Suboptimal cardiovascular risk management in rheumatoid arthritis patients despite an explicit cardiovascular risk screening programme.

Objective: In 2011, we started to offer cardiovascular (CV) risk screening to rheumatoid arthritis (RA) patients with a high CV risk. After 1 year, we assessed whether patients labelled as high CV risk had started preventive treatment when indicated, and whether the CV risk score had changed. Methods: CV risk screening was performed in both a large outpatient rheumatology clinic and a general hospital in the Netherlands, and the general practitioner or the internist was informed about the results of the CV screening, including specific advice on the initiation or adjustment of cardiopreventive drugs. National guidelines were used to assess how many patients were eligible for preventive treatment. After 1 year, CV risk, lifestyle, and treatment were re-evaluated. Patients with a history of CV disease at baseline or who experienced a CV event during follow-up were excluded from the analyses. Results: A high 10 year CV risk (> 20%) was present in 58%, and 55% had an indication for anti-hypertensives, statins, or both. At follow-up, cardiopreventive drug treatment had been started or adjusted in only one-third of patients with an indication for treatment. After screening, 42% of patients reported having changed their lifestyle, through more exercise (24%), diet adaption (20%), and weight loss (11%). Conclusion: Despite clear guidelines to improve CV risk, the results of a programme comprising active screening, targeted advice, and referral to the general practitioner or internist prove that primary prevention remains a major challenge in high-risk RA patients.

An Economic Evaluation of Stopping Versus Continuing Tumor Necrosis Factor Inhibitor Treatment in Rheumatoid Arthritis Patients With Disease Remission or Low Disease Activity: Results From a Pragmatic Open-Label Trial.

OBJECTIVE: To evaluate, from a societal perspective, the incremental cost-effectiveness of withdrawing tumor necrosis factor inhibitor (TNFi) treatment compared to continuation of these drugs within a 1-year, randomized trial among rheumatoid arthritis patients with longstanding, stable disease activity or remission. METHODS: Data were collected from a pragmatic, open-label trial. Cost-utility analysis was performed using the nonparametric bootstrapping method, and a cost-effectiveness acceptability curve was constructed using the net-monetary benefit framework, where a willingness-to-accept threshold (WTA) was defined as the minimal cost saved that a patient accepted for each quality-adjusted life year (QALY) lost. RESULTS: A total of 531 patients were randomized to the stop group and 286 patients to the continuation group. Withdrawal of TNFi treatment resulted in a >60% reduction of the total drug cost, but led to an increase of ∼30% in other health care expenditures. Compared to continuation, stopping TNFi resulted in a mean yearly cost saving of €7,133 (95% confidence interval [95% CI] €6,071, €8,234]) and was associated with a mean loss of QALYs of 0.02 (95% CI 0.002, 0.040). Mean saved cost per QALY lost and per extra flare incurred in the stop group compared to the continuation group was €368,269 (95% CI €155,132, €1,675,909) and €17,670 (95% CI €13,650, €22,721), respectively. At a WTA of €98,438 per QALY lost, the probability that stopping TNFi treatment is cost-effective was 100%. CONCLUSION: Although an official WTA is not defined, the mean saved cost of €368,269 per QALY lost seems acceptable in The Netherlands, given existing data on willingness to pay.

The formation of autoantibodies and antibodies to TNF-α blocking agents in relation to clinical response in patients with ankylosing spondylitis.

