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.     

ACTH expression in synovium of patients with rheumatoid arthritis and Lewis rats with adjuvant arthritis

 Adrenocorticotropic hormone (ACTH) and another pro-opiomelanocortin-derived neuropeptide, β-endorphin (β-End), are stimulated by corticotropin-releasing hormone (CRH) at the anterior pituitary. CRH and β-End have predominantly proinflammatory effects in peripheral inflammatory sites. We have supposed that inflammatory stimuli develop ACTH as well as β-End. In this study, we investigated the expression of ACTH in inflamed synovial tissue from patients with rheumatoid arthritis (RA) and osteoarthritis (OA), and at inflammatory joints with adjuvant-induced arthritis (AA) in female Lewis (LEW/N) rats. The expression of ACTH immunostaining was significantly greater in synovium of RA patients than in that of OA patients (P < 0.0001), and correlated with the extent of inflammatory mononuclear cell infiltration. Extensive and intense intracellular ACTH immunostaining, which correlated with the advance in arthritis score, was observed in the synovial lining layer, inflammatory mononuclear cells, and fibroblast-like cells of synovium and chondrocytes in LEW/N rats with AA. In addition, we performed double immunostaining of the same sections from arthritic joints in rats with anti-ACTH and anti-CRH antibodies. ACTH and CRH colocalized in inflammatory mononuclear cells and fibroblast-like cells. ACTH may play a role in the pathogenesis of RA as well as CRH. Received: July 4, 2001 / Accepted: January 23, 2002 Correspondence to: H. Sano     

Adrenocorticotropic hormone response to hypoglycemic stress was preserved by a single bedtime 3-mg dose of prednisolone in patients with rheumatoid arthritis

Abstract

We have studied the effect of low-dose prednisolone administered before sleep on the hypothalamic–pituitary–adrenal axis and the symptoms of patients with rheumatoid arthritis (RA). Plasma adrenocorticotropic hormone (ACTH) and serum cortisol levels were measured in the basal state and after hypoglycemic stress induced by the insulin tolerance test in 21 patients receiving prednisolone at 3–5?mg daily. The patient's global assessment of their disease activity scores on a 100-mm visual analogue scale (VAS) and self-reporting of their functional status using the health assessment questionnaire (HAQ) were evaluated. While both the cortisol and the ACTH responses were impaired dose-dependently in patients treated with prednisolone, the ACTH response was maintained in patients treated with a single daily 3-mg dose of prednisolone before sleep. There was an inverse correlation between the extent of the ACTH response and disease activity as revealed by the VAS (r = 0.521, P < 0.05). There was also a weak correlation between VAS and the self-rating depression scale (SDS) (r = 0.443), especially when only patients with an HAQ score > 10 were included in order to exclude any possible contribution of the limitations in the activities of daily living to the SDS score (r = 0.859, P < 0.05). These results suggest that a single daily low dose (3?mg) of prednisolone administered before sleep maintains the ACTH response in RA patients, and patients with a good ACTH response appear to be less depressed and have milder symptoms.     

Adrenocorticotropic hormone response to hypoglycemic stress was preserved by a single bedtime 3-mg dose of prednisolone in patients with rheumatoid arthritis

We have studied the effect of low-dose prednisolone administered before sleep on the hypothalamic–pituitary–adrenal axis and the symptoms of patients with rheumatoid arthritis (RA). Plasma adrenocorticotropic hormone (ACTH) and serum cortisol levels were measured in the basal state and after hypoglycemic stress induced by the insulin tolerance test in 21 patients receiving prednisolone at 3–5 mg daily. The patient's global assessment of their disease activity scores on a 100-mm visual analogue scale (VAS) and self-reporting of their functional status using the health assessment questionnaire (HAQ) were evaluated. While both the cortisol and the ACTH responses were impaired dose-dependently in patients treated with prednisolone, the ACTH response was maintained in patients treated with a single daily 3-mg dose of prednisolone before sleep. There was an inverse correlation between the extent of the ACTH response and disease activity as revealed by the VAS (r = 0.521, P < 0.05). There was also a weak correlation between VAS and the self-rating depression scale (SDS) (r = 0.443), especially when only patients with an HAQ score > 10 were included in order to exclude any possible contribution of the limitations in the activities of daily living to the SDS score (r = 0.859, P < 0.05). These results suggest that a single daily low dose (3 mg) of prednisolone administered before sleep maintains the ACTH response in RA patients, and patients with a good ACTH response appear to be less depressed and have milder symptoms.     

