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ID PMID Title PublicationDate abstract
8060760 Immunosuppressive drug therapy. 1994 May Interstitial lung disease frequently complicates rheumatic disorders, especially polymyositis-dermatomyositis, rheumatoid arthritis, systemic sclerosis, and mixed connective tissue disease. In this article, we review the current data supporting the use of azathioprine, cyclophosphamide, chlorambucil, cyclosporine, and methotrexate in the management of chronic interstitial pneumonitis-fibrosis. The literature addressing the utility of these immunosuppressive-cytotoxic agents, however, consists almost entirely of anecdotal successes and small, uncontrolled series. Although no convincing data have proven that the use of any of these agents with or without corticosteroids is superior to therapy with corticosteroids alone, the literature may suggest a slight long-term survival advantage when either azathioprine or cyclophosphamide is added to prednisone therapy. Studies in which cyclosporine was used, however, have been less encouraging. Data regarding the use of chlorambucil and methotrexate are too sparse to permit any conclusions. Further controlled studies are required to clarify the role of these immunosuppressive agents in the treatment of interstitial lung disease.
8283059 Soluble Fc gamma RIIIa is present in plasma and is derived from natural killer cells. 1994 Jan 15 Fc gamma RIII (CD16), a receptor for complexed IgG, is encoded by two very homologous genes: Fc gamma RIIIA and Fc gamma RIIIB. NK cells and macrophages express Fc gamma RIIIa, whereas only neutrophils constitutively express Fc gamma RIIIb. In a previous study we found that soluble (s)Fc gamma RIII in plasma seemed to originate only from neutrophils. However, CD16 mAb, directed against different epitopes of Fc gamma RIII, precipitated a glycoprotein from plasma of homozygous Fc gamma RIIIB gene-deficient donors. This glycoprotein migrated in a similar way as did released Fc gamma RIIIa derived from NK cells, whereas Fc gamma RIIIa released by cultured monocytes migrated differently and appeared to be more heavily glycosylated on SDS-PAGE. After deglycosylation, the M(r) of the plasma sFc gamma RIIIa was similar to that of released Fc gamma RIIIa. Moreover, V8-protease maps were identical. Therefore, we conclude that sFc gamma RIIIa is also present in plasma and is derived from NK cells. Because sFc gamma RIII levels are hardly detectable in the plasma of most homozygous Fc gamma RIIIB gene-deficient donors, we suspect that the sFc gamma RIIIa level is negligible compared with the level of sFc gamma RIIIb in plasma of healthy donors. Two patients with an NK cell lymphocytosis had a high plasma level of sFc gamma RIIIaNK. Furthermore, high levels of sFc gamma RIIIaNK were found in plasma of two patients with rheumatoid arthritis. Thus, the level of sFc gamma RIIIaNK might reflect either an increase in circulating NK cells or an enhanced release of Fc gamma RIIIaNK in certain diseases. This study shows that an assay that discriminates between sFc gamma RIIIa and sFc gamma RIIIb is necessary for the interpretation of sFc gamma RIII levels in patients.
8385798 IgA and IgG subclass deficiency in a poor population in a developing country. 1993 Apr The levels of IgG, IgG subclasses, IgM and IgA were determined in serum from 17 patients with IgA deficiency and severe or frequent infections, allergy and/or autoimmunity (median age 7 years, range 2-19), 11 healthy IgA-deficient adults and 35 controls (median age 7 years, range 2-19). In serum from all groups IgG, IgM and IgA antibodies were determined against beta-lactoglobulin, E. coli O antigens and poliovirus type 1 antigen. In saliva of 15 IgA-deficient patients and 12 of the controls IgG, IgM and secretory component-carrying antibodies against E. coli O antigens and poliovirus type 1 were determined. The majority of the studied individuals lived under poor socio-economic conditions in Brazil, with consequent heavy microbial exposure. One IgA-deficient patient with rheumatoid arthritis also had IgG2 deficiency but no infectious problems. Four out of the 35 controls without any obvious infectious problems were found with IgA or IgG subclass deficiency. One of the 11 healthy IgA-deficient adults was low in the IgG2 subclass, one in IgG1 and one in IgG3. Those with symptomatic IgA deficiency had significantly higher serum IgG than the controls, especially in the age group 6-11 years. This latter group also had significantly increased serum IgG1 and IgG2 levels when compared with the age-matched controls. Salivary IgM antibodies to E. coli and poliovirus antigens were significantly higher among the symptomatic IgA-deficient individuals than among the controls. It is not clear at present whether these increased Ig levels are secondary to frequent infections and/or part of mechanisms that may compensate for the IgA deficiency.
