The psychophysiological stress response in psoriasis and rheumatoid arthritis.

BACKGROUND: Psychosocial stress can be a risk factor for the maintenance and exacerbation of chronic inflammatory diseases, such as psoriasis and rheumatoid arthritis (RA). OBJECTIVES: To gain insight into the specificity of the psychophysiological stress response during chronic inflammation, we assessed autonomic and neuroendocrine responses to stress in different chronic inflammatory diseases. METHODS: Thirty patients with psoriasis (nine women, mean age 58·5 years ± 12·4), 34 patients with RA (16 women, mean age 60·8 years ± 9·2) and 25 healthy controls (16 women, mean age 55·6 years ± 8·7) underwent a standardized psychosocial stress task (Trier Social Stress Test). Salivary levels of α-amylase and cortisol and self-reported tension levels were measured before and after the stress test. RESULTS: The cortisol response to stress was heightened in patients with psoriasis compared with patients with RA and healthy controls, whereas there were no differences in the autonomic and self-reported measures. CONCLUSIONS: The altered neuroendocrine stress response in patients with psoriasis suggests that stressful events might have different physiological consequences for specific patient groups with chronic inflammatory conditions, possibly adversely affecting disease status.

Excess mortality emerges after 10 years in an inception cohort of early rheumatoid arthritis.

OBJECTIVE: To investigate mortality rates, causes of death, time trends in mortality, prognostic factors for mortality, and the relationship between disease activity and mortality over a 23-year period in an inception cohort of rheumatoid arthritis (RA) patients. METHODS: A prospective inception cohort of RA patients diagnosed between January 1985 and October 2007 was followed for up to 23 years after diagnosis. Excess mortality was analyzed by comparing the observed mortality in the RA cohort with the expected mortality based on the general population of The Netherlands, matched for age, sex, and calendar year. Period analysis was used to examine time trends in survival across calendar time. Prognostic factors for mortality and the influence of the time-varying Disease Activity Score in 28 joints (DAS28) on mortality were analyzed using multivariable Cox proportional hazards models. Causes of death were analyzed. RESULTS: Of the 1,049 patients in the cohort, 207 patients died. Differences in observed and expected mortality emerged after 10 years of followup. No improvement in survival was noted over calendar time. Significant baseline predictors of survival were sex, age, rheumatoid factor, disability, and comorbidity. Higher levels of DAS28 over time, adjusted for age, were associated with lower survival rates, more so in men (hazard ratio [HR] 1.58, 95% confidence interval [95% CI] 1.35-1.85) than in women (HR 1.21, 95% CI 1.04-1.42). CONCLUSION: Excess mortality in RA emerged after 10 years of disease duration. Absolute survival rates have not improved in the last 23 years and a trend toward a widening mortality gap between RA patients and the general population was visible. Higher disease activity levels contribute to premature death in RA patients.

Formation of antibodies against infliximab and adalimumab strongly correlates with functional drug levels and clinical responses in rheumatoid arthritis.

BACKGROUND: Tumour necrosis factor alpha (TNFalpha) neutralising antibody constructs are increasingly being used to treat rheumatoid arthritis (RA). OBJECTIVE: To determine potential differences in clinical responses, soluble drug levels and antibody formation between patients with RA receiving infliximab and adalimumab. METHODS: 69 patients with RA fulfilling the 1987 American College of Rheumatology criteria and about to start treatment with infliximab or adalimumab, were enrolled consecutively. All patients had active disease (28-joint count Disease Activity Score >3.2). Infliximab was given intravenously at 3 mg/kg at baseline and after 2, 6 and 14 weeks. Adalimumab was administered as 40 mg biweekly subcutaneously. Concomitant drug treatment was monitored and continued at constant dosage during the study. All serum samples were tested for infliximab/adalimumab levels and anti-infliximab/anti-adalimumab antibodies. RESULTS: 35 patients received infliximab, 34 received adalimumab. At 6 months, 15 (43%), 6 (17%) and 14 (40%) of the infliximab-treated patients fulfilled the EULAR criteria for good, moderate and non-responders, respectively, whereas the corresponding figures for adalimumab-treated patients were 16 (47%), 8 (24%) and 10 (29%). Clinical responses correlated with the levels of S-infliximab/adalimumab and the formation of anti-infliximab/anti-adalimumab antibodies. CONCLUSION: The clinical response to two anti-TNFalpha biological agents closely follows the trough drug levels and the presence of antibodies directed against the drugs. Further studies that focus on the underlying pathways leading to antibody formation are warranted to predict immunogenicity of these expensive biological agents and treatment outcomes.

