D-penicillamine in patients with rheumatoid arthritis serum levels,pharmacokinetic aspects,and correlation with clinical course and side effects

After administration of D-penicillamine to patients with rheumatoid arthritis, measurements of serum level and urinary excretion showed half-life times of 1.6 hours in the rapid phase and 4–6 days in the slow phase. The latter evidence suggests that tissue pooling occurs. With a dosage of 750 mg/day, basic serum levels of 100 μM are gradually reached. Serum D-penicillamine levels were shown to be the same for patients who responded well to treatment, those who did not respond, and for patients who had adverse side effects as well as those who had none. Intestinal resorption decreased when D-penicillamine was taken close to meals and was greatly reduced by iron preparations.     

Adrenocorticotropic hormone and dehydroepiandrosterone sulfate levels of rheumatoid arthritis patients treated with glucocorticoids

To assess adrenal function with respect to the presence or absence of steroid therapy, we investigated differences in the blood levels of adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone sulfate (DHEAS) in relation to steroid (prednisolone) administration in 123 patients with rheumatoid arthritis (RA). Levels of ACTH and DHEAS were significantly lower in the steroid-treated group than in the non-treated group (ACTH: 11.79 pg/ml vs 27.92 pg/ml) (DHEAS: 418.12 ng/ml vs 883.91 ng/ml) (P < 0.0001). We observed no steroid dose-related differences in ACTH levels. However, DHEAS levels showed a slight decrease at a prednisolone dose of 2.5 mg/day, with a significant decrease being observed at a dose of 5 mg/day when statistical adjustments were made for age and sex (P < 0.0001). At doses of 7.5 mg/day or greater, DHEAS levels were significantly lower than those for 5 mg/day (P < 0.0006). These results suggest that low-dose prednisolone reduces adrenal function in patients with RA. We recommend that doses of prednisolone should be limited to 5 mg/day or less in consideration of adrenal function when treating RA patients. The measurement of ACTH and DHEAS may be useful for evaluating adrenal function in patients with RA.     

Adrenocorticotropic hormone and dehydroepiandrosterone sulfate levels of rheumatoid arthritis patients treated with glucocorticoids

Abstract

To assess adrenal function with respect to the presence or absence of steroid therapy, we investigated differences in the blood levels of adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone sulfate (DHEAS) in relation to steroid (prednisolone) administration in 123 patients with rheumatoid arthritis (RA). Levels of ACTH and DHEAS were significantly lower in the steroid-treated group than in the non-treated group (ACTH: 11.79?pg/ml vs 27.92?pg/ml) (DHEAS: 418.12?ng/ml vs 883.91?ng/ml) (P < 0.0001). We observed no steroid dose-related differences in ACTH levels. However, DHEAS levels showed a slight decrease at a prednisolone dose of 2.5?mg/day, with a significant decrease being observed at a dose of 5?mg/day when statistical adjustments were made for age and sex (P < 0.0001). At doses of 7.5?mg/day or greater, DHEAS levels were significantly lower than those for 5?mg/day (P < 0.0006). These results suggest that low-dose prednisolone reduces adrenal function in patients with RA. We recommend that doses of prednisolone should be limited to 5?mg/day or less in consideration of adrenal function when treating RA patients. The measurement of ACTH and DHEAS may be useful for evaluating adrenal function in patients with RA.     

Lp(a) lipoprotein and lipids in patients with rheumatoid arthritis: serum levels and relationship to inflammation

Objectives Changes in lipid profiles, Lp(a) lipoprotein, and acute phase reactants are associated with early atherosclerosis in rheumatoid arthritis (RA). The associations of Lp(a) levels with atherosclerotic disorders, diabetes, RA, and renal diseases suggest that Lp(a) might be involved in autoimmune reactions.Methods Eighty-seven women with RA diagnosed according to American Rheumatism Association criteria (mean age 45.4±9.4 years) were recruited and 50 healthy women (mean age 44±10.7 years) included as a control group. Serum Lp(a), total cholesterol (TC), triglyceride (TG), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), and C-reactive protein levels were analyzed.Results In the RA and C groups, serum Lp(a) levels were 39.2±20.6 mg/dl and 14.8±9.7 mg/dl, respectively (P<0.001). The TC levels were 188.4±41.8 mg/dl and 185.3±19.3 mg/dl (P>0.05), TG levels were 124.5±50.1 mg/dl and 94.6±24.9 mg/dl (P<0.01), HDL-C levels were 40.0±7.4 mg/dl and 52.8±4.8 mg/dl (P<0.01), and LDL-C levels were 123.4±24.6 mg/dl and 113.3±21.1 mg/dl (P>0.05). While serum CRP levels showed a positive correlation with Lp(a), they correlated negatively with HDL-C levels (r=0.83 and P<0.0001, r=–0.49 and P<0.0001, respectively). It was meaningful that Lp(a) correlated negatively with serum HDL-C level (r=–0.36, P<0.001).Conclusions It is suggested that higher serum Lp(a), lower HDL-C, higher TG level, and a high ratio of TC/HDL-C might show high risk of atherosclerosis. Inflammation in RA may cause changes in HDL-C and Lp(a) metabolisms.     