10146962 Misoprostol: pharmacoeconomics of its use as prophylaxis against gastroduodenal damage ind 1993 Feb Misoprostol effectively prevents nonsteroidal anti-inflammatory drugs (NSAID)-induced gastric ulcer and is the only agent currently indicated for this purpose. In addition, misoprostol is effective as prophylaxis against NSAID-induced duodenal ulcer. Because of the widespread use of NSAIDs, the cost of routine misoprostol prophylaxis would be high, and thus its pharmacoeconomic evaluation is an important factor in assessing the most appropriate role of misoprostol in this group of patients. Current cost-benefit analyses undertaken in major European centres and the US have generally indicated that, depending on initial assumptions, misoprostol prophylaxis over a 3-month period is cost-saving in patients with osteoarthritis taking NSAIDs. The net savings (costs) realised were dependent on several variables, including the acquisition cost of misoprostol, silent ulcer rate and patients' compliance. Importantly, misoprostol prophylaxis was consistently more cost-beneficial in elderly patients aged greater than 60 to 65 years than in their younger counterparts. In contrast, in one study misoprostol was found to reduce patients' quality of life and, although misoprostol therapy is potentially cost-saving to society, patients generally preferred no therapy. A single study assessing the cost-effectiveness of misoprostol prophylaxis in preventing ulcerative complications concluded that primary treatment was not an economically viable option for all NSAID users. Misoprostol was most cost-effective in the prevention of recurrent or secondary gastric ulcer complications in 'high-risk' patients, for example patients aged over 60 years and patients with rheumatoid arthritis. Thus, although there are areas of interest awaiting further pharmacoeconomic investigation, misoprostol prophylaxis appears to be cost-effective in elderly and high risk patients receiving NSAIDs. Additionally, misoprostol prophylaxis is cost-saving in elderly patients with osteoarthritis requiring NSAID therapy.
1522390 Levamisole causes differential cytokine expression by elicited mouse peritoneal macrophage 1992 Sep Thioglycolate-elicited peritoneal macrophages from normal C57B1/6J mice were examined in vitro for bacterial lipopolysaccharide (LPS)-stimulated interleukin-1 (IL-1), IL-6, and tumor necrosis factor (TNF) production. Macrophages from mice administered a single oral dose of levamisole (3 mg/kg) 1 to 4 days prior to macrophage harvest demonstrated a twofold enhancement of IL-1 production compared to vehicle-treated mice. In contrast, IL-6 production and TNF production by the same macrophages were inhibited up to 36 and 62%, respectively, compared to production by macrophages harvested from vehicle-treated mice. Similar results were observed when IL-1 production and TNF production were followed in peritoneal exidate cells directly stimulated with levamisole in vitro. The ex vivo LPS-stimulated IL-1 production was enhanced 4 days after macrophage elicitation, whereas TNF and IL-6 production returned to baseline by 72 h after macrophage recruitment and augmentation. No evidence could be found for the presence of inhibitors of TNF or IL-6. The specificity of the IL-1, IL-6, and TNF bioactivities was demonstrated by neutralization with specific antisera. Immunoprecipitation studies of supernatants from biosynthetically labeled macrophages also revealed augmented IL-1 production and decreased IL-6 and TNF, indicating that levamisole may have affected cytokine production at the translational level. Kinetics studies revealed that ex vivo release of IL-6 and TNF by macrophages from levamisole-dosed mice was delayed compared to production of these cytokines by macrophages harvested from mice given vehicle only. The results may explain, in part, the reported ability of levamisole to ameliorate cases of rheumatoid arthritis or other autoimmune and inflammatory diseases by affecting the relative levels of cytokines produced by macrophages recruited to sites of injury, which are associated with inflammation and acute-phase protein synthesis.
