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ID PMID Title PublicationDate abstract
8018238 [Autoantibodies against cartilage components: clinical relevance for reconstructive surger 1994 May The clinical relevance of antibodies against components of cartilage in the reconstructive surgery has not yet been clarified. In our study four groups of patients with successful and unsuccessful autologous cartilage transplantation in rhinosurgery, patients with ear perichondritis and patients with tracheal stenosis after long-term intubation were investigated for the presence of a humoral immune reactivity to cartilage. The control groups consisted of healthy persons and patients with RA. The antibodies against cartilage matrix and chondrocytes were determined using indirect immunofluorescence methods. Patients with unsuccessful cartilage transplantation showed increased antibodies against autologous cartilage (until 1:100) compared to the patients with successful cartilage transplantation. Furthermore, patients suffering from ear perichondritis and tracheal stenosis showed also increased antibodies against cartilage. These data suggest that a humoral immune reactivity against autologous cartilage--independent of an infection--can be one cause for the destruction of cartilaginous tissue.
1373058 Double reactivity of monoclonal and polyclonal rheumatoid factors for IgG and histones: ma 1992 Feb Polyreactive antibodies able to bind various apparently unrelated structures represent a frequent antibody population in autoimmune diseases. In this work, the structural basis of the double reactivity of such autoantibodies was investigated using as models polyclonal and monoclonal human rheumatoid factors (RF) reacting with histones. Both direct ELISA binding and competitive inhibition experiments were performed. A more precise delineation of the histone regions recognized by the RFs was made by means of 27 synthetic peptides of these proteins. Anti-idiotope (Id) murine antibodies were used to map the binding sites involved on RF in the interaction with IgG and histones. Among the 13 polyclonal and six monoclonal RFs tested, four and two respectively were found to cross-react with IgG and histones. The fragments shown to be the most frequently recognized by RFs were located in residues 1-16 and 204-218 of H1, 1-20 and 65-85 of H2A, and 1-21 of H3. The results obtained by competitive ELISA assays using IgG, histone peptides and anti-Id monoclonal antibodies led us to confirm and characterize more precisely our previous finding suggesting the existence of topographically distinct binding sites for the different targets recognized by RFs.
7538296 Monoclonal antibodies that detect biochemical markers of arthritis in humans. 1995 May OBJECTIVE: To evaluate the potential of using monoclonal antibodies (MAb) 3-B-3(-) and 7-D-4 to detect biochemical markers of altered cartilage metabolism in human arthritides. METHODS: Fifty-five samples of normal articular cartilage (subjects' age range 18 weeks of gestation to 83 years of age) and 89 samples of arthritic cartilage (patients' age range 20-81 years) were collected, and their proteoglycans were extracted and analyzed for the presence of the epitopes recognized by MAb 3-B-3 and 7-D-4. RESULTS: Native 3-B-3(-) mimotope was expressed at a high incidence in proteoglycans extracted from the cartilage of patients with most of the arthritic diseases examined (osteoarthritis, juvenile rheumatoid arthritis, rheumatoid arthritis, avascular necrosis, and degenerative meniscal tears). Its expression in normal cartilage specimens was very low or absent, occurring mainly in the young, skeletally immature individuals. In contrast, expression of the 7-D-4 epitope was more variable in patients with different arthritides and was also frequently found in normal cartilage specimens. Immunohistochemical analyses with both 3-B-3(-) and 7-D-4 showed strong focal positive staining in superficial areas, where cartilage degeneration, remodeling, and repair were greatest. CONCLUSION: The biochemical markers recognized by MAb 3-B-3(-) and 7-D-4 are indicative of altered proteoglycan synthesis and metabolism in human articular cartilage. The data suggest that in human cartilage, the 3-B-3(-) epitope might be a better marker of biochemical changes than the 7-D-4 epitope.