Assessment of pain in patients with juvenile rheumatoid arthritis: relation between pain intensity and degree of joint inflammation.

The relation between pain and joint inflammation in patients with juvenile rheumatoid arthritis has not previously been systematically evaluated. Eighteen patients with juvenile rheumatoid arthritis completed paediatric pain questionnaires and the joints affected were examined by thermography. Although significant correlations were shown between parent and doctor pain intensity ratings and joint temperature, correlations of patient pain intensity ratings and joint temperature were only significant in younger children. The degree of joint inflammation is only one factor of several contributing to the amount of subjective pain experienced by children with juvenile rheumatoid arthritis, indicating the need for a comprehensive assessment of the relatively independent variables of inflammation and pain in children with juvenile rheumatoid arthritis.     

Relationship between pentosidine levels in serum and urine and activity in rheumatoid arthritis

Pentosidine is one of the advanced glycation end-products and is formed by glycosylation and oxidation. The aim of this study is to investigate the relationship between serum and urinary pentosidine levels and the activity of rheumatoid arthritis (RA). Using HPLC with column switching, we measured pentosidine in serum and urine from 77 patients with RA and 62 normal control subjects. The clinical features, blood biochemistry and activity of inflammation were examined in RA patients. Serum and urinary pentosidine in RA were significantly higher than in controls. Pentosidine significantly correlated with age, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), rheumatoid factor, joint score and Lansbury Index in RA. The levels of pentosidine were higher in patients with active RA than in those with inactive RA. Serum and urine levels of pentosidine correlated with the activity of RA, and serum and urinary pentosidine may be a significant and novel marker for evaluating the disease status and the activity of RA.      

Effect of insulin on serum levels of dehydroepiandrosterone metabolites in men

OBJECTIVE  Insulin was found to decrease the concentration of serum dehydroepiandrosterone (DHEA) and DHEA-sulphate (DHEAS) and recent data suggest that an increase in the metabolic clearance rate of DHEA (MCR_DHEA) may be involved. In this study, we have investigated the effects of insulin on DHEA metabolism in men.
PATIENTS  A total of 10 men were enrolled into the study, and all subjects completed the study. Subjects were healthy, non-obese, and 20–30 years old.
DESIGN  DHEA was administered intravenously to subjects, alone or in combination with insulin. A hyperinsulinaemic-euglycaemic clamp was initiated for subjects with the insulin infusion and euglycaemia was maintained by checking blood glucose and adjusting the rate of a 25% dextrose infusion as needed. Serum was collected before DHEA infusion, during DHEA infusion after attaining steady state (3.5–4h), and during DHEA plus insulin infusion (6–6.5h) (steady state) and then assayed for DHEA, DHEA metabolites, and DHEA acylation by LCAT.
RESULTS  Results showed rapid transformation of DHEA into androst-5-ene-3β,17β-diol, DHEA fatty-acid esters (DHEA-FA), androstenedione and 5α-androstan-3α-ol-17-one glucuronide (androsterone glucuronide) whereas DHEAS, testosterone, androstane-3α,17β-diol glucuronide and oestradiol serum levels were not affected. When insulin was simultaneously infused once steady-state DHEA levels had been attained, we observed a decline only in DHEA, DHEA-FA and DHEAS levels, with no effect on other steroids examined. Although serum DHEA esterification was not affected by DHEA, a stimulation by insulin was observed.
CONCLUSIONS  These results suggest that insulin increases the DHEA metabolic clearance rate by stimulating its conversion to DHEA-FA and by enhancing uptake of DHEA-FA by peripheral tissues.     