1315967 Intravenous infusion of n-3 polyunsaturated fatty acids. 1992 Jun Dietary supplementation with n-3 polyunsaturated fatty acids (PUFA) is regarded as beneficial for the prevention and treatment of atherosclerosis and thrombosis and chronic inflammatory diseases like rheumatoid arthritis and psoriasis. It may be possible to treat some acute diseases like acute myocardial infarction or acute rejection of grafted organs if it is possible to make n-3 PUFA take effect quickly (in hours instead of days). Three sets of experiments were done. In Experiment 1, emulsion of trieicosapentaenoyl-glycerol (EPA-TG) and tridocosahexaenoyl-glycerol was infused through rabbit ear veins, and the leukotriene B4/B5 production from polymorphonuclear leukocytes was measured at different time points by high-performance liquid chromatography. In Experiment 2, delayed type hypersensitivity (DTH) of mice was measured with sheep red blood cells as an antigen. Pure n-3 PUFA emulsions or a control solution were infused through tail veins just before the second challenge of the antigen. DTH was measured 24 hr after the second challenge. In Experiment 3, human natural killer cell activity was measured using K562 target cells before and after the infusion of pure EPA-TG emulsion to an antecubital vein. Leukotriene B4 production by rabbit polymorphonuclear leukocytes was depressed by 40% by EPA-TG infusion. DTH was suppressed almost completely by n-3 PUFA infusion. Natural killer cell activity was suppressed almost completely by EPA-TG infusion in 8 hr. DTH, natural killer cell activity, and leukotriene B4 production are probably related to acute rejection of grafted organs.(ABSTRACT TRUNCATED AT 250 WORDS)
1312060 Colchicine and methotrexate reduce leukocyte adherence and emigration in rat mesenteric ve 1992 Feb Colchicine and methotrexate are commonly used in the treatment of gout and rheumatoid arthritis, respectively; however the mechanism(s) of action of these drugs remain(s) unknown. The objective of this study was to determine whether colchicine and methotrexate can modify the adhesion and emigration of leukocytes in postcapillary venules that are exposed to inflammatory mediators such as platelet-activating factor (PAF) and leukotriene B4 (LTB4). The rat mesentery was prepared for in vivo microscopic observation. Venules with internal diameters ranging between 25 and 35 microns were selected for study. Erythrocyte velocity, vessel diameter, leukocyte rolling velocity, and the number of adherent (stationary for greater than or equal to 30 sec) and emigrated leukocytes were measured during superfusion of the mesentery with bicarbonate-buffered saline (BBS). Repeat measurements of adhesive and hemodynamic parameters were obtained between 50 and 60 min of superfusion with either 100 nM PAF or 20 nM LTB4 added to the superfusate. In some experiments, 1 microM of either colchicine or methotrexate was added to the superfusate containing either PAF or LTB4. Both PAF and LTB4 caused increases in leukocyte adherence and emigration and reductions in leukocyte rolling velocity and venular shear rate. Colchicine effectively prevented all of the adhesive and hemodynamic alterations induced by both inflammatory mediators, while methotrexate was largely effective in preventing the responses elicited by PAF, but not LTB4. These results indicate that the therapeutic actions of colchicine and methotrexate may result from the ability of these agents to interfere with the adhesion and emigration of leukocytes from postcapillary venules.
