermaat JJ, Bergemann TL, Basu S, Fan R, Liu L, Bourgey M, Clerget-Darpoux F, Lin WY, Elston RC, Cupples LA, Apprey V, Cui J, Dupuis J, Ionita-Laza I, Li R, Lou X, Perdry H, Sherva R, Shugart YY, Suarez B, Wang H, Wormald H, Xing G, Xing C. · Department of Biostatistics, Boston University School of Public Health, 715 Albany Street, Boston, MA 02118, USA. · Genet Epidemiol. · Pubmed #18046758 No free full text.

Abstract: Group 4 at Genetic Analysis Workshop 15 focused on methods that exploited both linkage and association information to map disease loci. All contributions considered the dichotomous trait of rheumatoid arthritis, using either affected sibpairs and/or unrelated controls. While one contribution investigated linkage and association approaches separately in genome-wide analyses, the remaining others focused on joint linkage and association methods in specific genomic regions. The latter contributions proposed new methods and/or examined existing methods that addressed whether one or more polymorphisms partially or fully explained a linkage signal, particularly the methods proposed by Li et al. that are implemented in the computer program Linkage and Association Modeling in Pedigrees (LAMP). Using simulated SNP data under linkage peaks, several contributions found that existing family-based association approaches such as those of Martin et al. and Lake et al. had power similar to LAMP and to several methods proposed by the contributors for testing that a single nucleotide polymorphism partially explains a linkage peak. In evaluating methods for identifying if a polymorphism or a set of polymorphisms fully accounted for a linkage signal, several contributions found that it was important to understand that these methods may be subject to low power in some situations and thus, a non-significant result was not necessarily indicative of the polymorphism(s) being fully responsible for the linkage signal. Finally, modeling the disease using association evidence conditional on linkage may improve understanding of the etiology of disease.

Weng X, Liu L, Barcellos LF, Allison JE, Herrinton LJ. · Division of Research, Kaiser Permanente, Oakland, California 94612, USA. · Am J Gastroenterol. · Pubmed #17437504 No free full text.

Abstract: BACKGROUND AND AIMS: Previous studies provide evidence that some immune-mediated diseases occur at greater frequency among inflammatory bowel disease (IBD) patients than in the general population. The present study examined the co-occurrence of IBD with common immune-mediated disorders including asthma, psoriasis, type 1 diabetes, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, vitiligo, autoimmune thyroiditis (Grave's and Hashimoto's), and chronic glomerulonephritis. METHODS: We conducted a cross-sectional study among members of the Kaiser Permanente Medical Care Program for the period 1996-2005. A total of 12,601 patients with at least two IBD diagnoses in computerized visit data were ascertained. Four persons without IBD were matched to each IBD patient on age, gender, and length of enrollment. Information on co-occurring diseases was obtained from computerized visit data for 1996-2005. Conditional logistic regression was used to estimate the odds ratio and 95% confidence interval for the association of IBD with immune-mediated disorders after adjusting for smoking. RESULTS: Seventeen percent of the IBD patients and 10% of the persons without IBD had a diagnosis for at least one immune-mediated disease. IBD patients were more likely to have asthma (1.5, 95% CI 1.4-1.6), psoriasis (1.7, 95% CI 1.5-2.0), rheumatoid arthritis (1.9, 95% CI 1.5-2.3), and multiple sclerosis (2.3, 95% CI 1.6-3.3). CONCLUSIONS: Among the immune-mediated diseases we studied, most were more common in IBD patients than in persons without IBD, suggesting that IBD shares common etiologic factors with other immune-mediated diseases.

Zhang FC, Liu L, Xu D. · Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China. · Zhonghua Yi Xue Za Zhi. · Pubmed #17403303 No free full text.

