R.F.J.M. Laan

Low-Dose Prednisone Induces Rapid Reversible Axial Bone Loss in Patients with Rheumatoid Arthritis: A Randomized, Controlled Study

Published data on the effects of low-dose ( 10 mg/d of prednisone) glucocorticoid agents on bone in patients with rheumatoid arthritis (RA) are controversial, and it has been suggested that the favorable effects of glucocorticoid agents on the inflammatory process and on physical activity may outweigh the negative effects of these drugs on bone. Previous, mostly cross-sectional studies have shown contradictory results [1]. Longitudinal studies have been done in patients who had been receiving glucocorticoid treatment for some time, and no increased rates of bone loss were noted [2, 3]. Several explanations may be offered for the discrepancies in the literature. First, nonrandomized studies may be subject to selection bias, because RA itself, and its concomitant decreased mobility, may adversely affect bone mass [1]. Second, it has been documented that negative influences of glucocorticoid agents may be most pronounced in the first months of therapy [4], and studies evaluating bone loss in the chronic phase of treatment may thus underestimate the effects of these drugs on bone. Randomized, controlled studies are necessary to avoid selection bias. We report the results of the first randomized, placebo-controlled study of the initial effects of low-dose prednisone on bone mineral density in patients with active RA. Methods Patients Patients were selected from a single university outpatient clinic, from April 1988 to April 1991. All patients with classical or definite RA [5] who started taking intramuscular gold salts were considered for participation in the trial. The decision to start intramuscular gold therapy was left to the rheumatologists in charge of the patients. Patients were admitted to the study only if they fulfilled at least three of five criteria: five or more joints that were tender or painful during motion; three or more swollen joints; an erythrocyte sedimentation rate more than 28 mm/h; morning stiffness for at least 60 minutes; and a hemoglobin level less than normal limits. Patients with other diseases or medication, including calcium supplements and postmenopausal hormone replacement therapy, that might affect bone mass, were excluded from the study. Introduction of these medications during the study was not permitted. Premenopausal patients were allowed to continue taking oral contraceptive drugs. Female patients who were postmenopausal for fewer than 3 years, or who had irregular menstrual cycles, were also excluded from the study. All patients were white. Informed consent was obtained from all patients. The study was approved by the local Ethics Committee. Study Design and Medication All patients were treated with intramuscular aurothioglucose (Auromyose; 20% oily suspension, Noury Pharma, Oss, the Netherlands) according to a standard dosage regimen. All patients started with a test dose of 10 mg before the trial. They then continued with a dose of 50 mg weekly, for 20 weeks. Modification of this regimen was possible if side effects occurred. Aurothioglucose was discontinued after 20 weeks if it was not effective. If a satisfactory response occurred, the dose was decreased. Patients were monitored for side effects weekly during the first 8 weeks of treatment and once every 2 weeks thereafter. The trial was a double-blind, placebo-controlled study for 20 weeks. Patients were followed for an additional 24 weeks after this period. All patients were randomly assigned to receive either prednisone or placebo treatment. No stratification or block randomization was used. All assessments were done without knowledge of the patients treatment status. Prednisone was given in a dose of 10 mg once daily for 12 weeks. Thereafter, the dose was gradually reduced: 7.5 mg/d in weeks 13 and 14, 5.0 mg/d in weeks 15 and 16, 2.5 mg/d in weeks 17 and 18, and no prednisone in weeks 19 and 20. This resulted in a total dosage after 20 weeks of 1050 mg and a mean daily dose of 7.5 mg. All patients used nonsteroidal anti-inflammatory drugs throughout the study. Assessments of Rheumatoid Arthritis All clinical assessments were done by a single observer. Disease activity was measured by a composite index (disease activity score) consisting of the erythrocyte sedimentation rate (millimeters in first hour), the Ritchie articular index [6], the number of swollen joints, and a visual analogue scale for general health (range, 0 to 100 mm; a zero score indicating excellent health), which has been constructed and validated previously [7, 8]. Assessments were done at baseline; after 1, 2, and 4 weeks; and thereafter every 4 weeks. Functional capacity was assessed at baseline and after 12, 20, and 44 weeks using a health-assessment questionnaire (range, 0 to 3; a zero score indicating no functional impairment) [9]. Assessments of Bone Mineral Density Bone mineral density (BMD) was measured in the lumbar spine by dual-energy, quantitative computed tomography (effective radiation dose less than 300 microSievert) with a Somatom DR3 (Siemens AG, Erlangen, Germany). The details of this method have been published previously [10-12]. In short, patients were positioned with the lumbar spine over a calibration phantom, consisting of two stable plastics: a water-equivalent and a bone-equivalent standard containing 200 mg of hydroxyapatite per milliliter. Scans were made through the midvertebral level of lumbar vertebrae L2 to L4, with a slice thickness of 8 mm. Separate regions of interest were automatically defined for the trabecular bone and the anterior cortical bone of the vertebral body. The BMD was then calculated by comparison of the absorption in the region of interest with the absorption in the calibration phantom and was expressed in milligrams of hydroxyapatite per milliliter. Measurements were made at 125 and 85 kilovolt (kVp), and three images were reconstructed from each scan: at 125 kVp, at 85 kVp, and a calcium-equivalent density image after processing by material decomposition techniques. Dual-energy quantitative computed tomography results were calculated from the calcium density image. For duplicate measurements, the in vivo coefficient of variation ranged between 6.1% for the trabecular bone and 5.2% for the cortical bone. To exclude the possibility that new vertebral fractures caused changes in the BMD, lateral spine radiographs were obtained in all patients at baseline and after 44 weeks and were evaluated by an experienced radiologist. Statistical Analysis The change in BMD (expressed as percentage from baseline) was chosen as an outcome measurement. This variable followed a normal distribution sufficiently enough to allow the use of t-tests. Paired and unpaired t-tests were used for within- and between-group comparisons, respectively. Ninety-five percent confidence intervals (95% CI) were also calculated. The possible influence of an imbalance between the two groups with respect to menopausal state was evaluated using analysis of variance. Cumulative disease activity and cumulative functional capacity were defined as areas under the curve for the disease-activity scores and the health-assessment questionnaire scores, respectively. Differences between placebo and prednisone-treated patients were analyzed using the t-test. All analyses were done using intention-to-treat principles. Results During the recruitment period, 55 patients started aurothioglucose treatment. Three patients were inadvertently not reported by their treating physician. Nine patients refused to be included in the study for various reasons. One patient did not fulfill the required criteria for active disease. Two patients were excluded because of irregular menstrual cycles, indicating that menopause might be starting. The remaining 40 patients consented to participate in the study. The baseline BMD was similar in both groups. The mean trabecular BMD was 111 mg/mL in the prednisone group and was 111 mg/mL in the placebo group. The mean cortical BMD was 272 mg/mL in the prednisone-treated patients and was 276 mg/mL in the placebo-treated patients. Other baseline characteristics were also similar in the two treatment groups for most variables (Table 1). There were more postmenopausal women in the prednisone group, and the duration of postmenopause was longer in the placebo group. During the first period of the study, aurothioglucose was discontinued in nine patients (four in the prednisone and five in the placebo group) due to side effects. One of the five patients in the placebo group developed an acute, irreversible, and lethal pancytopenia. At the end of the first period of the trial, 16 patients in the prednisone group and 15 in the placebo group still used aurothioglucose. One patient in the prednisone group started methotrexate (7.5 mg weekly) after 18 weeks. Three patients in the prednisone group and four in the placebo group used no second-line antirheumatic treatment at the end of the first trial period. One patient in the placebo group with progressive disease refused further treatment with the trial medication after 4 weeks. She was then treated with prednisone, 10 mg/d, but assessments were carried out according to the protocol and data from this patient were included in the placebo group for all analyses (according to intention-to-treat principles). Table 1. Patient Characteristics During the second period of the trial, six patients who were originally assigned to the prednisone group, and who had all discontinued the trial medication according to the protocol, again started to use prednisone. Two patients from the placebo group used prednisone between weeks 20 and 44. For one patient, who was originally assigned to prednisone therapy, no BMD data were available at week 44. The composite disease-activity score and its four constituents all showed a marked and rapid improvement of disease activity in the prednisone-treated patients. Cumulative disease activity, as expressed by the area under the curve for the disease-activity scores, in

Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study

OBJECTIVEnTo study the effect of folates on discontinuation of methotrexate (MTX) as single-drug antirheumatic treatment due to toxicity, to determine which type of adverse events are reduced, to study the effects on the efficacy of MTX, and to compare folic with folinic acid supplementation in a 48-week, randomized, double-blind, placebo-controlled trial.nnnMETHODSnPatients with active RA (n = 434) were randomly assigned to receive MTX plus either placebo, folic acid (1 mg/day), or folinic acid (2.5 mg/week). The initial MTX dosage was 7.5 mg/week; dosage increases were allowed up to a maximum of 25 mg/week for insufficient responses. Folate dosages were doubled once the dosage of MTX reached 15 mg/week. The primary end point was MTX withdrawal because of adverse events. Secondary end points were the MTX dosage and parameters of efficacy and toxicity of MTX.nnnRESULTSnToxicity-related discontinuation of MTX occurred in 38% of the placebo group, 17% of the folic acid group, and 12% of the folinic acid group. These between-group differences were explained by a decreased incidence of elevated liver enzyme levels in the folate supplementation groups. No between-group differences were found in the frequency of other adverse events or in the duration of adverse events. Parameters of disease activity improved equally in all groups. Mean dosages of MTX at the end of the study were lower in the placebo group (14.5 mg/week) than in the folic and folinic acid groups (18.0 and 16.4 mg/week, respectively).nnnCONCLUSIONnBoth folate supplementation regimens reduced the incidence of elevated liver enzyme levels during MTX therapy, and as a consequence, MTX was discontinued less frequently in these patients. Folates seem to have no effect on the incidence, severity, and duration of other adverse events, including gastrointestinal and mucosal side effects. Slightly higher dosages of MTX were prescribed to obtain similar improvement in disease activity in the folate supplementation groups.

The C677T mutation in the methylenetetrahydrofolate reductase gene: A genetic risk factor for methotrexate-related elevation of liver enzymes in rheumatoid arthritis patients

OBJECTIVEnTo study the possible relationship between the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and the toxicity and efficacy of treatment with methotrexate (MTX) in patients with rheumatoid arthritis (RA).nnnMETHODSnGenotype analysis of the MTHFR gene was done in 236 patients who started MTX treatment with (n = 157) or without (n = 79) folic or folinic acid supplementation. Outcomes were parameters of efficacy of MTX treatment, patient withdrawal due to adverse events, discontinuation of MTX treatment because of elevated liver enzyme levels, and the total occurrence of elevated liver enzyme levels during the study. Multivariate logistic regression analysis was used to study the relationship between the presence of the MTHFR C677T mutation and toxicity outcomes of MTX treatment.nnnRESULTSnForty-eight percent of the patients showed the homozygous (T/T) or heterozygous (T/C) mutation. The presence of the C677CT or C677TT genotypes was associated with an increased risk of discontinuing MTX treatment because of adverse events (relative risk 2.01; 95% confidence interval 1.09, 3.70), mainly due to an increased risk of elevated liver enzyme levels (relative risk 2.38; 95% confidence interval 1.06, 5.34). Efficacy parameters were not significantly different between the patients with and those without the mutation.nnnCONCLUSIONnThe C677T mutation is the first identified genetic risk factor for elevated alanine aminotransferase values during MTX treatment in patients with RA. We postulate that the incidence of clinically important elevation of liver enzyme levels during MTX treatment is mediated by homocysteine metabolism. Supplementation with folic or folinic acid reduced the risk of toxicity-related discontinuation of MTX treatment both in patients with and in patients without the mutation.

Methotrexate in rheumatoid arthritis: An updatewith focus on mechanisms involved in toxicity

OBJECTIVESnTo provide an update of the current knowledge of the mechanism of action of low-dose methotrexate (MTX) in the treatment of patients with rheumatoid arthritis (RA), with an emphasis on the mechanisms involved in toxicity. We also considered strategies currently used to prevent or decrease toxicity of MTX.nnnMETHODSnWe reviewed the literature dealing with the subjects of MTX treatment of RA, the mechanisms of action of low-dose MTX regarding efficacy and toxicity, and strategies used to prevent or decrease MTX toxicity.nnnRESULTSnMTX is a fast working and effective second-line antirheumatic agent (SLA). Its use is limited mainly because of side effects. The mechanisms of action regarding efficacy and toxicity are probably determined by different metabolic pathways. Recent data indicate that the antiinflammatory effect of MTX is mediated by adenosine. However, MTX side effects can only partly be explained by folate antagonism and may also depend on its action on other related metabolic pathways. The latter include the homocysteine-methionine-polyamine pathway and purine metabolism. Variants in these metabolic routes (ie, the C677T mutation in the methylene-tetrahydrofolate reductase [MTHFR] gene), may predispose to the development of side effects. Currently the most promising strategy to decrease or prevent toxicity of MTX is concomitant prescription of folic acid or folinic acid. Other strategies are currently under investigation.nnnCONCLUSIONSnMTX benefits a majority of RA patients. Approximately 30% of patients, however, abandon treatment because of drug-related side effects. Folic acid or folinic acid likely reduces MTX toxicity. More data, however, are needed to evaluate a potential detrimental effect on the antirheumatic efficacy of MTX.