1535518 Natural and recombinant interleukin 1 receptor antagonist does not inhibit human T-cell pr 1992 Jan Interleukin 1 receptor antagonist (IL-1ra) has been found in glycosylated form in the urine of febrile patients or of children with rheumatoid arthritis, and in the supernatant of monocytes cultured in the presence of immune complexes. It blocks competitively the binding of IL-1 alpha and beta to their receptors. Produced amongst others by mononuclear cell lines and matured monocytes and alveolar macrophages, it prevents prostaglandin E2 and collagenase production by fibroblasts and synovial cells. In mice, IL-1ra improves survival after lethal endotoxemia. In this study, both natural and recombinant human IL-1ra (rhIL-1ra) were tested in an allogeneic T-cell reaction, and in mitogen- or antigen-induced lymphocyte proliferation. Neither the natural nor the rhIL-1ra blocked T-cell proliferation, but rhIL-1ra abolished the effect of exogenous IL-1 beta. This was not due to a loss of bioactivity of IL-1ra in culture, as the IL-1ra of the supernatant still completely inhibited 125I-IL-1 alpha binding to EL 4-6.1 cells and markedly reduced PGE2 production during antigen presentation. We conclude that IL-1ra alone, even at high concentrations, is not sufficient to block human T-cell proliferation in vitro.
1441312 Prevalence and classification of anemia in elective orthopedic surgery patients: implicati 1992 We audited 281 consecutive orthopedic patients scheduled for surgery for whom blood type/cross-matching was requested over a 6-month period. One hundred and sixty-two patients predonated autologous blood at University Hospitals of Cleveland, and 34 (21%) of these were anemic [hematocrit (Hct) less than or equal to 39%] at initial donation. Twelve (35%) of these 34 anemic autologous blood donors subsequently received homologous blood. In contrast, 18 (15%) of 128 nonanemic autologous blood donors received homologous blood (p = 0.05). In 119 patients who did not donate autologous blood, 39 (33%) were anemic at admission. Of these, 22 (56%) received homologous blood. In the 80 remaining nonanemic patients, 33 (41%) received homologous blood (p = 0.119). Analysis of discharge Hct indicates that 31 (12%) of 263 evaluable patients were possibly transfused inappropriately. The anemias of a cohort of 30 autologous donors were analyzed: 5 had rheumatoid arthritis without iron deficiency. Nine (30%) others had evidence of iron deficiency. Sixteen (53%) had an unclassified anemia of chronic disease. We conclude: (1) the high rates of homologous blood exposure indicate a need for innovative blood conservation strategies in anemic autologous blood donors; (2) the prevalence of anemia and the high rates of homologous blood exposure in anemic patients who did not donate autologous blood demonstrate a need for early recognition and treatment in order to procure autologous blood and reduce homologous blood exposure; (3) the presence of inappropriate autologous and homologous transfusions demonstrates a need for more effective physician education programs that emphasize 'no blood transfusion' as an alternative to enhance blood conservation effectiveness.
1349444 Making sense of NSAID gastropathy and considering the therapeutic options. 1992 There is increasing recognition that nonsteroidal anti-inflammatory drugs (NSAIDs), while quite effective in treating arthritic symptoms, are associated with gastrointestinal mucosal damage. Although therapy for patients with NSAID-induced ulcers or those at high risk of developing them is still a matter of debate, the current literature supports the use of misoprostol as the only drug effective for the prevention of both NSAID-induced gastric and duodenal ulceration. It has also been shown to treat NSAID-induced gastropathy in patients continuing their NSAID therapy. In a study of misoprostol (100 or 200 micrograms QID) plus NSAID, after three months of continuous therapy, a significantly lower frequency of gastric ulcers in the misoprostol-treated group was revealed: 100 micrograms misoprostol, 5.6%; 200 micrograms misoprostol, 1.4%; placebo, 21.7%. A recent three-month, placebo-controlled study established the efficacy of misoprostol 200 micrograms QID in the prevention of NSAID-induced duodenal ulcers in 429 patients with osteoarthritis (OA), rheumatoid arthritis (RA), or other rheumatic disease, who were receiving daily treatment with various NSAIDs. The incidence of duodenal ulcer development over three months was 1.0% in patients treated with misoprostol versus 6.3% in placebo-treated patients (P = 0.004). The same trial also evaluated the efficacy of misoprostol 200 micrograms QID versus placebo in preventing NSAID-induced gastric ulcers. The incidence of gastric ulcer over the three-month treatment period was 1.5% in patients treated with misoprostol versus 9.0% in placebo-treated patients (P = 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