Abstract: OBJECTIVE: To investigate the correlation of anti-60 000 SSA antibody and anti-52 000 SSA antibody with systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS). METHODS: Western blotting against purified 60 000 SSA antigenic polypeptide and 52 000 SSA antigenic polypeptide were done to detect the anti-60 000 SSA and anti-52 000 SSA antibodies in 59 serum samples positive in anti-SSA antibodies, among which 44 samples were from SLE patients and 15 samples from SS patients. RESULT: There was no significant difference in positive rate of anti-60 000 SSA antibodies between the SLE and pSS patients (P > 0.05). But the sole positive rate of anti-60 000 SSA antibodies of the SLA patients was 39.47% (15/38), significantly higher than that of the primary SS (pSS) patients ((6.67%, 1/15, P < 0.05). The positive rate of anti-52 000 SSA antibodies of the pSS patients was 93.33% (14/15), significantly higher than that of the SLE patients (23/38, 60.53%, P < 0.05). There was no significant differences in positive rates of anti-60 000 SSA antibodies and anti-52 000 SSA antibodies between the secondary SS (sSS) and pSS patients (P > 0.05). CONCLUSION: The pSS patients mainly present anti-52 000 antibodies and with a very low sole anti-60 000 SSA antibody positive rate. Sole positivity of anti-52 000 SSA antibodies maybe correlated with pSS and is not a strong implication for the diagnosis of sSS. Sole positive anti-60000 SSA antibodies rate can be seen mainly in SLE.

Cai X, Zhou H, Wong YF, Xie Y, Liu ZQ, Jiang ZH, Bian ZX, Xu HX, Liu L. · Research and Development Division, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Kowloon, Hong Kong, China. · J Ethnopharmacol. · Pubmed #17049776 No free full text.

Abstract: QFGJS is an herbal preparation, and its pronounced effectiveness in treating adjuvant-induced arthritis (AIA) has been previously demonstrated. We herein aimed to confirm its anti-arthritic effect on collagen-induced arthritis (CIA) in rats. CIA was established in female Wistar rats with intradermal injection of type II bovine collagen at the base of the tail of animals. CIA rats were treated daily with oral administration of different doses of QFGJS beginning on the day of the induction of arthritis (day 0, the prophylactic treatment) or on the day after the onset of arthritis (day 13, the therapeutic treatment) until day 30. The results showed that prophylactic treatment with QFGJS significantly suppressed the onset of arthritis, and therapeutic treatment with QFGJS markedly reduced paw swelling and ESR levels even in the established CIA. Radiologic and histopathologic changes in the arthritic joints were also significantly reduced in the QFGJS-treated versus vehicle-treated rats. Moreover, the serum levels of pro-inflammatory cytokines TNF-alpha, IL-1beta, and IL-6 were markedly lowered in the QFGJS-treated rats. Hence, our studies demonstrate the quality, safety, and effectiveness of QFGJS as an anti-arthritic agent, which makes QFGJS a strong candidate for further clinical trials on rheumatoid arthritis (RA) patients.

Cai X, Zhou H, Wong YF, Xie Y, Liu ZQ, Jiang ZH, Bian ZX, Xu HX, Liu L. · Research and Development Division, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, China. · Biochem Biophys Res Commun. · Pubmed #16199007 No free full text.

Abstract: To analyze the anti-arthritic effects of QFGJS (a pharmaceutical preparation from herbs) on rheumatoid arthritis, adjuvant-induced arthritis (AIA) was established in male SD rats, and two administration protocols, i.e., oral treatment with different doses of QFGJS on the day of arthritis induction or on the day when visible clinical signs of arthritis occurred, were initiated and continued until day 30. Treatments with QFGJS using both administration protocols significantly suppressed the incidence and severity of arthritis in a dose-dependent manner, showing dramatic reduction of paw swelling and ESR throughout the disease progression of AIA. Radiological and histopathological examinations showed markedly decreased tissue and bone destruction of ankle joints in the QFGJS-treated rats. The serum levels of TNF-alpha, IL-1beta, and IL-6 were significantly decreased in the QFGJS-treated rats. QFGJS demonstrates pronounced anti-arthritic effects on AIA, indicating that this herbal preparation would be a potent candidate as a novel botanical drug for further investigation.