9020410 In vivo migration of tonsil lymphocytes in rheumatoid synovial tissue engrafted in SCID mi 1996 Integrin-adressin binding is a critical step in lymphocte attachment to target tissues. The mucosal recognition systems (alpha E beta 7, alpha 4 beta 7, MADcam-1) have been implicated in the autoimmune process in rheumatoid arthritis. We developed a model for in vivo study of radio-labelled lymphocyte circulation and their attachment to human rheumatoid synovium. We studied the homing of tonsil lymphocytes, considered as mucosal lymphocytes, and the involvement of alpha E beta 7 integrin and LFA1 in the homing of tonsil lymphocytes. We engrafted human rheumatoid synovium subcutaneously in 6 week old SCID CB17 mice. Three weeks later, we injected intraperitoneally 20 IO6 human peripheral blood or tonsil mononuclear cells, previously labelled with 3 mCFi HMPAO-99mTc. A mouse total body scintigram was obtained 20 h postinjection. The same protocol was performed after treatment of the MNC and mAb against LFA-1 (CD11a) or alpha E beta 7 (CD103). Tonsil MNC retention in the rheumatoid synovial graft 20 h post-injection was enhanced compared to blood MNC (12731 +/- 8297cpm/200 pixel) versus 5982 +/- 4713cpm/200 pixel, p < 0.05). A monoclonal antibody against LFA 1 decreased the activity in the graft (4152 +/- 1287 cpm/200 pixel), p < 0.05. No significant difference in tonsil MNC attachment to rheumatoid synovial tissue was observed with a mAb against alpha E beta 7 (8057 +/- 5009 cpm/200 pixel). Our results showed an increase in radiolabelled mucosal MNC migration in synovial tissue engrafted in SCID mice compared with blood MNC. Moreover, the date suggest that LFA-1 but not the alpha E beta 7 integrin is involved in tonsil MNC binding to synovial tissue in RA.
8808647 Anti-monocyte cytoplasmic antibodies in granulomatous disease. 1996 Oct Antibodies reactive with cytoplasmic components of neutrophils (ANCA) have received much attention because of their association with vasculitis and other inflammatory disorders. In this study, ELISA and immunofluorescence assays were employed to detect antimonocyte-specific antibodies and similar assays were used in parallel to detect anti-neutrophil cytoplasmic antibodies in a range of patient sera: Wegener's granulomatosis (14), Crohn's disease (46), ulcerative colitis (43), sarcoidosis (40), rheumatoid factor positive (15), and normal controls (22). Using an ELISA, anti-monocyte antibodies were detected in (figures in parentheses represent anti-neutrophil results): Wegener's granulomatosis, 79% (93%); sarcoidosis, 30% (5%); Crohn's disease, 20% (11%); ulcerative colitis, 0% (49%); rheumatoid factor-positive sera, 0% (0%). Excellent concordance (>98%) was found between the ELISA and immunofluorescence assays and all of the anti-monocyte antibodies gave a cytoplasmic pattern of staining. This is the first report demonstrating the presence of antibodies specific to the cytoplasmic components of monocytes in patients with granulomatous disease and these findings enhance our understanding of auto-antibody responses against phagocytic cell components.
7679271 Adhesion molecule expression in human synovial tissue. 1993 Feb OBJECTIVE: We have previously shown that E-selectin is expressed on endothelium in rheumatoid arthritis (RA) synovial tissues, and hence may be important in recruitment of leukocytes into the inflamed joint. In the present study, we determined whether other cellular adhesion molecules, including selectins and members of the integrin and immunoglobulin supergene families, are expressed in frozen synovium. METHODS: We employed immunohistochemical staining to determine the distribution of CD31 (PECAM), CD44 (hyaluronate receptor), CD62 (P-selectin), Leu-8 (L-selectin), and the integrin subunits alpha 5 (VLA-5), alpha 6 (VLA-6), beta 1 (VLA 1-6), and beta 3 (vitro-nectin receptor), in synovial tissue from 9 RA and 9 osteoarthritis (OA) patients, and from 3 normal (NL) subjects. RESULTS: P-selectin was expressed on vascular endothelium in all synovial tissues examined. L-selectin and alpha 5-integrin, while expressed on a variety of cell types, were not differentially expressed on RA synovial tissues. Integrin subunits alpha 6 and beta 1 were down-regulated on some RA synovial tissue components. In contrast, CD31 was expressed to a greater extent on RA than on OA lining cells and macrophages (P < 0.05). CD44 was expressed to a greater extent on RA or OA macrophages, lining cells, and fibroblasts compared with NL (P < 0.05). Integrin subunit beta 3 was strongly expressed on RA synovial blood vessels compared with NL (P < 0.05). CONCLUSION: The expression of integrins VLA 1-6, and selectins P and L is not up-regulated in RA synovial tissues. CD31 and CD44 are up-regulated on RA macrophages and lining cells, CD44 on RA fibroblasts, and beta 3-integrin on RA blood vessels. The up-regulation of CD31, CD44, and beta 3-integrin in RA synovial tissues may help tip the balance of adhesive interactions toward passage and retention of leukocytes in the inflamed joint.