18476258 The cellular metabolism and effects of gold complexes. 1994 Leads to the cellular effects of the anti-arthritic gold complexes may come from the determination of their metabolism by target cells and, possibly, cells in the immediate environment of the target cells. Polymorphonuclear leukocytes (PMN) and mononuclear cells (monocytes and lymphocytes) are present in inflamed joints of patients with rheumatoid arthritis and these cells have been widely used in pharmacological studies on the gold complexes. It is suggested that the cellular effects of the gold complexes are mediated by the production of aurocyanide. According to this hypothesis, PMN metabolize small quantities of thiocyanate to cyanide which, in turn, converts gold complexes, such as aurothiomalate, to aurocyanide (dicyanogold(I)) which inhibits the functions of PMN and other cells. There is now considerable evidence for this hypothesis from in vitro studies but there is little in vivo work to back up the hypothesis. One of the few in vivo studies which tested the hypothesis involved the examination of the activity of aurothiomalate in the treatment of polyarthritis in Hooded Wistar rats. Activity of aurothiomalate is only shown in animals which received thiocyanate. Hydrogen cyanide is a constituent of cigarette smoke and the aurocyanide formed by the interaction with gold complexes and inhaled hydrogen cyanide rapidly diffuses into red blood cells. Because of the metabolism of hydrogen cyanide to thiocyanate in the liver, there are higher plasma levels of thiocyanate in smokers than in non-smokers. Smokers may have a greater incidence of side effects than non-smokers but there appears to be little difference in therapeutic response, possibly because there is sufficient thiocyanate in extracellular fluid, even in non-smokers, to support the conversion of gold complexes to aurocyanide. The relationship between the metabolism and effects of the orally active gold complex, auranofin are less clear. Auranofin itself is taken up by cells with the loss of the ligands bound to gold while its inhibitory activity against the oxidative burst of PMN decreases with increasing cell density. For example, the lucigenin-dependent chemiluminescence of 10(6) PMN/ml is 46 percent of control at 0.5 muM auranofin but only 2.2 percent in 2.10(5) PMN/ml in the presence of the same concentration of auranofin. A potentially active gold complex is a plasma component which is taken up by red blood cells.
8970971 A cytotoxic nonstructural protein, NS1, of human parvovirus B19 induces activation of inte 1996 Dec We examined the biological function of a nonstructural regulatory protein, NS1, of human parvovirus B19. Because of the cytotoxic activity of NS1, human hematopoietic cell lines, K562, Raji, and THP-1, were established as transfectants which produce the viral NS1 protein upon induction by using bacterial lactose repressor/operator system. NS1 was significantly produced in the three transfectant cells in an inducer dose- and time-dependent manner. Surprisingly, these three transfectants secreted an inflammatory cytokine, interleukin-6 (IL-6), in response to induction. However, no production of other related cytokines, IL-1beta, IL-8, or tumor necrosis factor alpha, was seen. Moreover, NS1-primed IL-6 induction was transiently demonstrated in primary human endothelial cells. Analysis with luciferase reporter plasmids carrying IL-6 promoter mutant fragments demonstrated that NS1 effect is mediated by a NF-kappaB binding site in the IL-6 promoter region, strongly implying that NS1 functions as a trans-acting transcriptional activator on the IL-6 promoter. Our novel finding, IL-6 induction by NS1, supports the possible relationship between parvovirus B19 infection and polyclonal activation of B cells in rheumatoid arthritis and indicates that NS1 protein may play a significant role in the pathogenesis of some B19-associated diseases by modulating the expression of host cellular genes.