Wagner R, Mollison KW, Liu L, Henry CL, Rosenberg TA, Bamaung N, Tu N, Wiedeman PE, Or Y, Luly JR, Lane BC, Trevillyan J, Chen YW, Fey T, Hsieh G, Marsh K, Nuss M, Jacobson PB, Wilcox D, Carlson RP, Carter GW, Djuric SW. · Abbott Laboratories, Global Pharmaceutical Research and Development, Abbott Park, IL 60064, USA. · Bioorg Med Chem Lett. · Pubmed #16185865 No free full text.

Abstract: The synthesis and biological activities of rapamycin (I) analogs modified at the C-40 position are reported. Emphasis placed on compounds that potentially have an improved safety profile on account of their shorter in vivo half-life when compared with rapamycin.

Kok TW, Yue PY, Mak NK, Fan TP, Liu L, Wong RN. · Department of Biology, Science Faculty, Hong Kong Baptist University, Hong Kong. · Angiogenesis. · Pubmed #16132613 No free full text.

Abstract: Sinomenine is an alkaloid extracted from the Chinese medicinal plant, Sinomenium acutum, which has been utilized to treat rheumatoid arthritis (RA) in China for over 2000 years. Sinomenine has been shown to mediate a wide range of pharmacological actions which includes anti-inflammatory and anti-rheumatic effects. RA has been classified as a chronic immune-mediated disease that exhibits overlapping manifestation of inflammatory, abnormal cellular and hormonal immune responses with synovial hyperplasia. Since, angiogenesis is recognized to play a critical role in the development of RA and anti-angiogenic therapy has been proposed as a new therapeutic strategy for treatment of RA, we would like to see if sinomenine possesses anti-angiogenic property. In this study, sinomenine inhibited bFGF-induced proliferation of human umbilical vein endothelial cells (HUVEC) and arrested its cell cycle in G1 phase. Sinomenine disrupted tube formation of HUVEC on Matrigel and suppressed the chemotaxis of HUVEC. In addition, sinomenine reduced neovascularization in Matrigel plug assay as well as microvascular outgrowth in rat aorta ring sprouting assay. These results suggest that sinomenine inhibited bFGF-induced angiogenesis in vitro and in vivo. As the leukocytes-endothelial adhesive interactions also play an important role in inflammation, we found that sinomenine reduced the transmigration of granulocytic differentiated HL60 cells across IL-1beta activated HUVEC monolayer. Therefore, the inhibition of leukocytes migration across blood vessel walls and the anti-angiogenic effect of sinomenine may contribute towards its therapeutic mechanisms in alleviating the pathogenesis of RA.

Yang JH, Zhang J, Cai Q, Zhao DB, Wang J, Guo PE, Liu L, Han XH, Shen Q. · Department of Laboratory Diagnosis, Changhai Hospital, Second Military Medical University, 174 Changhai Road, Shanghai 200433, P. R. China. · Rheumatology (Oxford). · Pubmed #15987711 links to  free full text

Abstract: OBJECTIVE: To investigate the role of inducible costimulator (ICOS) in the pathogenesis of SLE, we assessed its expression on peripheral blood CD4 and CD8 T cells and functional roles in patients with systemic lupus erythematosus (SLE). METHODS: Expression of ICOS on peripheral blood CD4 and CD8 T cells and ICOS ligand (ICOSL) on peripheral blood CD19 B cells from patients with SLE, patients with rheumatoid arthritis (RA) and healthy volunteers were determined by two-colour flow cytometry. The functional costimulatory effects of ICOS on peripheral blood mononuclear cells (PBMC) were assessed by T-cell proliferative responses, cytokines, anti-double-stranded DNA (anti-dsDNA) antibody and total IgG production. RESULTS: Peripheral blood CD4 and CD8 T cells expressing ICOS were significantly increased in patients with SLE compared with patients with RA and healthy subjects. Peripheral blood CD19 B cells expressing ICOSL in SLE were markedly reduced compared with RA. Proliferative responses of anti-CD3/ICOS costimulation were significantly higher than those of anti-CD3/hamster IgG (HIgG) in healthy subjects, but not in patients with SLE. Anti-CD3/ICOS-stimulated SLE PBMC secreted similar levels of IL-10 and IFN-gamma but a significantly lower level of IL-2 than healthy PBMC. Anti-CD3/ICOS-mediated costimulation significantly enhanced the production of anti-dsDNA antibodies and total IgG in patients with SLE. CONCLUSION: Hyperexpression of ICOS on peripheral blood CD4 and CD8 T cells from patients with SLE contributed to the dysregulated T-cell proliferation, T-cell activation and pathogenic autoantibody production, which showed that the abnormality of ICOS costimulation may play an immunopathological role(s) in the pathogenesis of SLE.