OBJECTIVES: To investigate the influence of antibody formation to TNF-α blocking agents on the clinical response in AS patients treated with infliximab (IFX), etanercept (ETA), or adalimumab (ADA), and to investigate the development of ANA, ANCA, and anti-dsDNA antibodies in association with the formation of antibodies to TNF-α blocking agents. METHODS: Consecutive AS outpatients with active disease who started treatment with IFX (n=20), ETA (n=20), or ADA (n=20) were included in this longitudinal observational study. Clinical data were collected prospectively at baseline and after 3, 6, and 12 months of anti-TNF-α treatment. At the same time points, serum samples were collected. In these samples, antibodies to TNF-α blocking agents, serum TNF-α blocker levels, and ANA, ANCA, and anti-dsDNA antibodies were measured retrospectively. RESULTS: Anti-IFX, anti-ETA, and anti-ADA antibodies were induced in 20%, 0%, and 30% of patients, respectively. Although ANA, ANCA, and anti-dsDNA antibodies were detected during anti-TNF-α treatment, no significant association was found between the presence of these autoantibodies and the formation of antibodies to TNF-α blocking agents. Patients with anti-IFX or anti-ADA antibodies had significantly lower serum TNF-α blocker levels compared to patients without these antibodies. Furthermore, significant negative correlations were found between serum TNF-α blocker levels and assessments of disease activity. CONCLUSIONS: This study indicates that antibody formation to IFX or ADA is related to a decrease in efficacy and early discontinuation of anti-TNF-α treatment in AS patients. Furthermore, autoantibody formation does not seem to be associated with antibody formation to TNF-α blocking agents.

Efficacy and tolerability of urate-lowering drugs in gout: a randomised controlled trial of benzbromarone versus probenecid after failure of allopurinol.

OBJECTIVES: To investigate the efficacy and tolerability of allopurinol as the first-choice antihyperuricaemic treatment for gout, and compare the efficacy and tolerability of benzbromarone and probenecid as second-choice treatment. METHODS: Prospective, multicentre, open-label, two-stage randomised controlled trial in gout patients with normal renal function. Enrolled patients were given 300 mg allopurinol for 2 months (stage 1). Those patients who could not tolerate allopurinol or who did not attain the target serum urate concentration (sUr) < or=0.30 mmol/l (5.0 mg/dl), which was defined as successful, were randomised to benzbromarone 200 mg/day or probenecid 2 g/day for another 2 months (stage 2). RESULTS: 96 patients were enrolled in stage 1. 82 patients (85%) were eligible for the analysis at the end of stage 1: there was a mean (SD) decrease in sUr concentration of 35 (11)% from baseline; 20 patients (24%) attained target sUr < or=0.30 mmol/l; and 9 patients (11%) stopped allopurinol because of adverse drug reactions. 62 patients were enrolled in stage 2. 27 patients received benzbromarone (3 patients not eligible for analysis) and 35 received probenecid (4 patients not eligible for analysis). Treatment with benzbromarone was successful in 22/24 patients (92%) and with probenecid in 20/31 patients (65%) (p = 0.03 compared with benzbromarone). Compared with baseline values, there was a mean (SD) decrease of sUr concentration of 64 (9)% with benzbromarone and 50 (7)% with probenecid (p<0.001). CONCLUSION: This study showed that allopurinol 300 mg/day has a poor efficacy and tolerability profile when used to attain a biochemical predefined target level of sUr < or =0.30 mmol/l, following 2 months of treatment. In stage 2, benzbromarone 200 mg/day was more effective and better tolerated than probenecid 2 g/day.

Leflunomide in active rheumatoid arthritis: a prospective study in daily practice.

AIMS: We prospectively studied the efficacy, incidence of adverse drug reactions and withdrawal from leflunomide in an outpatient population with rheumatoid arthritis in a setting of care-as-usual. METHODS: In this prospective case series study, a standard dataset was collected from outpatient medical records, including patient and disease characteristics, data on leflunomide use and adverse drug reactions. RESULTS: During the study period 136 rheumatoid arthritis patients started leflunomide. Median (range) follow-up duration was 317 (11-911) days. Sixty-five percent of patients experienced at least one adverse drug reaction related to leflunomide. During follow-up 76 patients (56%) withdrew from leflunomide treatment, mainly because of adverse drug reactions (29%) or lack of efficacy (13%). The overall incidence density for withdrawal from leflunomide was 56.2 per 100 patient years. Complete data for calculating efficacy using a validated disease activity score on 28 joints (DAS(28)) was available for 48, 36, and 35% of patients at 2, 6, and 12 months follow-up, respectively. Within a 12-month period after start of leflunomide treatment 76% of the evaluable patients were classified as moderate or good responders according to the DAS(28) response criteria. CONCLUSIONS: In the setting of care-as-usual rheumatoid arthritis patients starting leflunomide frequently experienced adverse drug reactions. More than half of the patients withdrew from leflunomide treatment within 1 year of starting leflunomide treatment, mainly because of adverse drug reactions.