Long-term outcome of patients with rheumatoid arthritis treated by multiple arthroplasty

Abstract

We conducted a study of 82 patients with rheumatoid arthritis (RA) who had undergone multiple arthroplasty and investigated their clinical findings and clinical courses. We reviewed the significance of multiple arthroplasty in the treatment of RA, its problems, and measures to solve them. All patients initially regained and maintained good walking capacity. However, the walking capacity of many patients again decreased over the long term; in the tenth year, 79% of patients were capable of a practical gait. The causes of decreased walking capacity included complications of artificial joints, cervical lesions, and vertebral compression fractures. Fractures were observed in as many as nine patients, indicating that it is important to prevent and treat their cause, that is, osteoporosis. The survival rate was 71% in 10 years. In RA patients, particularly those who have undergone multiple arthroplasty, the major causes of death are infection and rheumatic disease, suggesting that prevention of such diseases should be considered paramount. Appropriate systemic treatment of RA, patient education, and measures against osteoporosis for prevention of complications may preserve the worth of multiple arthroplasty for RA patients with multiple joint destruction.     

Long-term outcome of patients with rheumatoid arthritis treated by multiple arthroplasty

We conducted a study of 82 patients with rheumatoid arthritis (RA) who had undergone multiple arthroplasty and investigated their clinical findings and clinical courses. We reviewed the significance of multiple arthroplasty in the treatment of RA, its problems, and measures to solve them. All patients initially regained and maintained good walking capacity. However, the walking capacity of many patients again decreased over the long term; in the tenth year, 79% of patients were capable of a practical gait. The causes of decreased walking capacity included complications of artificial joints, cervical lesions, and vertebral compression fractures. Fractures were observed in as many as nine patients, indicating that it is important to prevent and treat their cause, that is, osteoporosis. The survival rate was 71% in 10 years. In RA patients, particularly those who have undergone multiple arthroplasty, the major causes of death are infection and rheumatic disease, suggesting that prevention of such diseases should be considered paramount. Appropriate systemic treatment of RA, patient education, and measures against osteoporosis for prevention of complications may preserve the worth of multiple arthroplasty for RA patients with multiple joint destruction.     

A case of idiopathic portal hypertension associated with rheumatoid arthritis

Abstract

A 53-year-old woman who had been diagnosed with rheumatoid arthritis was found to have thrombocytopenia, splenomegaly, and gastric varices. She was diagnosed as having idiopathic portal hypertension on the basis of liver biopsy and angiography. Treatment with prednisolone was not sufficiently effective for thrombocytopenia. After transabdominal devascularization with splenectomy, thrombocytopenia subsided and gastric varices disappeared. In this case, the autoimmune mechanism as well as hypersplenism was suspected of being involved in the mechanism of thrombocytopenia.     

Serum levels and pharmacodynamics of methotrexate and its metabolite 7-hydroxy methotrexate in Japanese patients with rheumatoid arthritis treated with 2-mg capsule of methotrexate three times per week

Methotrexate (MTX) is the first-choice drug for rheumatoid arthritis (RA); however, the pharmacodynamics of MTX in Japanese patients with RA treated legitimately according to the government recommended dosage, 6 mg per week, are unknown. Methotrexate and its metabolite, 7-hydroxy MTX (7-OH MTX), were measured in sera of 16 outpatients with active RA in the first week of MTX treatment and 4–12 weeks after the introduction at 0, 1, 2, 4, and 8 h after administration of the first and the third 2-mg capsule, followed by sampling at 48, 96, and 168 h. The mean maximal serum drug concentration (mean C_max) of MTX attained at 1–2 h after ingestion of the first capsule was 0.215 and 0.252 μM, respectively, in the first and the follow-up week. The mean C_max after ingestion of the third capsule was 0.223 μM and 0.357 μM. The mean C_max of 7-OH MTX was 0.0334 and 0.0289 μM for the first capsule, and 0.0495 and 0.0672 μM for the third capsule. The results indicate that MTX does not accumulate or deposit in the body of Japanese patients with RA when treated with 6 mg per week, and pharmacodynamics of MTX are comparable to those in overseas patients treated with 7.5 mg per week.     