1597301 [Studies on flow cytometric analysis of neutrophil functions of systemic lupus erythematos 1992 Mar Flow cytometric quantitative methods of (1) phagocytosis and (2) oxidative product formation by neutrophils were investigated by using whole blood. The neutrophil function of systemic lupus erythematosus (SLE) patients was analyzed by these methods. Kinetics of phagocytosis were investigated by using 1.97 microns fluorescent carboxylated microspheres (Polyscience, USA). The rate of phagocytosis (P) was increased logarithmically according to the T/C (target particle-to-cell) ratio (P = K1 x log (T/C ratio) +K2 K1, K2: constant). The value of Ph 50 were defined as the value of T/C ratio at which rate of phagocytosis was 50%. The PH 50 in SLE patients were statistically higher than in normal controls, which indicated the decreased phagocytic activity in SLE. Active SLE serum increased Ph 50 more than inactive SLE serum, and heat inactivated normal serum (30 min at 56 degrees C) increased Ph 50. Amount of oxidative products of neutrophils was measured by using dichlorofluorescein (DCF), which was converted from dichlorofluorescin diacetate (DCFH-DA) in the cells. After pre-incubation in room temperature from sampling to assay, the DCF fluorescent intensity of neutrophil of a normal control was low and revealed one-peak histogram, but that of SLE neutrophils revealed two peaks in histogram. The 2nd peak of high fluorescent intensity was thought to be composed of the subpopulation of neutrophil. The rate of the cells with oxidative products in unstimulated neutrophils was higher in SLE patients than in normal control and correlated with some clinical markers of disease activities. These two flow cytometric methods were rapid and accurate, and the whole blood could be used without separation of neutrophils by these methods. These methods might be useful technique to investigate the neutrophil functions.
7562781 Cyclosporin A in the treatment of adult Still's disease. 1995 Jul Cyclosporin A (CyA) has been used successfully in the treatment of rheumatoid arthritis. There is one case report of CyA used successfully in the treatment of severe systemic onset Still's disease. To our knowledge, there are no reports of CyA used in adult Still's disease. We present the first report of a patient with refractory adult Still's disease successfully treated with CyA. We submit that cyclosporine treatment may induce remission of symptoms in patients with adult Still's disease and reduce the steroid requirements.
8292662 A trypsin sensitive stromelysin isolated from rheumatoid synovial fluid is an activator fo 1993 Oct The processing of synovial fluids of patients suffering from rheumatoid arthritis led to the characterization of a neutral metalloproteinase with polymorphonuclear leukocyte progelatinase and polymorphonuclear leukocyte procollagenase activating properties. The activator exhibits a relative molecular mass of M(r) 27,000 and is an active form of stromelysin. Thus, it reacts specifically with antibodies raised against human stromelysin, splits polymorphonuclear leukocyte progelatinase in a manner characteristic of stromelysin, and is inhibited by EDTA as well as by a tissue inhibitor of metalloproteinases (TIMP-2). The activator shows a high specificity for the matrix metalloproteinases, polymorphonuclear leukocyte progelatinase and polymorphonuclear leukocyte procollagenase. It shows only weak hydrolysis of casein and gelatin, and it does not activate fibroblast M(r) 72,000 progelatinase. Brief treatment with trypsin does not lead to a significant change in the activator's relative molecular mass, but induces a rapid loss of its activating activity for polymorphonuclear leukocyte progelatinase, while its proteolytic activity against the synthetic substrate, N-(2,4)-dinitrophenyl-Pro-Gln-Gly-Ile-Ala-Gly-Gln-D-Arg, is increased about 3-fold. The same tryptic treatment does not affect the activator's proteolytic activity towards casein and gelatin.