Leflunomide in active rheumatoid arthritis: a prospective study in daily practice.

AIMS: We prospectively studied the efficacy, incidence of adverse drug reactions and withdrawal from leflunomide in an outpatient population with rheumatoid arthritis in a setting of care-as-usual. METHODS: In this prospective case series study, from outpatient medical records a standard dataset was collected including patient and disease characteristics, data on leflunomide use and adverse drug reactions. RESULTS: During the study period 136 rheumatoid arthritis patients started leflunomide. Median (range) follow-up duration was 317 (11-911) days. Sixty-five percent of patients experienced at least one adverse drug reaction related to leflunomide. During follow-up 76 patients (56%) withdrew from leflunomide treatment, mainly because of adverse drug reactions (29%) or lack of efficacy (13%). The overall incidence density for withdrawal from leflunomide was 56.2 per 100 patient-years. Complete data for calculating efficacy using a validated disease activity score on 28 joints (DAS(28)) was available for 48, 36, and 35% of patients at 2, 6, and 12 months follow-up, respectively. Within a 12-month period after start of leflunomide treatment 76% of the evaluable patients were classified as moderate or good responders according to the DAS(28) response criteria. CONCLUSIONS: In the setting of care-as-usual, rheumatoid arthritis patients starting leflunomide frequently experienced adverse drug reactions. More than half of the patients withdrew from leflunomide treatment within a year after start of leflunomide treatment, mainly because of adverse drug reactions.

Chloroquine therapy in patients with recent-onset rheumatoid arthritis: the clinical response can be predicted by the low level of acute-phase reaction at baseline.

If rheumatoid arthritis (RA) patients with a mild disease course could be identified early in the phase of the disease, therapy with less aggressive and probably less toxic antirheumatic drugs seems to be rational. The aim of this study was to investigate which factors at baseline could predict a clinical response (American College of Rheumatology preliminary response criteria) after treatment with chloroquine for 16 weeks. Two hundred and three early RA patients with active disease were treated with oral chloroquine sulphate (Nivaquine) at a daily dose of 300 mg during the first 4 weeks, 200 mg during the second 4 weeks and 100 mg thereafter. One hundred and eighty-three patients (90%) completed the study and 20 patients prematurely discontinued treatment. Of all the patients, 43 patients (21%) met the response criteria. A low level of C-reactive protein (CRP) was the only independent predictor for clinical response [relative risk: 0.97 (95% confidence interval: 0.95-0.98)]. It was concluded that a clinical response to chloroquine therapy in early RA patients can be predicted by a low CRP level at baseline.

Fatigue in rheumatoid arthritis: the role of self-efficacy and problematic social support.

OBJECTIVE: To examine the relationship of fatigue in people with rheumatoid arthritis (RA) with self-efficacy, positive and problematic aspects of social support, and demographic and disease-related variables. METHOD: Out-patients with at least 5 yr RA were studied. Fatigue was measured with a visual analogue scale. Other variables included were: positive social support [Social Support List-Interactions (SSL12-I)] and problematic social support; self-efficacy towards coping with RA and towards mobilizing support; health status (Dutch-AIMS2); and laboratory tests: erythrocyte sedimentation rate (ESR), haemoglobin (Hb) and rheumatoid factor (RF); and disease duration. RESULTS: A total of 229 out-patients were included. Fatigue correlated with all scales of the Dutch-AIMS2: with pain, physical function and affect (P < 0.001). There was no significant correlation with social support, but there was a highly significant correlation of fatigue with problematic social support (P < 0.001). Both forms of self-efficacy correlated strongly with fatigue: patients with high self-efficacy expectations towards coping with RA, and towards mobilizing the social network (P < 0.001), had less fatigue. In the regression analysis to explain the variation in fatigue, only pain, self-efficacy expectations towards coping with RA, and towards asking for help and problematic social support remained significant. CONCLUSIONS: Fatigue can to a large extent (37%) be explained by pain, self-efficacy towards coping with RA, and towards asking for help and problematic social support. It is known that self-efficacy can be enhanced by self-management courses and it may thus be possible to improve fatigue.

