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ID PMID Title PublicationDate abstract
8929772 Human gelatinase B, a marker enzyme in rheumatoid arthritis, is inhibited by D-penicillami 1996 Jan The direct and indirect inhibitory potential of D-penicillamine toward human neutrophil and synovial fluid gelatinase B, a marker enzyme for disease severity in RA, was investigated. Gelatinase and plasminogen activator activities were assessed by SDS-polyacrylamide gel electrophoresis zymography. D-penicillamine significantly inhibits purified and synovial fluid gelatinase B in vitro at concentrations attainable in vivo and also blocks in vitro plasminogen activation. Protease inhibition may be a mechanism of action for D-penicillamine as DMARD.
1541693 Chemical gastritis and Helicobacter pylori related gastritis in patients receiving non-ste 1992 Feb AIMS: To evaluate the prevalence and significance of chemical gastritis, in comparison with gastritis related to Helicobacter pylori in patients receiving non-steroidal anti inflammatory drugs (NSAIDs). METHODS: Two hundred and eighteen patients were studied, 174 of whom were taking NSAIDs. Chemical gastritis was defined as the presence of foveolar hyperplasia, muscle fibres in the lamina propria, oedema and vasodilation, in the absence of a chronic inflammatory cell infiltrate. RESULTS: Chemical gastritis was found in 46 (26%) patients taking NSAIDs, and three (7%) in subjects not taking these drugs (p less than 0.01). H pylori was detected in 56 (32%) subjects taking NSAIDs compared with 22 (50%) not taking these agents (p less than 0.02). Ulcers were found in 16 out of 72 patients (22%) taking NSAIDs and without H pylori infection or chemical gastritis compared with 27 out of 56 (48%) with H pylori related gastritis (p less than 0.01), and 25 out of 46 (54%) with chemical gastritis (p less than 0.01). CONCLUSIONS: Peptic ulcers associated with the use of NSAIDs seem to occur more commonly in patients with chemical gastritis or H pylori infection. Patients taking NSAIDs also seem to have a greater prevalence of chemical gastritis but a lower prevalence of H pylori than those not taking these drugs.
8035402 Measurement of plasma calprotectin as an indicator of arthritis and disease activity in pa 1994 Apr OBJECTIVE: To investigate if the plasma level of the granulocyte protein calprotectin is a useful indicator of severity of arthritis in patients with inflammatory rheumatic diseases, and to analyze which factors contribute to the raised plasma calprotectin levels. METHODS: Plasma calprotectin levels were measured by ELISA: In a cross sectional study of 154 patients with various inflammatory rheumatic diseases, calprotectin levels were correlated with laboratory and clinical variables. RESULTS: The plasma levels of calprotectin and C-reactive protein (CRP) correlated significantly with the clinical evaluation of swollen joints (r = 0.51, p < or = 0.01 and r = 0.29, p < or = 0.01, respectively). Calprotectin levels, but not CRP levels or erythrocyte sedimentation rate, were significantly lower in patients with no swollen joints than in patients with one or more swollen joints (2613.6 micrograms/l vs 6287.0 micrograms/l, p < 0.001). A significant correlation between calprotectin and number of neutrophils was demonstrated (r = 0.43, p < or = 0.01), indicating that circulating neutrophils contribute to plasma calprotectin levels. CONCLUSION: The plasma calprotectin level may be a useful indicator of arthritis in inflammatory rheumatic diseases.