Liu ZQ, Zhou H, Liu L, Jiang ZH, Wong YF, Xie Y, Cai X, Xu HX, Chan K. · School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Kowloon, Hong Kong, PR China. · J Ethnopharmacol. · Pubmed #15848021 No free full text.

Abstract: Paeonia lactiflora Pall. (Ranunculaceae) root and Sinomenium acutum Rehder and Wilson (Menispermaceae) stem are two herbs widely used in Chinese medicine to treat rheumatoid arthritis. While, in theory, either herb could be used alone, in practice, Chinese medicine practitioners prescribe them together. Studies on pharmacokinetic interaction between the active constituents of these two herbs (paeoniflorin and sinomenine, respectively) provide empirical evidence to support their clinical practice. A single dose of paeoniflorin (150 mg/kg) alone and with sinomenine hydrochloride (90 mg/kg) was administered by gastric gavage to unrestrained conscious male Sprague-Dawley rats (n=5 or 6, 240-270 [corrected] g). Blood samples were collected periodically via a jugular vein before and after dosing from 10 min to 12 h. A high-performance liquid chromatographic (HPLC) assay was developed to determine the plasma concentrations of paeoniflorin. Non-compartmental pharmacokinetic profiles were constructed by using the software PK Solutions 2.0. The pharmacokinetic parameters were compared using unpaired Student t-test. After co-administration of sinomenine, the peak plasma concentration of paeoniflorin was elevated (P<0.01), the peak time was delayed (P<0.01), the AUC(0-t) was increased (P<0.001), the mean residence time (MRT) was prolonged (P<0.01), the C(L) was decreased (P<0.01) and the V(d) was reduced (P<0.05). These results indicate that sinomenine hydrochloride at 90 mg/kg significantly improved the bioavailability of paeoniflorin in rats.

Shim GJ, Warner M, Kim HJ, Andersson S, Liu L, Ekman J, Imamov O, Jones ME, Simpson ER, Gustafsson JA. · Department of Biosciences, Karolinska Institute, Novum Research Park, S-141 57 Huddinge, Sweden. · Proc Natl Acad Sci U S A. · Pubmed #15314222 links to  free full text

Abstract: Sjögren's syndrome (SS) is an incurable, autoimmune exocrinopathy that predominantly affects females and whose pathogenesis remains unknown. Like rheumatoid arthritis, its severity increases after menopause, and estrogen deficiency has been implicated. We have reported that estrogen receptor-alpha and -beta-knockout mice develop autoimmune nephritis and myeloid leukemia, respectively, but neither develops SS. One model of estrogen deficiency in rodents is the aromatase-knockout (ArKO) mouse. In these animals, there is elevated B lymphopoiesis in bone marrow. We now report that ArKO mice develop severe autoimmune exocrinopathy resembling SS. By 1 year of age, there is B cell hyperplasia in the bone marrow, spleen, and blood of ArKO mice and spontaneous autoimmune manifestations such as proteinuria and severe leukocyte infiltration in the salivary glands and kidney. Also, as is typically found in human SS, there were proteolytic fragments of alpha-fodrin in the salivary glands and anti-alpha-fodrin antibodies in the serum of both female and male ArKO mice. When mice were raised on a phytoestrogen-free diet, there was a mild but significant incidence of infiltration of B lymphocytes in WT mice and severe destructive autoimmune lesions in ArKO mice. In age-matched WT mice fed a diet containing normal levels of phytoestrogen, there were no autoimmune lesions. These results reveal that estrogen deficiency results in a lymphoproliferative autoimmune disease resembling SS and suggest that estrogen might have clinical value in the prevention or treatment of this disease.