Pharmacokinetics and efficacy of low-dose methotrexate in patients with rheumatoid arthritis

This article evaluates the relationship between the pharmacokinetics of methotrexate (MTX), its efficacy in the treatment of rheumatoid arthritis (RA), and serum folic acid (FA) levels. The pharmacokinetics of MTX was studied in 29 patients with RA treated with low-dose MTX. The weekly dose of MTX was given orally at 2–4mg every 12h over a period of 24–36h. Blood samples were taken 4h after the first administration in any given week. A Bayesian method was used to estimate individual MTX pharmacokinetic variables. We then investigated the efficacy of MTX and the serum FA levels in these patients. We examined C-reactive protein levels (CRP) and the erythrocyte sedimentation rate (ESR), and analyzed the values obtained before and after MTX treatment in order to evaluate the efficacy of the MTX treatment. The degree of improvement in CRP and ESR was significantly correlated with the length of time the MTX concentration–time curve remained above 0.02µM in one week. Furthermore, the degree of improvement in CRP was also significantly correlated with the area under the concentration–time curve (AUC) for MTX. These results suggest that serum MTX measurements could be useful in determining individual patient regimens.     

A case of idiopathic portal hypertension associated with rheumatoid arthritis

A 53-year-old woman who had been diagnosed with rheumatoid arthritis was found to have thrombocytopenia, splenomegaly, and gastric varices. She was diagnosed as having idiopathic portal hypertension on the basis of liver biopsy and angiography. Treatment with prednisolone was not sufficiently effective for thrombocytopenia. After transabdominal devascularization with splenectomy, thrombocytopenia subsided and gastric varices disappeared. In this case, the autoimmune mechanism as well as hypersplenism was suspected of being involved in the mechanism of thrombocytopenia.     

Serum levels and pharmacodynamics of methotrexate and its metabolite 7-hydroxy methotrexate in Japanese patients with rheumatoid arthritis treated with 2-mg capsule of methotrexate three times per week

Abstract

Methotrexate (MTX) is the first-choice drug for rheumatoid arthritis (RA); however, the pharmacodynamics of MTX in Japanese patients with RA treated legitimately according to the government recommended dosage, 6?mg per week, are unknown. Methotrexate and its metabolite, 7-hydroxy MTX (7-OH MTX), were measured in sera of 16 outpatients with active RA in the first week of MTX treatment and 4–12 weeks after the introduction at 0, 1, 2, 4, and 8?h after administration of the first and the third 2-mg capsule, followed by sampling at 48, 96, and 168?h. The mean maximal serum drug concentration (mean C_max) of MTX attained at 1–2?h after ingestion of the first capsule was 0.215 and 0.252?µM, respectively, in the first and the follow-up week. The mean C_max after ingestion of the third capsule was 0.223?µM and 0.357?µM. The mean C_max of 7-OH MTX was 0.0334 and 0.0289?µM for the first capsule, and 0.0495 and 0.0672?µM for the third capsule. The results indicate that MTX does not accumulate or deposit in the body of Japanese patients with RA when treated with 6?mg per week, and pharmacodynamics of MTX are comparable to those in overseas patients treated with 7.5?mg per week.     

Alendronate in rheumatoid arthritis patients treated with methotrexate and glucocorticoids

Rheumatoid arthritis (RA) is a systemic inflammatory disease. Along with synovial joint inflammation, extra-articular involvement is a common feature of RA. Periarticular and generalized osteoporosis are seen both as an extra-articular feature of the disease itself and due to various medications like glucocorticoids and methotrexate (MTX). In this study, we investigated the effects of oral alendronate in RA patients treated with MTX and prednisolone by comparing the effects of “alendronate+calcium” and “only calcium” on bone mineral density (BMD). Fifty RA patients classified according to American Rheumatism Association (ARA) criteria were included in the study. The control group consisted of 20 postmenopausal osteoporotic patients. The RA patients were divided randomly into two groups. All patients were started on MTX 7.5 mg/week, 2.5-mg daily folic acid, and 7.5-mg daily prednisolone. The first group, consisting of 25 female RA patients, was also given 10-mg daily alendronate and 1000-mg daily calcium. The second group also consisted of 25 female patients and was given only 1000-mg calcium per day. The postmenopausal control group was given daily 10-mg alendronate and 1000-mg calcium. Bone mineral densities were measured by dual-energy x-ray absorptiometry (DEXA) and again at the end of the sixth month. At the end of the study, RA patients given only calcium had reduced mean BMD, and patients treated with alendronate and calcium showed increased mean BMD almost in all regions. This increase was significant in the L2 and L1–4 total regions. In postmenopausal osteoporotic patients, we saw statistically significant increases in BMD in all regions. The increase in BMD values in RA patients treated with alendronate was smaller than in those of the control group of postmenopausal osteoporosis patients. In conclusion, RA itself has a risk factor for osteoporosis in addition to the risks of the medications like corticosteroids and MTX. In the prevention and treatment of RA-associated osteoporosis, alendronate and calcium therapy is effective and well tolerated. Received: 16 June 2000 / Accepted: 20 August 2000     