7691501 Cyclosporin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeut 1993 Jun Cyclosporin is a lipophilic cyclic polypeptide which produces calcium-dependent, specific, reversible inhibition of transcription of interleukin-2 and several other cytokines, most notably in T helper lymphocytes. This reduces the production of a range of cytokines, inhibiting the activation and/or maturation of various cell types, including those involved in cell-mediated immunity. Thus, cyclosporin has immunosuppressive properties, and has a proven place as first line therapy in the prophylaxis and treatment of transplant rejection. Cyclosporin has also been evaluated in a large range of disorders where immunoregulatory dysfunction is a suspected or proven aetiological factor, and this is the focus of the present review. In patients with severe disease refractory to standard treatment, oral cyclosporin is an effective therapy in acute ocular Behçet's syndrome, endogenous uveitis, psoriasis, atopic dermatitis, rheumatoid arthritis, active Crohn's disease and nephrotic syndrome. Concomitant low dose corticosteroid therapy may improve response rates in some disorders. The drug can be considered as a first line therapy in patients with moderate or severe aplastic anaemia who are ineligible for bone marrow transplantation, with the additional benefit of reducing platelet alloantibody titres. It may also be of considerable therapeutic benefit in patients with primary biliary cirrhosis, particularly those with less advanced disease. Limited evidence suggests cyclosporin is effective in patients with intractable pyoderma gangrenosum, polymyositis/dermatomyositis or severe, corticosteroid-dependent asthma. Indeed, the steroid-sparing effect of cyclosporin is a significant advantage in a number of indications. Furthermore, the drug has shown some efficacy in a wide range of other, generally uncommon disorders in which controlled clinical trials are lacking and/or are unlikely to be performed. Cyclosporin does not appear to be effective in patients with allergic contact dermatitis, multiple sclerosis or amyotrophic lateral sclerosis. It is only temporarily effective in patients with type I (insulin-dependent) diabetes mellitus and should not be used in this indication. To avoid relapse after control of active disease, patients should receive cyclosporin maintenance therapy at the lowest effective dosage. However, maintenance therapy appears to be of no benefit in patients with Crohn's disease and cyclosporin should be discontinued in these patients once active disease is controlled. Hypertrichosis, gingival hyperplasia, and neurological and gastrointestinal effects are the most common adverse events in cyclosporin recipients, but are usually mild to moderate and resolve on dosage reduction. Changes in laboratory variables indicating renal dysfunction are relatively common, although serious irreversible damage is rare.(ABSTRACT TRUNCATED AT 400 WORDS)
8656264 Spontaneous regression of lymphoproliferative disorders in patients treated with methotrex 1996 Jun PURPOSE: To determine the clinicopathologic features of lymphoproliferative disorders (LPD) that occur in the setting of methotrexate (MTX) therapy for rheumatic diseases (RD) and to define the relationship between the presence of Epstein-Barr virus (EBV) in tumor cells and the response of LPD to MTX withdrawal. PATIENTS AND METHODS: In addition to nine new cases, we analyzed 28 cases previously reported in the literature of LPD in patients receiving MTX for RD. In addition to MTX, immunosuppressive therapy included corticosteroids in 19 patients, azathioprine in three, and cyclosporine in one. Extranodal disease was identified in 16 patients, but none had CNS involvement. Pathologic findings included five cases of Hodgkin's disease and seven low-grade lymphomas. The remaining patients had intermediate or aggressive lymphomas. In situ hybridization studies (ISHS) for EBV-RNA transcripts were positive in 12 of 27 patients (44%). RESULTS: Among 37 patients, 16 were initially observed after MTX withdrawal without additional antitumor therapy. Six achieved a spontaneous complete remission (CR), three had a partial response (PR), one had a minimal response, and six had no response to MTX withdrawal. Of 10 responding patients, EBV was detected by ISHS (n = 6) or polymerase chain reaction (PCR) (n = 2); one patient had a CR despite the absence of EBV by PCR and one had a CR but did not have viral assays performed. Only one of six patients with negative EBV by ISHS or PCR responded to MTX withdrawal. CONCLUSION: MTX withdrawal and observation for a short period should be considered in the initial management of patients who develop LPD while on MTX therapy. Responses were consistently observed, but not limited to patients in whom EBV was detected by ISHS or PCR. Further studies are required to confirm these findings and to evaluate the role for EBV in LPD that occur in patients receiving MTX.
7962779 Monitoring patients taking methotrexate for hepatotoxicity. Does the standard of care matc 1994 Dec BACKGROUND: Controversy persists regarding the validity of published guidelines for the monitoring of methotrexate-induced hepatotoxicity. OBJECTIVE: The purpose of our study was to assess the standard of care by gastroenterologists in the monitoring of methotrexate-induced hepatotoxicity and to compare this standard of care with guidelines in the medical literature. METHODS: Gastroenterologists in Connecticut and Massachusetts were surveyed by a mail-in questionnaire that inquired about their protocol for the monitoring of hepatotoxicity in patients taking methotrexate. RESULTS: Gastroenterologists in Connecticut and Massachusetts generally follow the guidelines in the medical literature. Variation in recommendations from the rheumatologic and the dermatologic literature is reflected in the practice habits of gastroenterologists whose patients are restricted to one particular population. CONCLUSION: Long-term follow-up studies should be continued to obtain further data from which to make future recommendations, especially with regard to the effects of large cumulative doses of methotrexate.
