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Objective. To measure the extent of atherosclerosis in patients with rheumatoid arthritis (RA) with a disease duration of considerable length, and in age and sex matched individuals. Methods. Thirty-nine patients with RA (30 women, 9 men) with disease onset occurring between 1974 and 1978, and less than 65 years of age at the time of investigation, were enrolled together with 39 sex and age matched controls. Quantitative measurement of intima-media thickness (IMT) and semiquantitative assessment of the presence of plaque were undertaken by B-mode ultrasound of the common carotid artery (CCA-IMT) and the common femoral artery on the right-hand side. Echo Doppler cardiography was performed with an Accuson Aspen. The results were related to disease activity variables and accumulated disease activity, to lipid levels [i.e., cholesterol, high density lipoproteins, low density lipoproteins, triglycerides (TG)], to hemostatic factors [tissue plasminogen activator antigen (tPAag), plasminogen activator inhibitor-1 (PAI-1), von Willebrand factor (vWF)], and to soluble adhesion molecules (sICAM-1 and sE-selectin). Results. Patients with RA had higher maximal and mean IMT values compared with controls. The difference concerning mean CCA-IMT reached statistical significance in patients with RA and correlated significantly with lipids (cholesterol, LDL, LDL/HDL ratio, TG) and tPAag. The prevalence of plaques, as well as of aortic cusp sclerosis, was higher in RA but only the difference in aortic cusp sclerosis was statistically significant. Patients with plaques had significantly higher levels of lipids (cholesterol, LDL, LDL/HDL ratio) than patients without plaques, while patients with cusp sclerosis had significantly higher cholesterol and TG levels. sICAM-1 was significantly higher both in patients with plaques and in those with aortic cusp sclerosis compared to patients without. Conclusion. Our results suggest an accelerated atherosclerosis in patients with RA that is relate

Objective. To investigate the prospective effect of hemostatic factors and inflammatory variables on the progression of cardiovascular disease in rheumatoid arthritis (RA). Methods. Von Willebrand factor (vWF) and the fibrinolytic factors tissue plasminogen activator (tPA), measured as tPA capacity, and plasminogen activator inhibitor 1 (PAI-1), platelets, fibrinogen, and inflammatory markers were measured in 74 patients with active seropositive RA. Lipid levels, lipoprotein(a), and cardiolipin antibodies were also analyzed. Cardiovascular disease, measured by past cardiovascular events including thrombotic events, was registered in an 8 year followup. Results. Patients with a cardiovascular event during the followup period (n = 26) had significantly higher levels of vWF PAI-1, erythrocyte sedimentation rate (ESR), and haptoglobin at entry to the study. In a multiple logistic regression model controlling for several conventional cardiovascular risk factors and pharmacological treatment at sampling, PAI-1 and tPA were significantly associated with cardiovascular disease progression. Conclusion. The altered levels of vWF, PAI-1, and, in logistic regression, tPA in RA patients with cardiovascular disease progression indicates a status of hypofibrinolysis in these patients. Higher levels of ESR and haptoglobin may reflect the importance of the inflammatory process for the development of cardiovascular disease in RA.

To investigate the role of sex steroids in sex differences in the response of rats to the potent inflammatory mediator bradykinin (BK), we evaluated the effect of sex steroid manipulation on the magnitude of BK-induced synovial plasma extravasation (PE). The magnitude of BK-induced PE is markedly less in females. Ovariectomy of female rats increased BK-induced PE, and administration of 17 beta-estradiol to ovariectomized female rats reconstituted the female phenotype. Castration in male rats decreased BK-induced PE, and administration of testosterone or its nonmetabolizable analog dihydrotestosterone reconstituted the male phenotype. The results of these experiments strongly support the role of both male and female sex steroids in sex differences in the inflammatory response. Because the stress axes are sexually dimorphic and are important in the regulation of the inflammatory response, we evaluated the contribution of the hypothalamic-pituitary-adrenal and the sympathoadrenal axes to sex differences in BK-induced PE. Neither hypophysectomy nor inhibition of corticosteroid synthesis affected BK-induced PE in female or male rats. Adrenal denervation in females produced the same magnitude increase in BK-induced PE as adrenalectomy or ovariectomy, suggesting that the adrenal medullary factor(s) in females may account for the female sex steroid effect on BK-induced PE. Furthermore, we have demonstrated that in female but not male rats, estrogen receptor a! immunoreactivity is present on medullary but not cortical cells in the adrenal gland. These data suggest that regulation of the inflammatory response by female sex steroids is strongly dependent on the sympathoadrenal axis, possibly by its action on estrogen receptors on adrenal medullary cells.