Li XJ, Chen GX, Liu L, Wang PX, Hu YJ, Zeng YY, Chen JF. · Laboratory of Immunology, Guangzhou University of TCM, Guangzhou 510405, China. · Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. · Pubmed #15182636 No free full text.

Abstract: AIM: To study the effects of total alkaloid of Tongbiling prescription(TBL) on Th1 type cytokine expression in T cells in order to elucidate the anti-inflammatory mechanism of TBL. METHODS: The lymphocytes were isolated from mouse mesenteric lymph nodes and cultured in-vitro. Various concentrations of TBL were added to the culture followed by phorbol ester and inomycin treatment and then incubated for another 4 hours. The expressions of IFN-gamma and TNF-alpha in the lymphocytes were analyzed by flow cytometry. RESULTS: 200 mg/L and 100 mg/L TBL could obviously inhibit IFN-gamma and TNF-alpha expressions in T lymphocytes. CONCLUSION: Inhibiting Th1 cytokine expression may be one mechanism by which TBL can treat rheumatoid arthritis.

Li YJ, Liu L, Zhang FC. · Department of Rheumatology and Immunology, Union Hospital of Peking Union Medical College, Chinese Academy of Medical Science, Beijing 100730, China. · Zhonghua Nei Ke Za Zhi. · Pubmed #12816697 No free full text.

Abstract: OBJECTIVE: To distinguish the difference among the pathogenesis of 60 000 SSA antigen mono-antigen peptides (MAPs), and to discuss the nosogenesis of anti-60 000 SSA antibodies in correlative rheumatic diseases. METHODS: MAPs were artificially synthesized according to the amino acid sequence of 20 positive epitopes and 1 control segment of 60 000 SSA antigen. ELISA against recombinant 60 000 SSA antigen MAPs were done to detect anti-MAPs antibodies in 59 sera with anti-SSA antibodies, and analyzing the relations of anti-MAPs antibodies and organism injuries. RESULTS: Anti-60 000 SSA antibodies are multiple clone autoantibodies. Different patients have different immune response to MAPs. Anti-MAP(1 approximately 21) antibodies have no relation to skin lesion; anti-MAP(2,14,15,21) antibodies have positive relation to salivary gland lesion; anti-MAP(7,16) antibodies have negative relation to kidney lesion; anti-MAP(6) antibodies have negative relation to heart lesion. CONCLUSIONS: The appearance of some anti-MAPs antibodies implies the lesions of some organs, while the appearance of some other anti-MAPs antibodies have the protection to some organs. We concluded that it is maybe the different anti-MAPs antibodies that result in different clinical manifestations.

Yin Z, Siegert S, Neure L, Grolms M, Liu L, Eggens U, Radbruch A, Braun J, Sieper J. · Department of Medicine, Division of Nephrology, Klinikum Benjamin Franklin, Free University, Berlin, Germany. · Rheumatology (Oxford). · Pubmed #10556256 links to  free full text