8072492 Immunocytochemical characterization of human NOR-90 (upstream binding factor) and associat 1994 Mar The 90-kDa nucleolus organizer region autoantigen (NOR-90) was previously shown to be identical to the human upstream binding factor (hUBF) and composed of two Mr forms. In this study, thirteen human anti-NOR-90/hUBF autoimmune sera were used to further characterize NOR-90/hUBF and its associated autoantigens. Nucleolar and nucleoplasmic staining of interphase cells and NOR staining in mitosis were observed with all sera by immunofluorescence. All sera showed equal reactivity with both high and low Mr forms in Western blotting and immunoprecipitation, suggesting that the cellular content and distribution for both Mr forms were approximately equal. Using extracts of [35S]methionine- and [32P]orthophosphate-labeled cells, phosphorylated and nonphosphorylated NOR-90/hUBF were identified for both Mr forms and these two populations were recognized by human autoantibodies. In immunoprecipitation analyses, the nonphosphorylated population was readily extracted while the phosphorylated population was tightly bound. Clinical data were available for 8 patients in whom anti-NOR-90/hUBF autoantibodies were present. They had diverse diagnoses including SLE, rheumatoid arthritis and malignancies. Although only one patient was diagnosed as scleroderma, Raynaud's phenomenon was observed in 4 of the 8 patients. Interestingly, one NOR-90/hUBF serum was shown to contain additional antibodies to RNA polymerases I and II.
8651983 Oligoclonal T cell proliferation in patients with rheumatoid arthritis and their unaffecte 1996 Jun OBJECTIVE: To analyze whether patients with rheumatoid arthritis (RA) have an intrinsic defect in T cell proliferation and survival, possibly contributing to the infiltration of the synovial membrane with CD4+ T cells. METHODS: Fifteen patients with seropositive RA, 11 patients with psoriatic arthritis, 20 normal controls, and 9 affected and 13 unaffected siblings from 7 multiplex families with RA were analyzed for clonal proliferation. To investigate this clonal T cell proliferation, CD4+ T cells were purified from peripheral blood and synovial fluid by magnetic bead separation. T cell receptor (TCR) beta-chain sequences were amplified by reverse transcriptase-polymerase chain reaction, using TCR BV and BJ gene segment-specific primer sets. Clonally expanded T cell specificities were identified by size fractionation and sequencing of the amplified product. RESULTS: All RA patients carried clonally expanded CD4+ T cells in the peripheral blood compartment. Such expanded CD4+ T cell clonotypes were only infrequently observed both in normal individuals (P < 0.0001) and in patients with psoriatic arthritis (P = 0.004). Lymphoproliferation of selected CD4+ T cells was shared by affected and unaffected siblings from RA multiplex families (P = 0.005 and P = 0.0003, respectively, compared with normal controls). Expanded clonotypes persisted for several years and contributed to the T cell infiltrate in the joint. Clonal T cell proliferation involved a diverse spectrum of TCR molecules. CONCLUSION: RA patients have an abnormality in the homeostasis of CD4+ T cells, characterized by the emergence of clonally proliferating populations. The presence of clonal outgrowth of selected CD4+ T cells specificities in unaffected siblings of RA patients suggests that oligoclonality of CD4+ T cells is inherited and is a risk factor for, rather than a result of, synovial inflammation.