Factors associated with toxicity, final dose, and efficacy of methotrexate in patients with rheumatoid arthritis

Objective: To study factors associated with toxicity, final dose, and efficacy of methotrexate (MTX) in patients with rheumatoid arthritis (RA). Methods: Data were used from a randomised clinical 48 week trial on 411 patients with RA all treated with MTX, comparing folates and placebo. Logistic regression was used to study the relation between baseline variables and various dependent factors, including hepatotoxicity (alanine aminotransferase ⩾3×upper limit of normal), MTX withdrawal, final MTX dose ⩾15 mg/week, and MTX efficacy. Results: Addition of folates to MTX treatment was strongly related to the lack of hepatotoxicity. Next to this, high body mass index was related to the occurrence of hepatotoxicity. Prior gastrointestinal (GI) events and younger age were related to the adverse event, diarrhoea. Hepatotoxicity and GI adverse events were the main reason for MTX withdrawal, which in turn was associated with the absence of folate supplementation, body mass index, prior GI events, and female sex. Renal function (creatinine clearance ⩾50 ml/min) was not associated with toxicity. Reaching a final dose of MTX of ⩾15 mg/week was related to folate supplementation and the absence of prior GI events. Efficacy of MTX treatment was associated with low disease activity at baseline, male sex, use of non-steroidal anti-inflammatory drugs (NSAIDs), and lower creatinine clearance. Conclusions: MTX toxicity, final dose, and efficacy are influenced by folate supplementation. Baseline characteristics predicting the outcome of MTX treatment are mainly prior GI events, body mass index, sex, use of NSAIDs, and creatinine clearance.

Effect of osteoporosis treatments on risk of non-vertebral fractures: review and meta-analysis of intention-to-treat studies

Most osteoporosis treatments have proven efficacy in reducing the risk of vertebral fractures, whereas evidence is less straightforward for prevention of non-vertebral fractures. Conclusions as to the efficacy of a treatment should be based primarily on analyses of the intention to treat (ITT) population rather than on exploratory subgroup analyses; however, non-vertebral anti-fracture efficacy has been largely derived by post-hoc subgroup analyses. This review and meta-analysis was performed to assess non-vertebral anti-fracture efficacy of several osteoporosis therapies, including a more stringent assessment of the ITT populations. Data on non-vertebral anti-fracture efficacy, a defined endpoint of the ITT analyses and confirmed by radiographs, were obtained from randomized, placebo-controlled, phase III clinical trials of at least 3-year duration. Meta-analyses were performed for the two bisphosphonates, alendronate and risedronate. Relative risks (RR), 95% confidence intervals (CI) and statistical significance for active treatment compared with placebo were calculated. Eleven clinical trials met the criteria for review, three of which showed statistically significant ( P ≤0.05) non-vertebral anti-fracture efficacy in the ITT population: two trials with risedronate and one trial with strontium. A meta-analysis showed significant reductions in the relative risk of non-vertebral fracture for both alendronate (RR=0.86; 95% CI: 0.76–0.97, P =0.012) and risedronate (RR=0.81; 95% CI: 0.71–0.92, P =0.001). Risedronate and strontium ranelate were the only treatments to show non-vertebral anti-fracture efficacy in this robust assessment of anti-fracture efficacy of osteoporosis therapy using ITT populations in trials of 3xa0years or more in duration. Risedronate was the only agent shown to demonstrate efficacy in more than one trial. Meta-analysis showed that both alendronate and risedronate provide non-vertebral anti-fracture efficacy.

Bone mineral density in patients with recent onset rheumatoid arthritis: influence of disease activity and functional capacity.

BACKGROUND. Generalised osteoporosis is often described in patients with rheumatoid arthritis (RA). The aim of this study was to evaluate disease related determinants of bone mineral density (BMD) in patients with RA. METHODS. Subjects were selected from a group of 147 patients with recent onset RA. Disease activity and functional capacity were studied prospectively in this cohort. Activity of the disease was assessed once every three months by various parameters, and functional capacity was measured with a health assessment questionnaire once every six months. Ninety seven patients consented to participate in the study. Bone mineral density was assessed with dual energy x ray absorptiometry in the lumbar spine, in a combined region of interest in the hips, and in Wards triangle. Multiple linear regression procedures were used to analyse the data. RESULTS. Duration of RA was negatively associated with BMD at all three sites of measurement. The mean erythrocyte sedimentation rate in the six months before BMD measurement was negatively associated with BMD in the hip and in Wards triangle. Other parameters of disease activity were not related to BMD. The mean health assessment questionnaire score in the 18 months before BMD measurement was negatively associated with BMD in the combined hip region only. Bone mineral density tended to be decreased when patients were compared with a normal reference group, especially in the femoral regions of interest. CONCLUSIONS. It is concluded that BMD may be affected in patients with recent onset RA by disease dependent mechanisms. Several factors have been suggested elsewhere as determinants of BMD in RA. The results of this study show that disease duration, disease activity, and functional impairment may, independently of each other, contribute to bone loss, especially in the proximal femur.