Disease activity as a risk factor for myocardial infarction in rheumatoid arthritis.

OBJECTIVE: Patients with rheumatoid arthritis (RA) are at greater risk of developing coronary heart disease than the general population. Systemic inflammation may contribute to this risk. This study investigated whether the level of disease activity is associated with the risk of developing myocardial infarction (MI) in patients with RA. METHODS: A case-control study was performed within a large prospective cohort of patients with RA. Cases were patients who developed their first MI after the diagnosis of RA, controls were patients with RA without MI. Cases and controls had similar RA disease duration. Traditional and disease-specific risk factors for MI were collected and a time-averaged disease activity score (DAS28) was calculated. The data were analysed using conditional logistic regression analysis. RESULTS: Cases of MI were significantly older, were more often male, with higher body mass index (BMI) and total cholesterol and lower high-density lipoprotein (HDL) serum levels than controls. Time-averaged disease activity was similar for cases and controls. The raw odds ratio for MI in patients with a "high" (>4.0) versus a "low" (

The tumour necrosis factor receptor superfamily member 1b 676T>G polymorphism in relation to response to infliximab and adalimumab treatment and disease severity in rheumatoid arthritis.

OBJECTIVE: To assess the effect of a functional polymorphism (676T>G, M196R) in the tumour necrosis factor receptor super family 1b (TNFSF1b) gene on disease activity, radiological joint damage and response to infliximab and adalimumab treatment in patients with rheumatoid arthritis (RA). METHODS: Two cohorts of patients with RA were genotyped for the 676T>G polymorphism (rs1061622) in exon 6 of the TNFSF1b gene by restriction fragment length polymorphism analysis. One cohort (n = 234) included patients from the Dutch Rheumatoid Arthritis Monitoring register with detailed information on their response to anti-TNF therapy (infliximab and adalimumab), the other cohort comprised patients from a long-term observational early inception cohort at our centre (n = 248). RESULTS: The 676T>G polymorphism was not associated with anti-TNF response after 3 or 6 months of treatment. Linear regression analysis showed no significant difference in the progression of radiological joint damage during the first 3 and 6 years of disease between the three genotype groups (TT, TG and GG). Additionally, no difference in mean disease activity between genotypes was seen after 3 and 6 years of disease. CONCLUSION: Despite its demonstrated functionality, the 676T>G polymorphism in the TNFSF1b gene does not have a major role in either the response to anti-TNF therapy or in the disease severity or radiological progression in RA.

Comment on the use of self-reporting instruments to assess patients with rheumatoid arthritis: the longitudinal association between the DAS28 and the VAS general health.

OBJECTIVE: Recently, the use of patient self-reporting instruments instead of clinical, objective measurements to assess rheumatoid arthritis (RA) patients was proposed. This assumes a constant association between disease activity and the self-reporting instruments. The objective was to explore the association (in time) between disease activity and patient perception of general health, disease activity, pain, and functional disability in patients with RA. METHODS: Data of 624 newly diagnosed RA patients who completed 3 years of followup were analyzed. Cross-sectional linear regression models and longitudinal regression models were estimated, with a visual analog scale (VAS) measuring general health (VAS-GH; 0 = best, 100 = worst) as a dependent variable and the Disease Activity Score (DAS28) without the VAS-GH as an independent variable. Other dependent variables were VAS disease activity, pain, and the Health Assessment Questionnaire. RESULTS: The DAS28 and VAS-GH were significantly associated in RA patients (P < 0.001). However, the explained variance was low (6.7%). From diagnosis to 3 years after the diagnosis, the intercept decreased given the same regression coefficient. The longitudinal regression model showed that the VAS-GH improved during disease course independent of a change in DAS28. Analyses on the other outcome parameters showed similar results. CONCLUSION: Patients' perception of health can be different with equal disease activity, depending on the moment in the disease course. Furthermore, our results indicate that self-reported measures on functionality, disease activity, and general health cannot substitute for objective measures of disease activity in RA in longitudinal studies; subsequently, both need to be measured.