8132778 Macrophage inflammatory protein-1 alpha. A novel chemotactic cytokine for macrophages in r 1994 Mar We have shown that human macrophages (m phi s) play an important role in the elaboration of chemotactic cytokines in rheumatoid arthritis (RA) (Koch, A. E., S. L. Kunkel, J. C. Burrows, H. L. Evanoff, G. K. Haines, R. M. Pope, and R. M. Strieter. 1991. J. Immunol. 147:2187; Koch, A. E., S. L. Kunkel, L. A. Harlow, B. Johnson, H. L. Evanoff, G. K. Haines, M. D. Burdick, R. M. Pope, and R. M. Strieter. 1992. J. Clin. Invest. 90:772; Koch, A. E., P. J. Polverini, S. L. Kunkel, L. A. Harlow, L. A. DiPietro, V. M. Elner, S. G. Elner, and R. M. Strieter. 1992. Science (Wash. DC). 258:1798). Recently, m phi inflammatory protein-1 (MIP-1 alpha), a cytokine with chemotactic activity for m phi s and neutrophils (PMNs), has been described. We have examined the production of MIP-1 alpha using sera, synovial fluid (SF), and synovial tissue (ST) from 63 arthritic patients. MIP-1 alpha was higher in RA SF (mean, 29 +/- 8 ng/ml [SE]) compared with other forms of arthritis (2.8 +/- 1.7), or osteoarthritis (0.7 +/- 0.4; P < 0.05). RA SF MIP-1 alpha was greater than that found in either RA or normal peripheral blood (PB) (P < 0.05). Anti-MIP-1 alpha neutralized 36 +/- 3% (mean +/- SE) of the chemotactic activity for m phi s, but not PMNs, found in RA SFs. RA SF and PB mononuclear cells produced antigenic MIP-1 alpha. Mononuclear cell MIP-1 alpha production was augmented with phytohemagglutinin or LPS. Isolated RA ST fibroblast production of antigenic MIP-1 alpha was augmented upon incubation of cells with LPS, and to a lesser extent with tumor necrosis factor-alpha. Isolated RA ST m phi s expressed constitutive MIP-1 alpha mRNA and antigenic MIP-1 alpha. Using ST immunohistochemistry, MIP-1 alpha+ cells from RA compared with normal were predominantly m phi s and lining cells (P < 0.05). These results suggest that MIP-1 alpha plays a role in the selective recruitment of m phi s in synovial inflammation associated with RA.
8382569 Monoclonal IgM, IgG, and IgA human rheumatoid factors produced by synovial tissue-derived, 1993 Jan In an effort to study disease-related autoantibodies in rheumatoid arthritis (RA), rheumatoid factor (RF)-producing B cell lines were developed from the heterogeneous B cell populations infiltrating the synovial tissue of patients with arthritis. Over 125 EBV-transformed B cell cultures were derived from three patients: one with early pre-erosive RA, one with advanced RA, and one with osteoarthritis (OA). IgM, IgG, and IgA RF-producing B cell lines were found in all three series but with several significant differences. In each of the two RA patients, 22% of the Ig-producing cell lines secreted RF compared to 7% in the OA patient. The isotypes of these RF were mostly IgM in the early RA (62%) and the OA patient (60%) as contrasted to predominantly IgA (75%) and, to a lesser extent, IgG (12.5%) in the advanced RA patient. Analyses of the light (L) chain composition of these RF revealed that 82% of the IgM RF used kappa L chains whereas only 31% of the non-IgM RF used kappa chains. Antigen-binding analyses of these RF revealed that all the synovial tissue-derived RF from the advanced RA patient exhibited antigen binding specificities restricted to a narrow range of gamma globulins. In contrast, the synovial RF of the other two patients were either reactive with a broader spectrum of gamma globulins or reactive with a variety of unrelated antigens. In every instance, the gamma globulin-specific RF were of all three major isotypes whereas the polyreactive RF were restricted to the IgM isotype. These data demonstrate that synovial B cells from both RA and OA patients can produce RF and that significant differences can exist among patients in the percentage of RF generated and their H and L chain isotype distribution. The reversal of the kappa:lambda ratio among the IgG and IgA RF and the more restricted antigen-binding specificities of the IgG and IgA vs IgM RF suggest that a non-stochastic, possibly antigen-driven selection process was involved in their generation. The relevance of these differences in RF precursor frequency, H and L chain distribution, and antigen specificity to these two diseases warrants further investigation.