8870692 Blood monocyte activation in rheumatoid arthritis: increased monocyte adhesiveness, integr 1996 Oct Infiltration of the synovium by mononuclear cells, namely lymphocytes and monocytes, is one of the main features of rheumatoid arthritis (RA) and is considered to be responsible for the development of the disease. In this study in 31 consecutive patients with RA, we investigated whether peripheral blood monocytes exhibited markers of cellular activation related to cell migration. Using flow cytometry with the respective specific antibodies, we studied the expression of integrins CD11a, CD11b, CD11c, CD49d (VLA-4), and CD49e (VLA-5) on monocytes from patients with RA and from normal (N) subjects. IL-1 beta, IL-6, and tumour necrosis factor-alpha (TNF-alpha) production by cultured monocytes was measured by immunoassay. Adhesiveness of monocytes was studied on various surfaces (plastic, human fibronectin, gelatin-coated plasma, subendothelial matrix) and on cultured endothelial cells under basal conditions or after stimulation by IL-1 beta. An increased number of CD14+ monocytes (Mo) from RA patients expressed the CD11b molecule (RA Mo = 90.3%, N Mo = 83.4%, P < 0.005). The expression of CD11b on CD14+ monocytes was significantly increased in RA patients (median fluorescence intensity (FI): RA Mo = 145 (range 80-466) units; normal Mo = 95 (range 24-164) units; P < 0.003). Production of extracellular IL-1 beta and IL-6 by RA monocytes was significantly enhanced compared with monocytes from normal subjects (IL-1 beta: RA = 2.65 +/- 0.91 ng/ml versus N = 1.35 +/- 0.85 pg/ml, P < 0.05; IL-6: RA = 4.83 +/- 0.90 ng/ml versus N = 2.40 +/- 0.95 ng/ml, P < 0.05). Compared with normal monocytes, RA monocytes exhibited increased adhesion to the various surfaces studied (plastic, P < 0.01; fibronectin, P < 0.01; and gelatin-coated normal or RA plasma, P < 0.01) as well as to unstimulated (P < 0.01) and IL-1 beta-stimulated endothelial cells (IL-1 beta for 4 h, P < 0.05; IL-1 beta for 24h, P < 0.05). In our study, blood monocytes from RA patients exhibited features of activation related to cell adhesion.
7957563 Evidence for the continuous recruitment and activation of T cells into the joints of patie 1994 Nov Rheumatoid arthritis (RA) synovial fluid (SF) T cells express the activation markers CD69, HLA-DR and very late antigen (VLA)-1, but surprisingly few bear interleukin-2 receptors (CD25). This unusual activation state is commonly assumed to be due to stimulation by local antigen, yet T cells activated in vitro express activation antigens in the clearly defined sequence: CD69, CD25, HLA-DR and finally VLA-1. Two possible explanations for the activation state of SF cells are: first, they comprise several subpopulations each expressing different activation antigens or, second, activation markers are up-regulated by mechanisms other than antigen stimulation. To examine these hypotheses, double- and triple-color immunofluorescence techniques were applied to four T cell populations: normal peripheral blood T cells activated in vitro, RA SF T cells, T cells from an in vivo model of migration [tuberculin purified protein derivative (PPD)-induced skin blisters] and T cells co-cultured with endothelial cells (EC). The results confirmed that in vitro activated T cells expressed activation markers in the sequence described above, with significant CD25 expression and few cells co-expressing CD69 with HLA-DR or VLA-1. In contrast, almost half the SF T cells were CD69+HLA-DR+ but CD25-; a significant minority were CD69+VLA-1+. T cells from PPD-induced skin blisters were already HLA-DR+ and VLA-1+ at 24 h, although, in vitro, PPD-activated T cells up-regulated HLA-DR and VLA-1 only after 1 week, suggesting that pre-activated T cells were preferentially recruited into the blisters. Finally, T cells were found to up-regulate CD69 and, to a lesser extent, HLA-DR after adhering to EC in vitro. In summary, the paradoxical activation state of SF T cells cannot be explained solely by single or multiple rounds of activation in situ. At least two other mechanisms, the preferential recruitment of pre-activated T cells and the induction of HLA-DR and especially CD69 by endothelial contact during migration, may also play a role.