Atypical mycobacteriosis in two patients with rheumatoid arthritis

We report two cases of rheumatoid arthritis (RA) with atypical mycobacteriosis. Opportunistic infections are critical complications for rheumatic diseases. The use of steroids or immunosuppressants may increase the risk of opportunistic infections. However, these reports are rare in that they demonstrate atypical mycobacterial infections as complications of RA, even though no immunosuppressive agents were used. We discuss the characteristics of atypical mycobacterial infections of the lung in RA. Received: January 22, 2001 / Accepted: July 21, 2001     

The role of leukotrienes in immunopathogenesis of rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disorder of joints for which there is no strict cure. However, conventional medications can reduce inflammation, relieve pain, and slow joint damage. Leukotrienes are a family of paracrine agents derived from oxidative metabolism of arachidonic acid. Synthesis of lipid mediators and subsequent induction of receptor activity are tightly regulated under normal physiological conditions, so that enzyme and/or receptor dysfunction can lead to a variety of clinical signs and symptoms of disease, such as local pain and tissue edema. In these tissues, immunocompetent cells accumulate at the site of injury, contributing to tissue damage and perpetuation of the disease process. Leukotrienes (often leukotriene B4) as potent chemotactic agents can provoke most signs and symptoms in rheumatoid arthritis by initiating, coordinating, sustaining, and amplifying the inflammatory response, through recruitment of leukocytes. A number of studies have reported that pharmacological modulation in this field can significantly attenuate clinical manifestations associated with different inflammatory pathologies.     

Treatment of infected total knee arthroplasty in patients with rheumatoid arthritis

Abstract

The primary aim of treating infected knee joints after total knee arthroplasty is to eradicate the infection, but this is difficult to achieve. We reviewed the treatment of infections that occurred after total knee arthroplasty in patients with rheumatoid arthritis. The subjects were 14 patients with rheumatoid arthritis (3 men, 11 women; ages 38–81 years) who had 14 infected knee joints. The outcome was preservation of the implant in two cases, revision arthroplasty in six cases, arthrodesis in three cases, resection arthroplasty in one case, amputation in one case, and death in one case. If there is no loosening, preservation of the implant should be attempted. If preservation is impossible, revision arthroplasty is the next best option considering the effect on daily activities in patients with the disease affecting multiple joints.     

Treatment of infected total knee arthroplasty in patients with rheumatoid arthritis

The primary aim of treating infected knee joints after total knee arthroplasty is to eradicate the infection, but this is difficult to achieve. We reviewed the treatment of infections that occurred after total knee arthroplasty in patients with rheumatoid arthritis. The subjects were 14 patients with rheumatoid arthritis (3 men, 11 women; ages 38–81 years) who had 14 infected knee joints. The outcome was preservation of the implant in two cases, revision arthroplasty in six cases, arthrodesis in three cases, resection arthroplasty in one case, amputation in one case, and death in one case. If there is no loosening, preservation of the implant should be attempted. If preservation is impossible, revision arthroplasty is the next best option considering the effect on daily activities in patients with the disease affecting multiple joints.     

Hemagglutination of preoperative blood donation in patients with rheumatoid arthritis

Abstract

We gave preoperative blood transfusions to 37 patients with rheumatoid arthritis (RA) and 35 patients with osteoarthritis (OA), including some whose baseline hemoglobin level was less than 10?g/dl. Transfusion packs can preserve whole blood containing citrate phosphate dextrose (CPD) for 3 weeks. The baseline hemoglobin level of RA cases was 10.4?g/dl (range 8.4–13.1?g/dl), and that of OA cases was 11.9?g/dl (range 10.4–15.0?g/dl). By collecting 200–400?g every week before the operation, the total was 800–1200?g. Erythropoietin was given to patients intramuscularly when their hemoglobin was less than 13?g/dl after blood had been collected. Hemagglutination, with diameters of more than 1?cm, made filter occlusions in 11 RA cases (30%) and one OA case (3%) (P < 0.0031) after retransfusion. There were no differences between hemagglutination patients (agglutination group) and nonhemagglutination patients (nonagglutination group) regarding baseline C-reactive protein (CRP), white blood cells, platelets, or fibrinogen. We could not predict the formation of macrohemagglutination in the packs collected during the clinical course. In RA cases, allogenic transfusions were performed for four cases (36%) in the agglutination group and for one case (12%) in the nonagglutination group. Preoperative transfusion for the RA patients showed hemagglutination in some cases, and highlighted the need for modifications to reduce these hemagglutinations.     