Function of the hypothalamic-pituitary-adrenal axis in patients with fibromyalgia and low back pain.

OBJECTIVE: We suggested fibromyalgia (FM) is a disorder associated with an altered functioning of the stress-response system. This was concluded from hyperreactive pituitary adrenocorticotropic hormone (ACTH) release in response to corticotropin-releasing hormone (CRH) and to insulin induced hypoglycemia in patients with FM. In this study, we tested the validity and specificity of this observation compared to another painful condition, low back pain. METHODS: We recruited 40 patients with primary FM (F:M 36:4), 28 patients (25:3) with chronic noninflammatory low back pain (LBP), and 14 (12:2) healthy, sedentary controls. A standard 100 microg CRH challenge test was performed with measurement of ACTH and cortisol levels at 9 time points. They were also subjected to an overnight dexamethasone suppression test, followed by injection of synthetic ACTH1-24. At 9 AM, the patients divided in 2 groups, received either 0.025 or 0.100 microg ACTH/kg body weight to test for adrenocortical sensitivity. Basal adrenocortical function was assessed mainly by measurement of 24 h urinary excretion of free cortisol. RESULTS: Compared to the controls, the patients with FM displayed a hyperreactive ACTH release in response to CRH challenge (ANOVA interaction effect p = 0.001). The mean ACTH response of the patients with low back pain appeared enhanced also, but to a significantly lesser extent (p = 0.02 at maximum level) than observed in the patients with FM. The cortisol response was the same in the 3 groups. Following dexamethasone intake there were 2 and 4 nonsuppressors in the FM and LBP groups, respectively. The very low and low dose of exogenous ACTH1-24 evoked a dose and time dependent cortisol response, which, however, was not significantly different between the 3 groups. The 24 h urinary free cortisol levels were significantly lower (p = 0.02) than controls in both patient groups; patients with FM also displayed significantly lower (p < 0.05) basal total plasma cortisol than controls. CONCLUSION: The present data validate and substantiate our preliminary evidence for a dysregulation of the HPA axis in patients with FM, marked by mild hypocortisolemia, hyperreactivity of pituitary ACTH release to CRH, and glucocorticoid feedback resistance. Patients with LBP also display hypocortisolemia, but only a tendency toward the disrupted HPA features observed in the patients with FM. We propose that a reduced containment of the stress-response system by corticosteroid hormones is associated with the symptoms of FM.

Glucocorticoid receptors, fibromyalgia and low back pain.