7955598 Rheumatic autoantibodies in the sera of patients with paraproteins. 1994 Jul OBJECTIVE: A high incidence of autoantibody activity has been previously described in the sera of patients with paraproteins. In this study we determined the incidence of autoantibodies of particular interest to rheumatologists (including antinuclear antibodies (ANA), anti-DNA, rheumatoid factor (RF), anticardiolipin antibodies (aCL) and the Sjögren's-related antibodies anti-SS.A/Ro and anti-SS.B/La) in the sera of patients with paraproteins, and the frequency with which the autoantibody activity isotype and the paraprotein isotype were identical. METHODS: ANA was determined by indirect immunofluorescence on HEp2 cells, anti-DNA by the Farr and Crithidia assays, aCL by ELISA, RF by nephelometry, antibodies to the extractable nuclear antigens (anti-ENA) by counter-immunoelectrophoresis (CIE), and anti-SS.B by immunoblot using a recombinant human SS.B antigen source. Incidences of these antibodies was compared in 3 groups of sera: 98 myeloma, 27 monoclonal gammopathy of uncertain significance (MGUS), and 24 age matched controls, using confidence interval analysis. RESULTS: There was no significant difference between the incidence of ANAs in paraprotein sera (8.8%) and control sera (16%). Neither was there a significant incidence of RF or aCL in the paraprotein sera. No anti-DNA antibodies were found and no anti-SS.B antibodies were found either with CIE or immunoblotting. Of the 11 ANAs detected in the paraprotein sera, isotype specific immunofluorescence suggested that 6 were monoclonal autoantibodies. CONCLUSIONS: These results indicate that the incidence of rheumatic autoantibodies is not raised in paraprotein sera compared to control sera. In particular, we could not confirm previous reports of a high incidence of anti-SS.B antibodies. However, of the ANAs detected half were monoclonal, unlike the polyclonality of the ANAs in the control group. That 4.8% of the paraproteins were monoclonal ANAs suggests that the process leading to paraproteinemia may activate usually silent autoreactive B cells as well as the normal B cell repertoire.
1382910 Lupus-like autoimmune disease induced by interferon therapy for myeloproliferative disorde 1992 Oct Symptoms of autoimmune disease were evaluated in 125 patients with chronic myelogenous leukemia (CML) and in 12 patients with essential thrombocythemia undergoing treatment with recombinant interferon (IFN)-alpha-2b plus/minus low-dose recombinant IFN-gamma. Twenty-seven of 137 patients (20%) developed rheumatoid symptoms. Furthermore, the incidence of antinuclear antibody (ANA) formation was studied. Elevated ANA titers were found in 5/19 (26%) of CML patients at the time of diagnosis and in 3/18 (17%) of patients treated with hydroxyurea or busulfan. During IFN treatment, 18 of 25 tested patients (72%) had elevated ANA titers. In 15 of these ANA-positive patients, clinical signs of autoimmune disease appeared. All these patients were under long-term IFN treatment and were in remission of disease. In three patients criteria for systemic lupus erythematosus were fulfilled. Severity of side effects had led to the discontinuation of IFN treatment in these patients. The data indicate that IFN-alpha and IFN-gamma can induce ANA associated with autoimmune disease in patients with myeloproliferative disorders.
8889493 Protection against peroxynitrite-dependent tyrosine nitration and alpha 1-antiproteinase i 1996 Sep Peroxynitrite, formed by reaction of superoxide and nitric oxide, appears to be an important tissue-damaging species generated at sites of inflammation. In this paper, we compare the abilities of several biological antioxidants to protect against peroxynitrite-dependent inactivation of alpha 1-antiproteinase, and to inhibit tyrosine nitration upon addition of peroxynitrite. GSH and ascorbate protected efficiently in both systems. Uric acid inhibited tyrosine nitration but not alpha 1-antiproteinase inactivation. The possibility that ascorbic acid is an important scavenger of reactive nitrogen species in vivo is discussed.
1579936 [Adult-onset Still's disease. Diagnosis, differential diagnosis and treatment]. 1992 Mar 30 The article describes two cases of adult Still's disease and reviews the relevant literature. Adult onset Still's disease is characterized by high peaks of fever, arthritis, arthralgia, rash, increased erythrocyte sedimentation rate, leucocytosis, liver dysfunction and negative tests for antinuclear antibodies and rheumatoid factors. Still's disease should be regarded as a possible differential diagnosis in adult patients who present such features.