8262619 Human T-cell responses to Mycoplasma arthritidis-derived superantigen. 1994 Jan When injected into mice, Mycoplasma arthritidis causes a chronic arthritis that resembles rheumatoid arthritis, histologically. The organism produces a superantigen termed Mycoplasma arthritidis mitogen or MAM, that in humans preferentially expands T cells whose antigen receptors express V beta 17. T cells with this phenotype appear to be increased in rheumatoid synovial effusions. We describe a novel approach to isolating and characterizing human MAM-reactive T-cell lines and determining their T-cell receptor (TCR) V beta usage. Lines were prepared from T cells that clustered with dendritic cells during a 2-day exposure to MAM. Cluster and noncluster fractions of T cells were then expanded by using feeder cells and a polyclonal mitogen. Most of the MAM reactivity was found in dendritic T-cell clusters, as were most of the T cells expressing TCR V beta 17. After expansion, 76% of the cluster-derived T-cell lines were MAM reactive, while no reactivity was seen in cell lines derived from the noncluster fraction. Of the MAM-reactive lines, 49% expressed V beta 17 on some or all of the cells. Cell lines from both cluster and noncluster fractions were analyzed for TCR V beta mRNA expression by PCR amplification. Other V beta genes (5.1, 7, 8, 12, and 20) were found to be expressed by lines that were MAM reactive, although these were not a major component of the cluster-derived T cells. Some non-cluster-derived lines expressed V beta s 17, 12, and 7, but these proved to be nonreactive to MAM. Therefore, dendritic cells can be used to immunoselect and characterize T cells that express superantigen-reactive TCRs.
8056036 Variable region gene usage of human monoclonal rheumatoid factors derived from healthy don 1994 Aug A study was performed to compare the use of immunoglobulin V gene segments by rheumatoid factors (RF) produced in physiological responses following a defined antigenic stimulus, with RF produced in rheumatoid arthritis (RA) and RF produced as monoclonal (M)-components in certain lympho-proliferative diseases. A panel of 46 monoclonal RF was produced, using hybridoma techniques, from healthy individuals following immunization with foreign antigens (mis-matched red blood cells). A panel of previously characterized monoclonal RF from RA synovial tissues was extended to a total of 24 and included in the study. The variable heavy (VH) and variable light (VL) chain gene families used by these RF were determined using idiotypic markers and polymerase chain reaction amplification with VH-specific primers. The frequencies of expression of the various gene families was compared between the two groups, and compared with the published expression frequencies seen amongst M-component RF. The majority (87%) of RF from healthy donors were found with light chains using V gene segments of the V chi 3 family, in conjunction with VH gene segments belonging to the VH1, VH3 and VH4 families. The over-expression of V chi 3, together with the distribution of VH families, demonstrates close similarities with RF found as M-components in lympho-proliferative diseases. In contrast, RF from RA patients showed a predominant use of VH3 gene segments (82%) and an unbiased expression of V chi 3 segments (29% of the chi light chains). These data suggest that RF found as M-components are representative of RF used in normal physiological responses, but have undergone neoplastic or other transformation. RF found in the synovial tissue of RA patients appear to be driven by different mechanisms than RF seen in physiological responses in healthy individuals.
8258716 Human granzyme B degrades aggrecan proteoglycan in matrix synthesized by chondrocytes. 1993 Dec 15 Cartilage degradation, a hallmark of rheumatoid arthritis, is attributed to serine and metalloproteases secreted by neutrophils, synovial lining cells, macrophages, and chondrocytes. A large proportion of synovial fluid lymphocytes contains the granule-associated serine proteases granzymes A and B. We report that lysates of IL-2-stimulated lymphocytes contain an enzymatic activity (ECMase; cartilage extracellular matrix 35S release assay; extracellular matrix degrading activity) that solubilizes matrix synthesized by chondrocyte monolayers. ECMase activity is inactivated by the serine protease inhibitor diisopropylfluorophosphate, is stored in dense granules and cleaves aggrecan proteoglycans but not free glycosaminoglycans, hyaluronic acid, or type II collagen. ECMase is mediated by a cationic protein with biochemical properties identical to granzyme B, inasmuch as it preferentially hydrolyzes the substrate Boc-Ala-Ala-Asp-SBzl, immunochemically cross-reacts with an antibody that binds to a conserved amino-terminal region of lymphoid-myeloid serine proteases, and has amino-terminal sequence identity with human Q31 granzyme B. Using an agarose gel electrophoresis technique to assess cleavage of the rat sarcoma aggrecan, the catalytic efficiency of granzyme B for the digestion of aggrecan (catalytic efficiency = 1.7 x 10(7) M-1 s-1) was 425-fold faster than the catalytic efficiency reported for human stromelysin-1 at pH 7.5 (catalytic efficiency 4000 M-1 s-1) and 3200-fold faster than granzyme A. Based on these observations, we propose that granzyme B, secreted from cytotoxic lymphocytes within the rheumatoid joint, may contribute to cartilage loss by degrading resident aggrecan.