Recently, fibromyalgia (FMS) was shown to be a disorder associated with an altered functioning of the stress response system. FMS patients display a hyperreactive pituitary adrenocorticotropic hormone (ACTH) release in response to corticotropin-releasing hormone (CRH) and to insulin-induced hypoglycemia. We suggested that negative feedback of cortisol could be deranged. Therefore we investigated the properties and function of the glucocorticoid receptors (GR) in FMS patients and compared the results with those of healthy persons and patients with chronic low back pain (LBP a localized pain condition). Forty primary FMS patients (F:M = 36:4), 28 LBP patients (25:3) and 14 (12:2) healthy, sedentary control persons were recruited for the study. Urinary free cortisol excretion in FMS and LBP patients was lower compared to controls. Only FMS patients displayed lower CBG and basal serum cortisol concentrations when compared to controls. However, plasma free cortisol concentrations were similar in the three groups. There was no difference in the number of GR per cell among the three groups (FMS: 6498 +/- 252, LBP: 6625 +/- 284, controls: 6576 +/- 304), but the dissociation constant (Kd) of the FMS (14.5 +/- 0.9 nmol/l) and LBP (14.7 +/- 1.3 nmol/l) subjects was significantly higher than that of the controls (10.9 +/- 0.8 nmol/l) (p < .05). The maximal stimulation of the lymphocytes, as measured by the maximal thymidine incorporation (in the absence of cortisol) in the FMS group was approximately 1.5 times higher (p < .05) than in the control or LBP group. The ED50 (the cortisol concentration giving 50% inhibition of the thymidine incorporation), however, was identical in all three groups. We conclude that FMS patients have a mild hypocortisolemia, increased cortisol feedback resistance in combination probably with a reduced CRH synthesis or release in the hypothalamus. The role of the GR and mineralocorticoid receptor (MR) in the CRH regulation in the FMS patients remains to be solved.

Lack of correlation between the mean tender point score and self-reported pain in fibromyalgia.

OBJECTIVES: To study the validity and nature of self-assessed symptoms among patients with fibromyalgia syndrome (FMS) and to compare our data with findings reported in the US. To determine whether tender point scores correlate with self-reported pain and other symptoms and to study the influence of disease duration. METHODS: Tender point scores were assessed in 113 consecutive patients with FMS. All patients completed 2 self-assessment questionnaires (an extended Campbell list, the Enschede Fibromyalgia Questionnaire, and the Dutch Arthritis Impact Measurement Scales). RESULTS: The self-assessed symptoms of the Dutch FMS patients seem to be valid and are comparable with those of American patients. No association between disease duration and number of self-reported symptoms was found. An association between self-reported pain and mean tender point score was lacking for patients with disease of shorter duration and was weak for patients with disease of longer duration. CONCLUSIONS: The use of a self-report questionnaire for patients with FMS is feasible and appears to be valid. Tender point scores and self-reported pain represent very different aspects of pain in FMS.

Pituitary release of growth hormone and prolactin in the primary fibromyalgia syndrome.

OBJECTIVE: Previously, we demonstrated hyperreactive adrenocorticotropic hormone (ACTH) release in patients with primary fibromyalgia syndrome (primary FMS). We investigated the pituitary release of growth hormone (GH) and prolactin (PRL) in search of further disturbances in neuroendocrine reactivity possibly associated with the pathophysiology of primary FMS. METHODS: Ten female patients with primary FMS fulfilling the 1981 Yunus criteria and 10 matched, healthy and sedentary controls were subjected to an insulin induced hypoglycemia test; samples for measurement of glucose, GH and PRL were taken at intervals. RESULTS: Compared to the controls, the patients with primary FMS displayed significantly lower basal GH levels, whereas their basal PRL levels were slightly, though significantly, higher (respectively p = 0.021 and p = 0.041). Following hypoglycemia, there was a marked, statistically highly significant (p = 0.001), hyperreactivity of the GH response in patients with primary FMS. The PRL response showed wide interindividual variation and did not differ between patients and controls. CONCLUSION: Our findings indicate that fibromyalgia, along with ACTH hyperreactivity, also exhibits a distinct disturbance in the GH-somatomedin C axis. With regard to PRL, the variation in individual responses limits conclusions. The hyperreactive response patterns of GH and ACTH previously suggest a common origin, which might be related to a subtle glucocorticoid deficiency.

Local muscle hypertrophy due to an arterio-venous malformation.

A 20-yr-old man with progressive, painful diffuse swelling of his right shoulder muscles is reported. The diagnosis was muscle hypertrophy secondary to a congenital arterio-venous malformation (CAVM). Since a CAVM is not infrequently asymptomatic until the age of 20 to 30 yr and develops insidiously, the diagnosis may be delayed. In our patient, MRI rather than ultrasound and CT, led to the final diagnosis.