8957102 Autoantibodies to the A/B proteins of the heterogeneous nuclear ribonucleoprotein complex: 1996 Dec Heterogeneous nuclear ribonucleoprotein (hnRNP) complexes are major constituents of the spliceosome. They are composed of approximately 30 different proteins which can bind to nascent pre-mRNA. Among these, the hnRNP-A/B proteins form a subgroup of highly related proteins: their N-terminal halves consist of two adjacent RNA-binding domains, whereas the C-terminal halves contain almost 50% glycine residues. These proteins represent a group of novel autoantigens which are targeted by autoantibodies from patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and mixed connective tissue disease (MCTD): thus, anti-A2/RA33 autoantibodies target the hnRNP proteins A2, B1, B2 (the 'RA33 complex'), and anti-A1 autoantibodies are directed to the hnRNP proteins A1 and A1b. In SLE, anti-hnRNP-A/B antibodies frequently occur together with antibodies to two other spliceosome-associated antigens, U1 small nuclear RNP (U1-snRNP) and Sm. Epitope-mapping studies have revealed that the major antibody binding sites are located in the RNA-binding regions. Furthermore, there is some indication of disease-specific epitope recognition. Studies in animal models have demonstrated the presence of anti-hnRNP-A/B antibodies in several lupus-prone mouse strains. Thus, autoantibodies to the spliceosomal hnRNP-A/B proteins are a common feature of RA, SLE, and MCTD. However, these diseases differ in their reactivities to other spliceosomal components, such as U1-snRNP and Sm antigens. Therefore, anti-hnRNP-A/B autoantibodies are not only valuable diagnostic markers but may also allow additional insights into the pathogenetic mechanisms of rheumatic autoimmune diseases.
8806236 The immunological effect of 8-methoxypsoralen and UVA treatment on murine T-cell leukemia. 1996 Sep 8-Methoxypsoralen (8-MOP) plus long-wavelength UV radiation (UVA, 320-400 nm) have been used to treat various diseases such as cutaneous T-cell lymphoma, systemic scleroderma, rheumatoid arthritis and rejection of heart transplants. However, the immunological mechanism of this treatment remains unknown. In this report, we investigated the effect of 8-MOP/UVA on the modulation of the immunogenicity of a T-cell leukemia cell line (RL male 1 cells). The results demonstrated that the stimulator function of the in vitro 8-MOP/UVA-treated RL male 1 cells was enhanced in both RL male 1-specific allogeneic and syngeneic immune responses. Furthermore, the enhancement of the immunogenicity of the 8-MOP/UVA-treated RL male 1 cells was found to be strongly associated with the increase of intercellular adhesion molecule-1 expression on these 8-MOP/UVA-treated tumor cells. Therefore, our findings suggested that the alteration of the expression of the immune-related cell surface molecules might be an important effect of 8-MOP/UVA treatment on the elevation of the immunogenicity of the 8-MOP/UVA-treated tumor cells.
8705860 Suppressive vaccination with DNA encoding a variable region gene of the T-cell receptor pr 1996 Aug A variable region gene of the T-cell receptor, V beta 8.2, is rearranged, and its product is expressed on pathogenic T cells that induce experimental autoimmune encephalomyelitis (EAE) in H-2u mice after immunization with myelin basic protein (MBP). Vaccination of these mice with naked DNA encoding V beta 8.2 protected mice from EAE. Analysis of T cells reacting to the pathogenic portion of the MBP molecule indicated that in the vaccinated mice there was a reduction in the Th1 cytokines interleukin-2 (IL-2) and interferon-gama. In parallel, there was an elevation in the production of IL-4, a Th2 cytokine associated with suppression of disease. A novel feature of DNA immunization for autoimmune disease, reversal of the autoimmune response from Th1 to Th2, may make this approach attractive for treatment of Th1-mediated diseases like multiple sclerosis, juvenile diabetes and rheumatoid arthritis.