Abstract: OBJECTIVES: To quantify the T-helper type (Th) 1 cytokine interferon gamma (IFN-gamma)-positive and the Th2 cytokine interleukin (IL)-4-positive cells in synovial fluid (SF) and synovial membrane (SM) at the single-cell level in rheumatoid arthritis (RA) in comparison to reactive arthritis (ReA), and to manipulate the cytokine pattern of RA patients in vitro. METHODS: Eighteen patients with RA and 17 with ReA were studied. For intracellular staining of cytokines, SF mononuclear cells (MNC) from seven patients with RA, in comparison to eight patients with ReA, were triple stained with anti-IFN-gamma, IL-4 and anti-CD4 or anti-CD8 monoclonal antibodies (mAb) and analysed by flow cytometry. Furthermore, in 13 patients with RA, immunohistology of SM was performed and compared with seven ReA patients. In addition, in six of the RA patients, synovial T cells were grown over 3 weeks in the presence of various cytokines and intracellular cytokine staining analysed by flow cytometry weekly. RESULTS: In SF, the mean percentage of IFN-gamma+/CD4+ T cells in RA was almost 4-fold higher than the number of IL-4+/CD4+ T cells (11.3+/-5 vs 3.02+/-1.04; P=0.0012), while the ratio of IFN-gamma/IL-4+ CD4+ T cells was only 1.59 in ReA (P=0.047 for the ratio difference). A similar result was obtained for SM: the ratio of IFN-gamma/IL-4+ cells in RA was 4.3 (P<0.0001 for the IFN-gamma/IL-4 difference), but only 1.2 for ReA (P=0.02 for the ratio difference). Of the CD3+ cells in SM, 2.8% were positive for IFN-gamma and 0.4% for IL-4 in three RA patients. A decrease in the number of IFN-gamma-positive SF T cells and an increase in the number of IL-4-positive SF T cells could be achieved in vitro through IL-4, but not by IL-10 or transforming growth factor beta. CONCLUSIONS: The Th1 pattern in the joint of RA patients demonstrated at the single-cell level may be important for the pathogenesis of RA and may provide a target for future immunotherapy. Our data suggest a therapeutic role for IL-4.

Braun J, Yin Z, Spiller I, Siegert S, Rudwaleit M, Liu L, Radbruch A, Sieper J. · Universitätsklinikum Benjamin Franklin, Berlin, Germany. · Arthritis Rheum. · Pubmed #10524674 links to  free full text

Abstract: OBJECTIVE: To determine Th1 and Th2 cytokine production in patients with reactive arthritis (ReA) in relation to disease outcome and in comparison with rheumatoid arthritis (RA). METHODS: Secretion of tumor necrosis factor alpha (TNFalpha), interferon-gamma, interleukin-10 (IL-10), and IL-4 by peripheral blood mononuclear cells (PBMC) from 53 patients with early ReA (disease duration <8 weeks, 64% HLA-B27 positive) and 30 patients with early, untreated RA (disease duration <6 months) was determined by enzyme-linked immunosorbent assay (ELISA) after ex vivo stimulation. Intracellular cytokine staining with quantification of positive T cells by fluorescence-activated cell sorting (FACS) was performed in 12 ReA patients and 12 RA patients. In 27 ReA patients, cytokine secretion was measured again after 3 months. Patients were followed up for 1 year, and cytokine patterns were correlated with disease duration. RESULTS: TNFalpha secreted by whole PBMC and by T cells was significantly lower, by ELISA and by FACS, in ReA patients than in RA patients, while no significant differences were detected for the other cytokines. ReA patients with a disease duration of > or =6 months showed significantly lower TNFalpha secretion than patients with a disease duration of <6 months (mean +/- SD 385 +/- 207 pg/ml versus 684 +/- 277 pg/ml; P = 0.003). Furthermore, low TNFalpha secretion after 3 months also correlated significantly with a more chronic course of disease. HLA-B27 positive patients secreted less TNFalpha than did those who were B27 negative (338 +/- 214 pg/ml versus 512 +/- 207 pg/ml; P = 0.05), and patients with a more chronic course had a higher frequency of B27 positivity (47% versus 80%; P = 0.01). Among the 27 HLA-B27 positive patients, TNFalpha secretion in those with a disease duration of > or = 6 months was lower than that in the 7 with a disease duration of <6 months (308 +/- 167 pg/ml versus 562 +/- 308 pg/ml; P = 0.04). CONCLUSION: Low TNFalpha secretion and HLA-B27 status correlate with longer disease duration in ReA patients, possibly with an additive effect. The diminished TNFalpha production might reflect a state of relative immunodeficiency contributing to bacterial persistence in ReA.

Herrinton LJ, Liu L, Shoor S, Mines D. · No affiliation provided · Ann Rheum Dis. · Pubmed #18349167 No free full text.

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