8070167 Rheumatoid pericarditis: new immunopathological aspects. 1994 May Rheumatoid pericarditis (RP) is a well known extraarticular manifestation of rheumatoid arthritis (RA). It is not frequently diagnosed despite its high reported prevalence in post-mortem studies. There have been no immunohistological studies of its presence in pericardial membranes. Here we report a complete immunohistological study of two RA patients with RP complications, using a panel of monoclonal antibodies (mAbs) for the recognition of B, T, and NK cells. Both cases showed strong and almost exclusive pericardial membrane infiltration of CD8+ T-cells which was correlated with a higher than expected similar increase in the subset of peripheral blood lymphocytes (PBL). These findings suggest an important role for CD8+ T-cells in chronic RA, especially in this extraarticular manifestation of the disease.
8219991 [The immunoactive properties of trekrezan]. 1993 May It was shown that in vivo trecrezan possessed strong immunoactive properties: it decreased the spot-forming activity of polypotent stem blood cells, stimulated lympho- and hemopoesis, antibody formation, possessed steady antiinflammatory activity. It stimulated in vitro mononuclear cell proliferation in man due to its direct action on B lymphocytes and increase in lymphokine and monokine production.
8508555 IgM rheumatoid factor and the inhibition of covalent binding of C4b to IgG in immune compl 1993 Mar Work by other investigators has shown that IgM-rheumatoid factors (IgM-RF's) can impede complement-mediated inhibition of immune precipitation. We examined the binding of complement component C4b to radiolabelled IgG in model immune complexes and demonstrate that IgM-RF's are capable of reducing the covalent binding of C4b to 125I-IgG in the complexes. Reduced binding to IgG, however, may not be accompanied by binding of C4b to IgM-RF's within the complex, as we also demonstrate that IgM-RF's are relatively poor at C4b capture compared with normal IgM.
7656013 Structure of the catalytic domain of human fibroblast collagenase complexed with an inhibi 1994 Feb In rheumatoid and osteoarthritis, degradation of articular cartilage is mediated by the matrix metalloproteinases collagenase, stromelysin and gelatinase. The key event in this process is the cleavage of triple helical collagen by collagenase. We have determined the crystal structure of the catalytic domain of human recombinant fibroblast collagenase complexed with a synthetic inhibitor at 2.2 A resolution. The protein fold is similar to the amino termini of the zinc endopeptidases astacin thermolysin and elastase despite a lack of primary sequence homology. The conformation of the bound inhibitor provides a molecular basis for the design of inhibitors of collagenase and other matrix metalloproteinases. Such inhibitors should be useful in the treatment of a variety of diseases including arthritis and cancer.
8816427 Reduced susceptibility to collagen-induced arthritis in mice deficient in intercellular ad 1996 Oct 1 Intercellular adhesion molecule-1 (ICAM-1) plays an important role in the firm adhesion of leukocytes to venular endothelium and facilitates leukocyte extravasation from the vasculature into inflamed tissue. In addition, ICAM-1 is an important costimulatory molecule during Ag presentation to lymphocytes. Using mice deficient in ICAM-1, we have investigated the role of this molecule in the development of collagen-induced arthritis. After immunization with type II collagen, 71% of wild-type mice developed arthritis compared with 50% of ICAM-1 heterozygote mutants and 18% of ICAM-1 homozygous mutants. In those ICAM-1 mutants that developed arthritis, the mean day of onset, the mean number of involved paws, and the severity of paw inflammation were not significantly different from those in wild-type mice. The reduced incidence of arthritis in the ICAM-1 homozygous mutant mice was not due to lack of immunity to type II collagen, since these mice developed similar levels of anti-type II collagen IgG compared with wild-type mice and had a positive delayed-type hypersensitivity reaction to type II collagen. The reduction of arthritis in heterozygous as well as homozygous deficient mice indicates that expression of ICAM-1 can be a pivotal variable in the pathogenesis of collagen-induced arthritis in mice. The results suggest that naturally occurring genetic variation in the expression of ICAM-1 or related inflammatory cell adhesion molecules might influence susceptibility to the complex disease of rheumatoid arthritis in humans and support the concept that pharmacologic approaches to chronic reduction in the expression or the function of ICAM-1 may be of therapeutic value.