8685481 [Bronchiolitis obliterans organizing pneumonia. Review of six cases]. 1996 Feb BACKGROUND: Bronchiolitis obliterans with organizing pneumonia (BOOP) is recently described clinicopathological entity, with only a few series of patients reported. Terminology is unclear, which together with its rarity lead to a poor understanding of the entity. OBJECTIVE: To review the clinical, radiological, and laboratory features and the response to therapy in cases of BOOP in our environment. MATERIALS AND METHODS: A total of 463 lung biopsies were obtained at Móstoles Hospital, Madrid, from 1992 to 1994. In six cases the anatomo-pathological diagnosis was BOOP. Clinical histories of these patients were reviewed. RESULTS: Six patients were diagnosed with BOOP. From these six patients, four (66%) were female, with a mean age of 59 years (45-74 years). Three patients (50%) were smokers. BOOP was idiopathic in four cases (66%) and secondary to rheumatoid arthritis in one (17%) and Legionella pneumonia in another patient (17%). Patients presented with cough and dyspnea (100%), chest pain and constitutional syndrome (66%) and fever (34%) of one to eight weeks evolution. Laboratory data included: increased ESR (100%), abnormal levels of liver enzymes (83%), hypoxemia (83%) and abnormal spirometry (50%). Radiological studies demonstrated alveolar infiltrates in 83%, predominantly in lower lobes, which were of a migratory nature in 33%. CT, performed in five patients, demonstrated alveolar infiltrates in all patients, which were bilateral and peripheric in two. Transbronchial biopsy was diagnostic in five cases, and in one patient thoracotomy had to be performed. One patient died (17%); the remaining patients (83%) improved with steroids, although 34% relapsed. Mean follow-up time was eleven months (5-24 months). CONCLUSIONS: BOOP observed in our environment is a rare entity, usually of an idiopathic nature, which presents with characteristic clinical course and laboratory findings. Transbronchial biopsy is diagnostic in many patients. The clinical course is good with steroids in most patients, although relapses are common.
8966498 Intermittent cyclic therapy with etidronate prevents corticosteroid-induced bone loss: two 1996 The purpose of this study was to evaluate the efficacy of intermittent cyclic therapy (ICT) with etidronate in preventing the loss of lumbar vertebral bone mineral density (BMD) in patients taking corticosteroids. The study population was a cohort of patients taking corticosteroids for at least two years for polymyalgia rheumatica, asthma, rheumatoid arthritis, systemic lupus erythematosus or other conditions. A tertiary care university teaching hospital-affiliated rheumatology office practice. Inclusion and exclusion criteria yielded eighty-eight patients taking corticosteroids for at least two years who had not taken estrogen or fluoride and had no causes of secondary osteoporosis. Changes relative to baseline in individual vertebral (L2-L4) BMD measurements after one and two years were compared between patients who had taken ICT with etidronate (n = 42) and those who had not (n = 46). We found that BMD in the lumbar spine increased significantly over baseline in patients who had taken ICT with etidronate, by 3.9% after one year and by 5.6% after two years, whereas it decreased by 3.7-3.8% in patients who had not. We conclude that ICT with etidronate prevents corticosteroid-induced osteoporosis and progressively ameliorates BMD over two years. Double blind trials are underway to evaluate whether this increased BMD is associated with reductions in vertebral fracture rates.
8922048 Cardiac involvement in connective tissue diseases and primary antiphospholipid syndrome: e 1996 The aim of this study was to determine the incidence of cardiac involvement in systemic lupus erythematosus (SLE), progressive systemic sclerosis (PSS), rheumatoid arthritis (RA) and primary antiphospholipid syndrome (PAPS), and to evaluate the correlation between cardiac involvement and antiphospholipid autoimmunization. M-mode, two-dimensional and Doppler echocardiography was performed in 101 consecutive patients (46 with SLE, 23 with PSS, 12 with RA, 20 with PAPS) and in 20 healthy subjects. None of the patients and of the controls had clinical evidence of cardiac disease. IgG anticardiolipin antibodies (aCL) were measured by an enzyme-linked immunosorbent assay. Valvular lesions were found in 18 SLE patients (39.1%), in 4 PSS patients (17.4%) and in 3 RA patients (25%). In comparison with the control subjects abnormal indexes of left ventricular filling (characterized by a reduced E/A end E/A-VTI ratios, a lower deceleration rate of EF slope and a prolonged IVRT) was only found in patients with connective tissue disease (15.1% in SLE patients, 30% in PSS patients and 40% in RA patients). The presence of aCL was not related to a different prevalence of valve alterations or alterated left ventricular diastolic function. None of the patients with PAPS showed valvular involvement or altered left ventricular filling. It is concluded that cardiac involvement is frequent in patients with connective tissue diseases but is apparently unrelated to increased aCL levels.