The levels of leukemia inhibitory factor in synovial tissues of patients with rheumatoid arthritis: inflammation and other proinflammatory cytokines

Abstract

To clarify the effect of leukemia inhibitory factor (LIF) on the destruction of rheumatoid arthritis (RA) joints, we investigated the production of LIF and the expression of LIF mRNA in synovial tissues from patients with RA and osteoarthritis (OA). Synovial fluids from RA were used to measure the LIF concentrations using enzyme-linked immunosorbent assay (ELISA). Immunohistochemistory and RT-PCR were used to examine the expression of LIF by synovial cells. LIF mRNA was detected in all cases in RA synovial cells. Although LIF protein was detected only in 20 cases (19%) in RA synovial fluids, LIF concentration in the synovial fluids significantly correlated with the peripheral leukocyte count (P < 0.001) and C-reactive protein (CRP) (P < 0.01). Moreover, levels of IL-1β, IL-6, and IL-8, but not TNF-α, were significantly correlated with LIF in the RA synovial fluids. LIF production was promoted by IL-1β and TNF-α stimulation; in contrast, IL-1 ra and IL-4 were found to markedly decrease LIF production by cultured synovial cells. LIF appeared to be a cytokine produced by RA synovium leading to a proinflammatory secretion profile. Moreover, IL-4 and IL-1 ra may represent attenuated activity for reducing the effect of the destruction of joints by LIF.     

Hemagglutination of preoperative blood donation in patients with rheumatoid arthritis

We gave preoperative blood transfusions to 37 patients with rheumatoid arthritis (RA) and 35 patients with osteoarthritis (OA), including some whose baseline hemoglobin level was less than 10g/dl. Transfusion packs can preserve whole blood containing citrate phosphate dextrose (CPD) for 3 weeks. The baseline hemoglobin level of RA cases was 10.4g/dl (range 8.4–13.1g/dl), and that of OA cases was 11.9g/dl (range 10.4–15.0g/dl). By collecting 200–400g every week before the operation, the total was 800–1200g. Erythropoietin was given to patients intramuscularly when their hemoglobin was less than 13g/dl after blood had been collected. Hemagglutination, with diameters of more than 1cm, made filter occlusions in 11 RA cases (30%) and one OA case (3%) (P 0.0031) after retransfusion. There were no differences between hemagglutination patients (agglutination group) and nonhemagglutination patients (nonagglutination group) regarding baseline C-reactive protein (CRP), white blood cells, platelets, or fibrinogen. We could not predict the formation of macrohemagglutination in the packs collected during the clinical course. In RA cases, allogenic transfusions were performed for four cases (36%) in the agglutination group and for one case (12%) in the nonagglutination group. Preoperative transfusion for the RA patients showed hemagglutination in some cases, and highlighted the need for modifications to reduce these hemagglutinations.     

Systematic review of NSAID-induced adverse reactions in patients with rheumatoid arthritis in Japan

Abstract

A systematic review of randomized controlled clinical trials of nonsteroidal antiinflammatory drugs (NSAIDs) in rheumatoid arthritis (RA) patients was conducted to evaluate the risk of NSAID-induced adverse reactions. Double-blind, randomized, controlled trials with 6-week treatments for RA patients were included in the study. The endpoints for the analysis included any adverse reactions, digestive adverse reactions, and upper gastrointestinal (GI) adverse reactions. A fixed-effect model was used for estimation of the risk. Time-to-event analysis of the incidence of adverse reactions was also conducted. A total of 28 trials was included for the analysis, and a total of 30 NSAIDs were used in the trials. The proportion of patients who experienced any adverse reaction was as follows: piroxicam 18.9% (3 trials), diclofenac 18.8% (4 trials), indomethacin 22.1% (14 trials), and aspirin 25.0% (4 trials). The proportion of patients who experienced digestive adverse reactions was as follows: piroxicam 10.2%, diclofenac 10.6%, indomethacin 13.1%, and aspirin 14.1%. Most withdrawals due to adverse reaction occurred during the first 3 weeks after administration of the NSAID. Although the risk of NSAID-induced adverse reaction was different from drug to drug, the risk of adverse reaction was clinically significant.