Hypothalamic-pituitary-adrenal axis activity in patients with rheumatoid arthritis.

OBJECTIVE: To study the hypothalamic-pituitary-adrenal (HPA) axis in patients with rheumatoid arthritis (RA). METHODS: Fifty patients with RA participated in 3 groups: recent onset active RA (n = 20), longstanding active RA (n = 20) and long-standing RA in remission (n = 10), and were compared with 20 healthy controls. The activity of the HPA-axis was assessed under basal conditions and in response to stress (insulin tolerance test, ITT). In addition, patients with recent onset RA underwent a corticotropin releasing hormone (CRH) test and a dexamethasone suppression test. Plasma levels of interleukin (IL)-1beta, tumor necrosis factor-alpha (TNF-alpha) and IL-6 were also measured. RESULTS: Basal plasma, salivary and urinary cortisol levels and plasma adrenocorticotropic hormone (ACTH) levels were not different between patients with RA and healthy controls. During the ITT, cortisol levels were consistently lower in RA patients than in healthy controls. ACTH levels during the ITT were not different between patients with RA and healthy controls. ACTH and cortisol responses to CRH were assessed only in patients with recent onset RA and were found to be within normal limits. Basal circulating plasma IL-6 levels were significantly higher in patients with active RA than in the other groups. CONCLUSION: Under the standardized conditions of the ITT, patients with RA have decreased plasma cortisol levels compared to healthy controls, despite elevated levels of IL-6. The defect is probably located at the adrenal level and may be of pathogenetic significance for the development of chronic arthritis.

Decreased prolactin response to hypoglycaemia in patients with rheumatoid arthritis: correlation with disease activity.

OBJECTIVE: To compare basal and stimulated prolactin levels between patients with rheumatoid arthritis and healthy controls, and to assess the effects of antirheumatic treatment on prolactin concentrations. METHODS: Serum prolactin was assessed under basal conditions and during an insulin tolerance test (ITT) in 20 patients with recently diagnosed active rheumatoid arthritis and 20 age and sex matched controls. The patients were reassessed after two weeks' treatment with naproxen and after six months' additional treatment with either sulfasalazine or methotrexate. Disease activity was assessed by the disease activity score (DAS). RESULTS: Basal levels of prolactin were not significantly different between patients with rheumatoid arthritis and controls. Prolactin responses to hypoglycaemia were less in untreated rheumatoid patients than in controls. DAS scores correlated negatively with the area under the curve (AUC) for prolactin concentrations during the ITT. Treatment with naproxen for two weeks did not influence either basal or stimulated prolactin levels. After six months of antirheumatic treatment, prolactin responses to hypoglycaemia increased significantly to levels observed in controls. At the same time point, DAS had improved considerably. The improvement correlated with the increase in AUC of prolactin during the ITT (r = 0.48; p = 0.05). CONCLUSIONS: Patients with active rheumatoid arthritis have a decreased prolactin response to hypoglycaemia induced stress. The response recovers following treatment with antirheumatic drugs.

The role of the hypothalamic-pituitary-adrenal axis in rheumatoid arthritis.

It has become clear that there is a bidirectional communication between the neuroendocrine and the immune system and that both systems influence each other and interact under physiological conditions and in response to inflammatory stimuli. The hypothalamic-pituitary axis plays an important role in regulating and controlling immune responses and dysfunction of the axis has been implicated in the pathogenesis of rheumatoid arthritis (RA). Corticotrophin-releasing hormone (CRH), one of the main hormones of the axis, is also released extra-hypothalamically, peripherally at the site of inflammation and may modulate inflammatory responses locally. In this chapter we will discuss the role of the hypothalamic-pituitary-adrenal (HPA) axis and peripheral CRH, its influences on immune function and what is known about the possible pathogenetic role of the HPA axis and peripheral CRH in RA.