8452574 The relative toxicity of disease-modifying antirheumatic drugs. 1993 Mar OBJECTIVE: To compare the toxicities of commonly employed disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA). METHODS: Toxicity Index scores, computed from symptoms, laboratory abnormalities, and hospitalizations attributable to DMARD therapy, were assessed in 2,747 patients with RA receiving 3,053 courses of 6 DMARDs and 1,309 courses of prednisone over 7,278 patient-years. Results were adjusted for severity of illness and other covariates. RESULTS: Least toxic was hydroxychloroquine (mean +/- SEM score 1.38 +/- 0.15), followed by intramuscular gold (2.27 +/- 0.17) and the closely grouped D-penicillamine (3.38 +/- 0.36), methotrexate (3.82 +/- 0.35), and azathioprine (3.92 +/- 0.39). Auranofin (5.25 +/- 0.32) was most toxic, but this toxicity resulted from a high frequency of minor complications. Hospitalizations because of auranofin or hydroxychloroquine therapy were not noted. Prednisone (3.83 +/- 0.39) was of comparable toxicity, although it is likely that not all events of prednisone toxicity were captured. For reference, the toxicity of methotrexate and azathioprine was similar to that of the most toxic nonsteroidal antiinflammatory drugs (NSAIDs) (indomethacin 3.99, tolmetin sodium 3.96, and meclofenamate 3.86). Hydroxychloroquine showed less toxicity than the most commonly used prescription NSAIDs. CONCLUSION: There are substantial differences in toxicity among DMARDs and less important differences in toxicity between specific DMARDs and specific NSAIDs.
7538295 CD28 expression on T cell subsets in vivo and CD28-mediated T cell response in vitro in pa 1995 May OBJECTIVE: In view of the critical importance of the CD28-CD80 (B7/BB1) costimulatory pathway in antigen-specific T cell activation and clonal expansion, we examined CD28 surface molecule expression in vivo, and T cell receptor/CD3-mediated and B7/BB1-costimulated T cell proliferation in vitro, in rheumatoid arthritis (RA). METHODS: Two-color immunofluorescence analyses of peripheral blood and synovial fluid-derived T cells, as well as 3H-thymidine incorporation assays, were performed. RESULTS: In the peripheral blood of 31 patients with active, untreated RA, a mean of 91% (range 48-100%) of CD4+ and 46% (range 13-82%) of CD8+ T cell subsets were CD28+, which was not significantly lower than normal. Although an overall decrease in the number of T cells was not observed, the numbers of CD28+CD8+ T cells were significantly lower in RA patients (mean 233/microliters, versus 292/microliters in controls), and this decrease was more pronounced in patients with severe disease (mean 172/microliters). CD28 expression on peripheral CD8+ T cells in RA patients, but not in healthy individuals, correlated inversely with T cell activation as assessed by HLA-DR antigen expression. In contrast to the peripheral blood, RA synovial fluid T cells were almost exclusively CD28+, suggesting that migration of CD28+CD8+ T cells to active sites of inflammation may occur. In vitro proliferative responses of peripheral blood T cells to B7/BB1 costimulation in the presence of mitogenic doses of anti-CD3 monoclonal antibody were identical in patients with RA and healthy individuals. CONCLUSION: Functionally intact CD28+ T cells may contribute to the abnormal immunoregulation and joint inflammation in RA.