Objectives: To investigate the association between the onset of polymyalgia rheumatica (PMR) and prior or persistent infection with Chlamydia pneumoniae or cytomegalovirus (CMV), (both known to infect the vessel wall) enteroviruses (EV) or respiratory syncytial virus (RSV). Methods: Serum samples were collected from 48 patients with newly-diagnosed PMR and from 22 controls of the same age. The presence of IgG, IgA and IgM antibodies to C. pneumoniae, IgG and IgM antibodies to CMV and EV, and complement fixing antibodies to RSV were analysed. Results: Clinical symptoms of infection preceding PMR symptoms were associated with the presence of synovitis at the first visit. There were no significant differences in the seroprevalence rates of antibodies to C. pneumoniae, CMV, EV or RSV between PMR patients and controls. IgM antibodies to EV were found in two patients and IgM antibodies to CMV in another two patients. Conclusion: Serological evidence of an association between newly-diagnosed PMR and prior or chronic infection with C. pneumoniae was not found. IgM antibodies to EV in two patients, consistent with ongoing or recent infection, suggest that EV could represent one of perhaps several microbes which are able to trigger PMR.

Chromosomal changes were assessed in 19 patients with rheumatoid arthritis (RA) treated with CPH82, a benzylidated podophyllotoxin glycoside, for up to one ve:lr. The frequency of chromosomal aberrations (CA) and sister chromatid exchanges (SCE) in peripheral lymphocytes increased significantly after 12 weeks of treatment and remained elevated after 48 weeks treatment in peripheral lymphocytes. The number of CA and SCE were significantly increased in CPH82 treated patients compared with the RA patients treated with other disease modifying anti-rheumatic drugs (sulphasalazine, gold, D-penicillamine, azathioprine, methotrexate, cyclophosphamide). Only two patients treated with cyclophosphamide and azathioprine had changes of comparable levels, The results of this study suggest a mutagenic potential of CPH82 similar to that described for other immunosuppressive drugs and the newer podophyllotoxin derivatives, etoposide and teniposide.

Peripheral blood lymphocytes from 23 patients with polymyalgia rheumatica (PMR) were characterized using monoclonal antibodies and flow cytometry in a two-year prospective study. There were no significant differences in absolute numbers or relative percentages of lymphocytes or CD3+, CD4+, CD8+ T cells or the CD4+ T cell functional subsets, virgin (CD4+ CD45RA+) and memory (CD4+ CD29+) T cells, in patients before or during corticosteroid treatment compared to controls. Previous reports on decreased levels of CD8+ T cells as a characteristic of PMR/giant cell arteritis was not confirmed. The absolute number and relative percentage of lymphocytes with natural killer cell activity, CD16+ CD56+ cells, were significantly lower in patients with active untreated PMR as well as during corticosteriod treatment compared to controls, but at the two-year follow-up the difference was less marked.

The benzylidated podophyllotoxin glycoside CPH82, a potentially useful drug for treatment of RA, was tested in vitro on nine human haematopoietic cell lines for cell kinetic effects. Previous studies have shown CPH82 to behave like a colchinetype ‘metaphase’ blocker.The distribution of cells within different cell cycle compartments (G1, S, G2 and M) was analysed by a novel method using dual parameter flow cytometric analysis of stage specific antigens (proliferating cell nuclear antigen and Ki-67). With CPH82 concentrations chosen to mimic clinical conditions, eight out of nine lines showed an accumulation of cells in the G2 phase of the cell cycle. In many lines a delayed progress through S seemed to occur. Three lines were blocked in both G1 and G2, whereas the major effect on one line (HL-60) was an accumulation of cells in the G1 phase. Progression of M cells seemed only slightly delayed for some cell lines. In comparison with two related ‘metaphase’ blocking agents (podophyllotoxin and taxol), CPH82 had a different and dose-dependent pattern of cell cycle retardation. It is speculated that the cell kinetic action of CPH82 might give insight into the question why it, unlike other ‘metaphase’ blockers, has proved valuable in the treatment of RA.

Objective. To investigate the relationships between personality traits, depressive symptomatology and continuous muscle tension. Methods. These were investigated by means of a visual analog scale and the presence of continuous muscle tension during repeated isokinetic shoulder flexions in patients with muscle or joint pain and controls. Results. A significantly higher level of muscle tension between contractions was found in the patient groups in painful muscles. The patients with primary fibromyalgia and trapezius myalgia differed in degree of depressive symptomatology compared to controls. Conclusion. Inhibition of aggression correlated significantly with the tension level between contractions during the isokinetic test indicating interaction between psychological and somatic factors.