Does osteoporosis predispose falls? a study on obstacle avoidance and balance confidence

The aim of the study was to investigate whether obstacle avoidance ability was affected in persons with osteoporosis compared to a comparison group of a community sample of older adults.BackgroundOsteoporosis is associated with changes in balance and physical performance and has psychosocial consequences which increase the risk of falling. Most falls occur during walking; therefore an efficient obstacle avoidance performance might contribute to a reduction in fall risk. Since it was shown that persons with osteoporosis are unstable during obstacle crossing it was hypothesized that they more frequently hit obstacles, specifically under challenging conditions.MethodsObstacle avoidance performance was measured on a treadmill and compared between persons with osteoporosis (n = 85) and the comparison group (n = 99). The obstacle was released at different available response times (ART) to create different levels of difficulty by increasing time pressure. Furthermore, balance confidence, measured with the short ABC-questionnaire, was compared between the groups.ResultsNo differences were found between the groups in success rates on the obstacle avoidance task (p = 0.173). Furthermore, the persons with osteoporosis had similar levels of balance confidence as the comparison group (p = 0.091). The level of balance confidence was not associated with the performance on the obstacle avoidance task (p = 0.145).ConclusionObstacle avoidance abilities were not impaired in persons with osteoporosis and they did not experience less balance confidence than the comparison group. These findings imply that persons with osteoporosis do not have an additional risk of falling because of poorer obstacle avoidance abilities.

Differential effects of glucocorticoids on cortical appendicular and cortical vertebral bone mineral content

SummaryThe susceptibility to glucocorticoid-induced bone loss may vary in different parts of the skeleton. We studied 62 patients with rheumatoid arthritis, 26 of whom were on low-dose glucocorticoid treatment. Bone mineral content (BMC) in the forearm was measured by single photon absorptiometry at a cortical, diaphyseal, and at a mixed cortical and trabecular, metaphyseal site. Lumbar BMC was measured by dual energy computed tomography in a trabecular and a cortical region of interest. The presence of vertebral deformities was evaluated on lateral spine radiographs. After correction for possibly confounding variables, prednisone therapy significantly influenced BMC at both the trabecular (-22.0%, 95% confidence interval-36.0% to-8.1%) and cortical (-24.8%, 95% confidence interval-39.3% to-10.3%) lumbar site. A significant effect was also seen at the metaphyseal (-15.7%, 95% confidence interval-27.1% to-4.2%), but not the diaphyseal (-3.9%, 95% confidence interval-14.1% to 6.4%) site in the forearm. Correlations between peripheral and vertebral BMC were moderate at best. The diaphyseal to metaphyseal BMC ratio did not identify patients with vertebral osteoporosis. It is concluded that the anterior cortical rim of the vertebral body is more susceptible to the effects of glucocorticoids than the cortical bone in the forearm, and that measurements of trabecular and anterior cortical vertebral BMC are essential in the management of patients with possible glucocorticoid-associated osteoporosis.

Methotrexate-related pulmonary complications in rheumatoid arthritis.

Methotrexate (MTX) was described as a drug in 1946 and first used in the treatment of human disease (childhood leukaemia) in 1948.2 Successful MTX treatment for rheumatoid arthritis (RA) and psoriasis was reported in 1951,3 although the interest in this drug at that time was probably overshadowed by the impressive results of cortico-steroid treatment until approximately 1980. MTX was approved by the food and drug administration (FDA) for the treatment of severe and disabling psoriasis in 1971 and for RA only in 1988.4 MTX-related pulmonary toxicity was first observed during treatment of childhood leukaemia in 19695 and later in malignancies, psoriasis6 7 and polymyositis.7 I Though it was postulated that pulmonary toxicity would appear only with a weekly dose higher than 20 mg,7 this did not prove to be true when in 1983 pneumonitis was also reported during low-dose MTX treatment for RA9 10