8752516 [Interstitial pneumonia associated with collagen vascular diseases: histological findings, 1995 Dec Collagen vascular diseases are systemic inflammatory disorders, and autoimmune abnormalities play an important role in their pathogenesis. The lungs are often involved and the manifestations can be quite heterogenous. Cases of interstitial pneumonia associated with collagen vascular disease must be distinguished from infection, malignancy, cardiac failure, and renal failure. The diversity of interstitial pneumonia can be seen in the results of computerized tomography and in cells found in bronchoalveolar lavage fluid (BALF). We examined the heterogeneity of interstitial pneumonia diagnosed by open lung biopsy, and evaluated the diagnostic accuracy of BALF cell findings by comparing then with results of histological studies. Three patterns of BALF cell findings were defined, and were used to study the heterogeneity of the interstitial pneumonia associated with collagen vascular diseases: sarcoidosis, usual interstitial pneumonia (UIP), and bronchiolitis obliterans organizing pneumonia (BOOP). In 36 patients with collagen vascular diseases, interstitial pneumonia was diagnosed by open lung biopsy: 15 patients had rheumatoid arthritis, 3 had systemic lupus erythematosus, 9 had systemic sclerosis, 6 had dermatomyositis/polymyositis, and 4 had Sjögren's syndrome. As disease controls, 78 patients with idiopathic pulmonary fibrosis and 12 with idiopathic BOOP diagnosed by open lung biopsy were used. BAL was done before the biopsy. In most patients, the interstitial pneumonia associated with systemic sclerosis was UIP and the BALF cell pattern was a UIP-pattern. In addition, BALF UIP-patterns were associated with histologic findings of UIP in samples obtained by open lung biopsy. In contrast, other collagen vascular diseases tended to be associated with a BALF BOOP-pattern, which included various histological findings. Thus, the BALF BOOP-pattern, is associated with BOOP, with cellular interstitial pneumonia, with lymphocytic interstitial pneumonia, and with UIP. The BALF sarcoidosis-pattern is rare in patients with interstitial pneumonia associated with collagen vascular diseases.
7575649 Inhibition of dihydroorotate dehydrogenase by the immunosuppressive agent leflunomide. 1995 Sep 7 Leflunomide [HWA 486 or RS-34821, 5-methyl-N-(4-trifluoromethylphenyl)-4-isoxazole carboximide] is an immunosuppressive agent effective in the treatment of rheumatoid arthritis. In spite of its clinical potential, its mechanism of action has not been elucidated. Recent studies suggest that leflunomide may interfere with the metabolism of pyrimidine nucleotides. In our studies, the active metabolite of leflunomide, RS-61980 (A77 1726, 2-hydroxyethylidene-cyanoacetic acid-4-trifluoromethyl anilide), was cytostatic towards a human T-lymphoblastoma cell line (A3.01). The inhibition of growth could be overcome completely by uridine. The other nucleosides, cytidine, adenosine and guanosine, did not overcome the effect of the compound. Since uridine is a precursor for the salvage synthesis of UMP, we propose that RS-61980 may be inhibiting the de novo pathway of UMP synthesis. Using human cells, the six enzymes catalyzing de novo UMP biosynthesis were tested for their sensitivity towards RS-61980. Only one of the enzymes, dihydroortate dehydrogenase (DHODH, EC 1.3.3.1) was inhibited by RS-61980 with a Ki value of 2.7 +/- 0.7 microM. The other five enzymes were not affected. The inhibition exhibited mixed-type kinetics towards both substrates, dihydroorotic acid and coenzyme Q. These results suggest that the molecular target of leflunomide action is DHODH. The immunomodulating activity may be related to the inhibition of UMP synthesis in proliferating lymphocytes.