8782128 Nutrient intake of patients with rheumatoid arthritis is deficient in pyridoxine, zinc, co 1996 Jun OBJECTIVE: To determine nutrient intake of patients with active rheumatoid arthritis and compare it with the typical American diet (TAD) and the recommended dietary allowance (RDA). METHODS: 41 patients with active RA recorded a detailed dietary history. Information collected was analyzed for nutrient intake of energy, fats, protein, carbohydrate, vitamins and minerals, which were then statistically compared with the TAD and the RDA. RESULTS: Both men and women ingested significantly less energy from carbohydrates [women 47.4% (6.4) vs 55% RDA. p = 0.0001: men = 48.9% (7.4). p = 0.025] and more energy from fat [women = 36.8% (4.5) vs 30% RDA. p = 0.001 and men = 35.2% (5.9) p = 0.02]. Women ingested significantly more saturated and mono-unsaturated fat than the RDA (p = 0.02 and p = 0.04 respectively) while men ingested significantly less polyunsaturated fat (PUFA) (p = 0.0001). Both groups took in less fiber (p = 0.0001). Deficient dietary intake of pyridoxine was observed vs the RDA for both sexes (men and women p = 0.0001). Deficient folate intake was seen vs the TAD for men (p = 0.02) with a deficient trend in women (p = 0.06). Zinc and magnesium intake was deficient vs the RDA in both sexes (p values < or = 0.001) and copper was deficient vs the TAD in both sexes (p = 0.004 women and p = 0.02 men). CONCLUSION: Patients with RA ingest too much total fat and too little PUFA and fiber. Their diets are deficient in pyridoxine, zinc and magnesium vs the RDA and copper and folate vs the TAD. These observations, also documented in previous studies, suggest that routine dietary supplementation with multivitamins and trace elements is appropriate in this population.
8403591 Erythropoietin and the anemia of chronic diseases. 1993 Jul The red-cell mass is continuously adjusted to the optimal size for its function as an oxygen carrier by messages transmitted to the bone marrow from an oxygen sensor in the kidney. These messages are mediated by the hormone erythropoietin. Erythropoietin is a glycoprotein growth factor synthesized by cells adjacent to the proximal renal tubule in response to signals from a renal oxygen-sensing device, probably a heme protein (1). In the bone marrow, erythropoietin binds to and activates specific receptors on the erythroid progenitor cells (2). In the presence of this erythropoietin-receptor complex the progenitor cells continue their predestined development into mature erythrocytes. Erythropoietin was the first hemopoietic growth factor to be molecularly cloned in 1985 (3). Our understanding of the biology and physiology of erythropoietin has been considerably improved with the advent of recombinant human erythropoietin (rHuEpo). During the past 7 years, rHuEpo has undergone extensive testing in clinical trials. It has been approved for treatment of the anemia of chronic renal failure, both in progressive renal failure and endstage renal failure (ESRD). In these instances, the administration of rHuEpo has been used in effect as a substitutive therapy, since patients' erythropoietin levels are very low despite severe anemia, due to the failure of affected kidneys to produce adequate amounts of the hormone. However, the application of rHuEpo has now moved largely from the primitive indication of renal diseases, and the hormone is currently under study in a number of anemic states of different etiologies, even with relatively high serum erythropoietin levels. Among these, some of the best documented indications are the anemia associated with malignancies, either due to neoplastic bone marrow infiltration or to chemotherapy-related myelosuppression, the anemia of myelodysplastic syndromes and AIDS, the anemia of chronic inflammatory diseases, prematurity, and bone marrow transplantation (4). The purpose of this review is to provide a summary of our present knowledge regarding rHuEpo therapy for the anemia of renal failure. We provide some clues for the correct use of rHuEpo in the treatment of the anemia of chronic inflammatory diseases. In addition, we address a series of new issues in the attempt to better understand the relationship between erythropoietin and liver disease.