HLA haplotypes (including A, B, C and DR loci) were studied in a family with members who had both rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Sacroiliitis was found in 7 family members, one of whom had AS and 2 others erosive, seropositive RA. They carried the B27-DR4 haplotype, suggesting a possible dual genetic association of the same haplotype in both RA and AS. Three other different HLA-B27 containing haplotype were found, 2 of which could be associated with sacroiliitis/AS. Within this family sacroiliitis and/or AS rather seemed associated with the B27 antigen itself than with the same haplotype.

A drug composed of two semisynthetic podophyltine derivatives, CPH 82, has recently been launched for the treatment of severe rheumatoid arthritis. The present in vitro study of PHA-stimulated human T-lymphocytes showed that CPH 82 arrested cell division in a metaphase-like configuration. The cell cycle effects of CPH 82 were indistinguishable from the cell cycle effects of the classical microtubule depolymerizers, Colcemid (a colchicine derivative) and podophyllotoxin. A CPH 82 concentration of 1 (µg/ml, which is close to therapeutic serum concentrations, had an almost maximal effect on cell division. It is suggested that at least part of the anti-inflammatory effect of CPH 82 is due to a colchicine-like activity on, for example, proliferating lymphocytes.

Serum protein markers (α1-AT, Bf, C3, C4A, C4B, Hp and Tf) were studied in a series of 36 patients with systemic lupus erythematosus (SLE) and compared to normal blood donors. In agreement with the results of previous investigations a significant increase of complement C4 deficiency was found among the SLE patients. The relative risks for AQO and BQ0 homozygosity were 7.2 and 4.1, respectively. Simultaneous occurrence of AQO and BQ0 was found in three patients with a calculated relative risk of about 65. A significant increase of the haptoglobin type 2–2 (p < 0.05) was found among SLE patients. The remaining serum protein systems showed no statistically significant associations with SLE.

The acetylator phenotype was determined in 59 patients with classical, seropositive and erosive rheumatoid arthritis (RA) treated with sodium-aurothiomalate or d-penicillamine. Patients with adverse drug reactions (ADR) leading to drug withdrawal (n=29) were compared with a group of patients without ADR (n=30). The frequency of slow acetylators was significantly (p< 0.05) increased in all RA patients, irrespective of the presence of ADR, particularly in the male patients, compared with a control population. No association was found between acetylator phenotype and clinical data or secondary Sjögrens's syndrome (SS).

A clinical and immunogenetic study was performed on a three-generation family with Reiter's disease (RD). Twelve of 56 members of the family (33 clinically examined) including one in-law, had symptoms of arthritis, urethritis, conjunctivitis, uveitis, and/or mucocutaneous manifestations, but only one had the complete triad of Reiter's syndrome (RS). Radiographic sacro-iliitis was found in 7 individuals, and monoarticular onset was reported in 5 out of 7 with peripheral arthritis. HLA B27 was found in 26 of the 37 family members who were tissue typed (including one in-law). All individuals with RD were B27-positive. Seven different B27 phenotypes were identified. This finding suggests that RD is associated with the B27 antigen itself, and not to a gene closely linked to B27. From a pedigree analysis of this family an autosomal dominant inheritance with incomplete penetrance or multifactorial inheritance seemed the most probable alternatives. The family history is a useful adjunct in the diagnosis of RD.

The frequency of radiographic signs of sacroiliac joint involvement (greater than or equal to 2 and greater than or equal to 3 according to the New York criteria) was significantly higher in 28 HLA-B27 positive patients with classical seropositive rheumatoid arthritis (RA), than in 28 B27 negative RA controls. The B27 positive RA patients had more subcutaneous nodules (p less than 0.01), worse functional class (p less than 0.05), and higher levels of erythrocyte sedimentation rate (ESR) (p less than 0.05) and haptoglobin (p less than 0.05). Sacroiliitis, independent of HLA-B27, was associated with higher levels of ESR (p less than 0.05), and with a higher frequency of positive ANA test (p less than 0.05). It is neither related to the functional class nor to the duration of the disease

Transferrin C subtypes were studied in patients with rheumatoid arthritis (RA) and controls. A significant association was found between the C2 type and RA. This association concerned mainly male patients and patients with a family history of polyarthritis. The results were discussed in relation to previous studies of the role of oxygen free radicals in the pathogenesis of RA and to a recently proposed hypothesis that the TfC2 gene confers an increased risk for cellular damage by hydroxyl radicals.