类风湿关节炎患者血清巨噬细胞移动抑制因子白细胞介素-17及-23表达与合并动脉粥样硬化的相关性研究

目的 通过颈部彩色多普勒超声检测类风湿关节炎(RA)患者合并动脉粥样硬化情况,检测血清巨噬细胞移动抑制因子(MIF)及白细胞介素(IL)-17、IL-23水平,分析它们之间的相关性及在RA致动脉粥样硬化中的作用.方法 收集69例RA患者,根据颈部血管彩色多普勒超声结果,分为合并动脉粥样硬化组36例及无动脉粥样硬化组33例,并设64名健康者为健康对照组.采用酶联免疫吸附试 验(ELISA)法检测3组血清MIF、IL-17及IL-23水平.采用t检验、方差分析进行统计分析,相关性分析采用Pearson相关分析和Logistic回归分析.结果 合并动脉粥样硬化组MIF水平明显高于无动脉粥样硬化组及健康对照组(3组分别为15.2±1.7,13.8±2.2,8.0±2.9,P<0.05),且与颈动脉内膜中层厚度(IMT)值(r=0.271,P=0.036)、斑块大小(r=0.291,P=0.024)、IL-17(r=0.328,P=0.007)及IL-23(r=0.316,P=0.010)水平呈正相关;合并动脉粥样硬化组IL-17和IL-23水平高于健康对照组(2.8±2.0和2.0±0.8,449±174和341±113),但与无动脉粥样硬化组比较差异无统计学意义.Logistic回归分析显示RA患者MIF水平与动脉粥样硬化的发生呈正相关.结论 RA合并动脉粥样硬化患者血清MIF水平显著升高,且与IL-17、IL-23表达密切相关,血清MIF水平升高可作为RA患者发生动脉粥样硬化的预测指标.

Abstract：

objective To detect the serum macrophage migration inhibitory factor(MIF)and interlbukin (IL)-17,IL-23 levels in rheumatoid arthritis patients with atherosclerosis and to analyze the association between them and their role in the pathogenesis of atherosclerosis in rheumatoid arthritis patients.Methods Total of 69 patients with RA were divided into atherosclerosis group(AS group)and those without atherosclerosis group(NAS group)according to neck vascular ultrasonography.Sixty-four healthy controls(the control group)were also enrolled into this study.MIF and IL-17,IL-23 levels were determined bv ELISA assay.The t test of two independent-samples and One-way ANOVA were used to compare the levels of MIF.IL-17 and IL-23 in different groups of patients and healthy individuals.The correlation between diffrent paramenters was assesed by Pearson's coefficient of correlation and Logistic regression.Results The serum MIF level in the AS group was significantly higher than that in the NAS group and healthy controls(15.2±1.7,13.8±2.2,8.0±2.9,P<0.05),and there were significant correlations between the serum MIF concentration,carotid intima-media thickness(IMT)(r=0.271,P=0.036).the size of atherosclerotic plaques(r=0.291,P=0.024),the serum level of IL-17(r=0.328,P=0.007)and IL-23(r=0.316,p=0.010).The serum IL-17 and IL-23 level in the AS group was higher than healthy controls(2.8±2.0 vs 2.0±0.8,449±174 vs 341±113),while there were no significant differences between AS group and NAS group.The serum MIF level in RA patients was positively correlated with atherosclerosis according to Logistic regression analysis.Conclusion The serum MIF level in RA patients with AS is significantly higher than that in NAS group and healthy controls,and it may be related with the serum level of IL-17 and IL-23.The elevated serum MIF level may be a predictor for atherosclerosis in patients with rheumatoid arthritis.     

Osteoprotegerin serum levels in men: correlation with age, estrogen, and testosterone status.

Previous studies have suggested an important role for androgens and estrogens in bone metabolism in men. However, their local mode of action has not been clearly established. Osteoprotegerin (OPG) is a secreted decoy receptor that inhibits osteoclast formation and activity by neutralizing its cognate ligand. To assess the role of OPG on bone metabolism in men, we conducted a study aimed at evaluating OPG serum levels and their correlation with age, bone mineral density, biochemical markers of bone turnover, and testosterone and estradiol levels in 252 men, aged 19-85 yr. Serum concentrations of OPG increased significantly with age (r = 0.41; P = 0.0001), and were positively correlated with free testosterone index and free estradiol index (r = 0.20; P < 0.002 and r = 0.15; P < 0.03, respectively) after adjustment for age and body weight. Beyond the age of 40 yr, OPG serum concentrations were negatively correlated with urinary excretion of total deoxypyridinoline (r = -0.20; P < 0.01) and PTH serum levels (r = -0.23; P < 0.01). In contrast, there was no correlation with biochemical markers of bone formation, 25-hydroxyvitamin D(3) levels, or bone mineral density at any site. Our data reveal that age as well as androgen and estrogen status are significant positive determinants, whereas PTH is a negative determinant, of OPG serum levels in men. These data suggest that OPG may be an important paracrine mediator of bone metabolism in elderly men and highlight the role of estrogens in the homeostasis of the male skeleton.     