Plasma metanephrines are markers of pheochromocytoma produced by catechol-O-methyltransferase within tumors.

This study examined whether the high sensitivity of plasma free metanephrines for diagnosis of pheochromocytoma may result from production of free metanephrines within tumors. Presence in pheochromocytomas of catechol-O-methyltransferase (COMT), the enzyme responsible for conversion of catecholamines to metanephrines, was confirmed by Western blot analysis, enzyme assay, and immunohistochemistry. Western blot analysis and enzyme assay indicated that membrane-bound and not soluble COMT was the predominant form of the enzyme in pheochromocytoma. Immunohistochemistry revealed colocalization of COMT in the same chromaffin cells where catecholamines are translocated into storage vesicles by the vesicular monoamine transporter. Levels of free metanephrines in pheochromocytoma over 10,000 times higher than plasma concentrations in the same patients before removal of tumors indicated production of metanephrines within tumors. Comparisons of the production of metanephrines in patients with pheochromocytoma with production from catecholamines released or infused into the circulation indicated that more than 93% of the consistently elevated levels of circulating free metanephrines in patients with pheochromocytoma are derived from metabolism before and not after release of catecholamines into the circulation. The data indicate that the elevated plasma levels of free metanephrines in patients with pheochromocytoma are derived from catecholamines produced and metabolized within tumors. Some tumors do not secrete catecholamines, but all appear to metabolize catecholamines to free metanephrines, thus explaining the better sensitivity of plasma free metanephrines over other tests for diagnosis of pheochromocytoma.

Undefined malabsorption syndrome with villous atrophy successfully reversed by treatment with cyclosporine.

A 47-year-old man with a flat jejunal mucosa complicated by malabsorption, diarrhoea and lymphocytic colitis is presented. There was no response to gluten withdrawal alone, combination of a gluten-free diet and prednisone therapy, or total parenteral nutrition. Complete clinical remission was only achieved after simultaneous treatment with cyclosporine and a gluten-free diet. Rechallenge with a gluten-containing diet while cyclosporine treatment continued resulted in a relapse of diarrhoea and malabsorption. We conclude that cyclosporine may be an effective agent for the treatment of undefined, refractory forms of malabsorption.

Nicotine enhances the circulatory effects of adenosine in human beings.

A randomized, double-blind, and placebo-controlled study was performed in 10 healthy volunteers to evaluate a possible interaction between adenosine and nicotine in human beings. The infusion of adenosine alone (0.07 mg/kg/min) induced an increase in heart rate of 4.7 beats/min versus 0.2 beats/min after placebo administration (p less than 0.02). The infusion of adenosine alone induced a decrease in finger skin temperature compared with placebo administration (-1.0 degrees versus 0.0 degrees C, p less than 0.01). When compared with baseline values, nicotine gum chewing increased systolic and diastolic blood pressures by 6.2 and 7.0 mm Hg, respectively (p less than 0.001), heart rate by 5.5 beats/min (p less than 0.01), and plasma adrenaline levels by 0.03 nmol/L (p less than 0.025), whereas skin temperatures fell by 1.3 degrees C (p less than 0.001). The nicotine-induced increase in heart rate was larger during adenosine infusion than during placebo administration (14.9 versus 5.5 beats/min, p less than 0.001), whereas the increment of diastolic blood pressure was lower (1.1 versus 4.0 mm Hg, p less than 0.05). The increment in systolic blood pressure was not altered by concomitant adenosine infusion. The rise in plasma noradrenaline levels during the combined administration of nicotine and adenosine differed significantly from the response to nicotine alone (+ 0.23 versus -0.05 nmol/L, p less than 0.02). We concluded that, in human beings, the characteristic hemodynamic response to adenosine infusion is enhanced by nicotine.