7575710 Interleukin-2 diphtheria fusion protein (DAB486IL-2) in refractory rheumatoid arthritis. A 1995 Sep OBJECTIVE: This pilot phase II, double-blind, placebo-controlled trial of 1 month duration, with a 2-3-month open-label extension, evaluated the safety, tolerability, biologic effects, and efficacy of interleukin-2 diphtheria fusion protein (DAB486IL-2) in refractory rheumatoid arthritis (RA). METHODS: Forty-five RA patients were enrolled in the trial, and were randomized, after a 3-4-week disease-modifying antirheumatic drug washout, to receive a daily intravenous dose of either DAB486IL-2 or placebo (saline) for 5 days. A blinded, third-party observer evaluated arthritis activity. Clinical response was defined as > or = 25% improvement in swollen and tender joints and > or = 25% improvement in at least 2 of 6 additional parameters. The double-blind phase was 4 weeks; placebo patients could cross over to receive open-label treatment for a maximum of 3 monthly DAB486IL-2 cycles. RESULTS: In the double-blind phase, 4 of 22 patients (18%) in the treated group and none in the placebo group (P = 0.05) met the criteria for clinical response. During the open-label treatment phase, 11 of 36 patients (31%) and 11 of 33 patients (33%) had a clinical response after completing 2 and 3 courses of DAB486IL-2, respectively. Adverse events included transient fever/chills (45%), nausea/vomiting (50%), elevated (< or = 3 x normal) transaminases (55%), and increased joint pain (45%). Twelve patients (8 placebo, 4 DAB486IL-2) did not complete 3 treatment cycles. No apparent differences were noted in CD4+ CD25+ cells of responders versus nonresponders, or of DAB486IL-2-treated versus placebo-treated patients. CONCLUSION: Clinical responses were noted in patients treated with DAB486IL-2 (18%) compared with placebo (0%) in the double-blind phase. In the open-label phase, 33% of patients completing 3 monthly DAB486IL-2 cycles had improvement in arthritis activity. Further studies of IL-2 diphtheria fusion proteins are warranted to elucidate factors that may predict clinical response and define mechanism(s) of action.
8973869 Serum secretory immunoglobulins in ankylosing spondylitis. 1996 Nov Humoral mucosal immunity may be implicated in pathophysiology of ankylosing spondylitis (AS). The aim of the study was to evaluate serum levels of IgA, IgM and secretory IgA (sIgA), secretory IgM (sIgM) as well as free secretory component (FSC) in patients with AS compared to controls and rheumatoid arthritis (RA) patients. Levels of sIgA, sIgM and FSC were measured with a specific ELISA in 37 AS patients, 45 controls and 27 RA. The results were as follows: Serum levels of IgA were higher in AS vs controls and in RA vs controls (p = 0.01). Levels of sIgA were higher in AS vs controls (p = 0.01), but higher in RA vs AS (p = 10(-4)). There was no difference of sIgM in AS vs controls, FSC levels were higher in AS vs controls, and higher in AS patients with elevated CRP. In view of elevated FSC, this increase of sIgA in AS may have been due to excessive production of mucosal IgA after bacterial stimulation according to the current hypothesis of the disease.
7837141 Stimulation of human synovial cell DNA synthesis by iron. 1994 Oct OBJECTIVE: To determine the effect of iron and cytokines on proliferation of synovial cells (SC), we isolated SC obtained at the time of total knee replacement from 11 patients with rheumatoid arthritis (RA) and 2 with osteoarthritis (OA) following enzymatic treatment of synovial tissue. METHODS: SC were cultured in the presence of ferric citrate or sodium citrate at concentrations of 0, 0.01, 0.1, and 1 mM for 72 h. In vitro synthesis of DNA by SC was measured by intracellular 3H-thymidine uptake. RESULTS: Synthesis of DNA by SC was significantly enhanced by ferric citrate but not sodium citrate. The maximum synthesis was observed following stimulation with 0.1 mM ferric citrate and was obtained after 3 days of culture, thereafter declining until Day 7. This stimulatory effect of ferric citrate was observed in all specimens of SC tested. In our examination of the concomitant addition of each of 8 different recombinant human cytokines with 0.1 mM ferric citrate on SC DNA synthesis, 4 of them, i.e., interleukin-1 beta (IL-1 beta), IL-7, tumor necrosis factor alpha (TNF alpha) and interferon gamma (IFN-gamma) each enhanced the synthesis of SC DNA at concentrations ranging from 1 to 100 u/ml, while IL-1 beta, IL-7, TNF alpha or IFN-gamma together showed an additive effect. No significant effect was shown by IL-2, IL-6, and IL-8, or granulocyte colony stimulating factor (G-CSF). CONCLUSION: Iron stimulated in vitro SC DNA synthesis and had an additive effect on the activity of human cytokines for SC proliferation. Iron may play a role in the proliferation of synovial cells in patients with RA synovitis.