Serum cytokines in juvenile rheumatoid arthritis: correlation with conventional inflammation parameters and clinical subtypes

Objective. To examine the usefulness of determining extended serum cytokine profiles in patients with juvenile rheumatoid arthritis (JRA), for the purpose of improving differential diagnosis and monitoring disease activity. Methods. In a 2-year prospective study, serum levels of interleukin-1β (IL-1β), soluble IL-2 receptor (sIL-2R), IL-6, IL-8, tumor necrosis factor α (TNFα), and the p55 soluble TNF receptor (sTNFR) were repeatedly determined by enzyme-linked immunosorbent assay in 40 patients with JRA, 13 patients with postinfectious arthropathies, and 30 healthy controls. The data were compared with conventional parameters of inflammation, such as C-reactive protein (CRP), iron and hemoglobin levels, erythrocyte sedimentation rate (ESR), white blood cell (WBC) counts, and platelet counts. WBC subsets were analyzed by flow cytofluorometry. Results. At the first visit and at the peak of inflammatory activity according to CRP levels and/or ESR, serum levels of sIL-2R, IL-6, and sTNFR in JRA patients correlated significantly with conventional inflammation indicators, whereas IL-1β, IL-8, and TNFα did not. No changes in leukocyte subset distribution were noted. Among the different clinical subtypes of JRA, sIL-2R, IL-6, and sTNFR values at the time of the initial visit showed a pattern similar to CRP, whereby patients with systemic disease exhibited by far the highest values. TNFα and IL-1β were variably elevated in certain JRA subtypes. Patients with postinfectious arthropathies showed elevated levels of CRP, sIL-2R, TNFα, and sTNFR, which did not differ significantly from levels in the various JRA subtypes with the exception of systemic disease. Detailed analysis of types I and II pauciarticular JRA revealed that levels of CRP, IL-1β, and TNFα were elevated in patients with type I disease. While these parameters were invariably normal in patients with type II disease, sTNFR and sIL-2R were still found to be significantly elevated. Followup studies suggested that persistently high sTNFR values are a better indicator of JRA activity than are measurements of other cytokines or CRP. Conclusion. JRA is associated with significant and consistent changes in serum levels of inflammatory cytokines and soluble receptors. For the clinical monitoring of JRA, determination of levels of sTNFR, and to some extent sIL-2R, may be particularly useful, since these determinations yield information about subtype and/or activity of disease that is not available from conventional parameters of inflammation.     

Gold serum levels in children with juvenile rheumatoid arthritis.

Serum gold levels were monitored in 66 children with juvenile rheumatoid arthritis, treated with different i.m. dosage schedules of sodium aurothiomalate (Myocrisin, Pharma Rhodia). The ages of the children varied from 1 to 15 years. Gold serum levels in children were related to the dose of Myocrisin calculated per kg of body weight or per square metre of body surface area. The results of our study indicate that in order to achieve a peak serum level at about 500--600 microgram/100 ml (25--30 micromol/l) with weekly injections, the dose of Myocrisin should be about 0.7 mg/kg, or 20 mg/m2. In order to avoid excessively high gold serum concentrations, the maximum single dose should not exceed 27 mg/m2 of body surface area.     

Steady-state serum salicylate levels in hospitalized patients with rheumatoid arthritis

When the total daily drug dose was individualized to produce a steady-state serum salicylate concentration between 20 and 35 mg/dl, clinically acceptable fluctuations of serum concentrations occurred during both twice daily and three times daily administration. In 6 rheumatoid arthritis patients receiving choline magnesium trisalicylate, mean steady-state serum levels were the same, and the ranges of hourly mean concentrations during 8 and 12 hour dosage intervals were 19 to 27 mg/dl and 17 to 30 mg/dl, respectively. Changing the dosing interval from 8 to 12 hours required a 50% increase in the fractional doses, but resulted in an increase of only 3 mg/dl in mean peak concentration and a decrease of 1 mg/dl in mean minimum concentration.     

Differences in symptom reports between men and women with rheumatoid arthritis

Objective. To determine if differences exist between men and women in their reports and evaluations of rheumatoid arthritis (RA) symptoms, and, if so, to identify explanations for those differences. Method. Data from a longitudinal panel study of persons with RA were used. Symptom reports were defined as individuals' evaluations of body states, e.g., evaluations of the severity of pain. Analyses were controlled for sociodemographic, clinical, and psychological characteristics. Results. In unadjusted analyses, women were more likely to evaluate their symptoms as severe. Adjustment for sociodemographic and clinical characteristics changed these results very little. Controlling for depressive symptoms decreased the magnitude of associations somewhat. Analyses controlling for additional respondent-reported clinical characteristics (Health Assessment Questionnaire score, number of painful joints) yielded dramatically different results; in no case did women evaluate their symptoms significantly more severely than men. Conclusion. Our analyses suggest that women reported more severe symptoms, but that these differences may be due to more severe disease rather than a tendency by women to over-report symptoms or overrate symptom severity. Future research should examine whether physicians respond to reports or prescribe treatments differently for men and women.     

Markers of inflammation are negatively correlated with serum leptin in rheumatoid arthritis

BACKGROUND: Leptin regulates food intake and modulates immunity and inflammation. A positive feedback mechanism has been described between tumour necrosis factor (TNF) and leptin, and it has been suggested that leptin potentiates inflammation in patients with rheumatoid arthritis (RA). OBJECTIVE: To assess whether inflammation correlates with leptin concentrations in patients with RA, and whether anti-TNF treatment modulates leptin concentrations in these patients. METHODS: Leptin, IL6 and CRP were measured (at baseline and after 2 weeks of treatment) in the blood of 31 patients with RA starting either anti-TNF treatment or placebo, and in 18 healthy controls. RESULTS: In patients with RA, plasma leptin concentrations at baseline correlated inversely with the degree of inflammation as assessed by C reactive protein (CRP; r(s)(2) = 0.21, p<0.01) or interleukin (IL) 6 concentrations (r(s)(2) = 0.22, p<0.008). Mean (SD) leptin concentrations did not differ between patients with RA and controls (6.0 (4.6) v 4.2 (2.8) ng/ml in men; 15.1 (7.9) v 13.4 (5.2) ng/ml in women). Short course anti-TNF treatment for 2 weeks did not modify leptin concentrations, despite significant reduction of CRP and IL6. CONCLUSION: A significant inverse correlation between inflammation and leptin concentrations was found in patients with active RA, although plasma leptin concentrations did not significantly differ from those in healthy controls. This suggests that active chronic inflammation may lower plasma leptin concentrations. Two weeks' treatment with anti-TNF did not change plasma leptin concentrations and longer treatment may be needed to see an effect on leptin.     

The relationship between fatigue,coping behavior,and inflammation in patients with rheumatoid arthritis

Abstract

This research investigated the relationships among the severity of inflammation, the extent of fatigue, and fatigue symptoms, and the relationship between fatigue and coping behavior in patients with rheumatoid arthritis (RA). Our study group consisted of 177 female patients with RA (105 women with CRP > 0.5 mg/dl and ESR > 30 mm/h (inflammatory group) and 72 women with CRP ≦ 0.5 and ESR ≦ 30 (noninflammatory group)) and 81 age-matched healthy women (control group) who were given self-assessment questionnaires. The extent of fatigue was higher in the inflammatory group than in the noninflammatory and control groups. The characteristics of fatigue symptoms in the inflammatory group were “decline in the strength to carry on the activities of daily life” and “difficulty in performing daily activity.” The patients in the inflammatory group adopted a technique of "reducing the burden on the body" as a pattern of coping behavior for reducing fatigue. The extent of fatigue and fatigue symptoms perceived by RA patients is strongly related to the severity of inflammation, and these patients adopt a coping behavior in response to the extent of fatigue and subjective symptoms.     

The relationship between fatigue, coping behavior, and inflammation in patients with rheumatoid arthritis

This research investigated the relationships among the severity of inflammation, the extent of fatigue, and fatigue symptoms, and the relationship between fatigue and coping behavior in patients with rheumatoid arthritis (RA). Our study group consisted of 177 female patients with RA (105 women with CRP > 0.5 mg/dl and ESR > 30 mm/h (inflammatory group) and 72 women with CRP ≦ 0.5 and ESR ≦ 30 (noninflammatory group)) and 81 age-matched healthy women (control group) who were given self-assessment questionnaires. The extent of fatigue was higher in the inflammatory group than in the noninflammatory and control groups. The characteristics of fatigue symptoms in the inflammatory group were “decline in the strength to carry on the activities of daily life” and “difficulty in performing daily activity.” The patients in the inflammatory group adopted a technique of "reducing the burden on the body" as a pattern of coping behavior for reducing fatigue. The extent of fatigue and fatigue symptoms perceived by RA patients is strongly related to the severity of inflammation, and these patients adopt a coping behavior in response to the extent of fatigue and subjective symptoms. Received: October 6, 1999 / Accepted: May 25, 2000