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.

[Pieter van Foreest: physician on the threshold of a new era]. / Pieter van Foreest: medicus op de drempel van een nieuwe tijd.

In a variety of ways attention is being drawn nowadays to the fact that Pieter van Foreest (1521-1597) died four hundred years ago. The question arises, however, whether such a comprehensive commemoration is justified by Van Foreest's contribution to the development of medical science. Medical history certainly does not attribute concrete substantial new findings to his name. Nevertheless, he earned the longstanding epithet 'Dutch Hippocrates' by his writings. Especially, his Observationes et curationes medicinales c.q. chirurgicales remained on vogue for some centuries after his death, mainly due to the accurate description of symptomatology of a wide variety of diseases. Van Foreest should be considered as a conspicuous representative of the new empirical medicine which gained favour after the humanistic rediscovery of the classical Greek authors, especially Hippocrates.

Interleukin-1 reversibly inhibits the synthesis of biglycan and decorin in intact articular cartilage in culture.

OBJECTIVE: To study the effect of interleukin-1 (IL-1) on the synthesis of proteoglycans biglycan (DSPG-I) and decorin (DSPG-II) in intact bovine articular cartilage. METHODS: Cartilage bearing sesamoid bones from the metacarpophalangeal joint were cultured with 10 ng/ml IL-1 for 2 days and labelled with [35S] sulfate. One sesamoid bone from each animal had been labelled ex vivo. The remaining 2 were cultured with IL-1 and allowed to recover in control medium before labelling. Control cultures were maintained in medium without IL-1 and labelled concurrently with the experimental series. The dermatan sulfate proteoglycans were purified from 4 M guanidinium chloride extracts of the cartilage by gel filtration on Sepharose CL-2B and CL-4B, on which they appeared as a single peak. Biglycan and decorin were separated by sodium dodecyl sulfide polyacrylamide gel electrophoresis in high salt. Individual lanes from the gel were cut in slices, which were dissolved and counted for radioactivity. RESULTS: Ex vivo, biglycan accounted for 4% and decorin for 2% of total incorporated sulfate. IL-1 reduced the synthesis of biglycan to 77% of the level of cultured controls and that of decorin to 73%. The synthesis of both proteoglycans returned to the control levels when the IL-1 was removed. IL-1 (10 ng/ml, 2 days) had no significant effect on total proteoglycan synthesis. CONCLUSION: The inhibition of synthesis of biglycan and decorin by IL-1 might be important in the pathophysiology of cartilage destruction in rheumatic diseases.

Quality of life assessment: a comparison of four questionnaires: for measuring improvements after total hip replacement.

Three experimental questionnaires were compared with the Influence of Rheumatic Diseases on Health and Lifestyle (IRGL) questionnaire, a Dutch version of the Arthritis Impact Measurement Scales. Sixty-two patients with osteoarthritis (OA) and 35 patients with rheumatoid arthritis (RA), all of whom underwent hip arthroplasty, completed the study. Results showed that visual analogue scales for pain, stiffness, fatigue, and anxiety were strongly correlated with a number of the IRGL scales. Patient preference scales were sensitive to change and provided additional information on aspects of the patients' quality of life (QOL) that were felt to be important by the patients themselves. The questionnaire on performance in various roles in life was insensitive to change. In existing questionnaires, there is an attempt to represent the concept of QOL in terms of its most important aspects. Such realizations of the concept of QOL are not entirely suitable for application in clinical trials. The IRGL is overly complex, and its sometimes comprehensive scales do not deal with the possible effects of treatment. Neither of these properties is conducive to sensitivity to change. Visual analogue scales reduce the complexity. A simpler representation of QOL that can evaluate aspects relevant to treatment is recommended.

Transforming growth factor-beta stimulates retinoic acid-induced proteoglycan depletion in intact articular cartilage.

Cartilage-bearing sesamoid bones from the metacarpophalangeal joints of adult cows were cultured with retinoic acid for 1 week and allowed to recover in control medium for another 2 weeks. Retinoic acid decreased the proteoglycan synthesis of the cartilage to 33% of control values, and induced 26% loss of proteoglycans from the matrix. During recovery, the synthesis of proteoglycans returned to the control level but their content remained reduced. Transforming growth factor-beta (TGF-beta 1, 5 ng/ml) was added to the culture medium to stimulate the recovery. However, TGF-beta depressed the synthesis of proteoglycans and increased their loss to 61%. Only the large aggregating species, aggrecan, was lost from the matrix. The half-life of proteoglycans synthesized during recovery in control medium was 12.7 days, which was reduced to 8.7 days by TGF-beta. The proteoglycan half-life in control cartilage cultured without retinoic acid or TGF-beta was 33.8 days. Neither retinoic acid nor TGF-beta-induced changes in the hyaluronate content of the tissue. Aggrecans and small proteoglycans synthesized in the presence of TGF-beta were larger than those in controls. The synthesis of the small proteoglycans was stimulated 4.5-fold by TGF-beta, and their content was increased. The results show that TGF-beta can stimulate depletion of aggrecan in retinoic acid-treated cartilage. This indicates a catabolic function of TGF-beta in cartilage remodeling.

Effects of total hip replacement on quality of life in patients with osteoarthritis and in patients with rheumatoid arthritis.

The effects of total hip replacement (THR) on quality of life were investigated in 62 patients with osteoarthrosis (OA) and 35 patients with rheumatoid arthritis (RA). Patients eligible for a first hip joint replacement were enrolled consecutively and examined at home before the operation and 3, 6, and 12 months after surgery. The IRGL (Influence of Rheumatic Diseases on Health and Lifestyle), a Dutch version of the AIMS (Arthritis Impact Measurement Scales), was used to operationalize quality of life in a questionnaire. Pain and mobility scores showed significant improvement among both OA and RA patients. The general mood of the OA patients also improved significantly, but the RA group showed only a favourable tendency in this respect. The interference of OA in several areas of life almost disappeared, whereas the impact of RA was only slightly reduced. There was no discernible effect on the social dimension in either group. A single THR apparently solves the main problem of most OA patients, but only one of a number of joint problems for most RA patients. The IRGL is complex and time-consuming and contains irrelevant scales. Its multidimensional evaluation of the quality of life is more informative than a purely somatic evaluation.

Extra-articular manifestations of rheumatoid arthritis: risk factors for serious gastrointestinal events.

OBJECTIVES: Serious upper gastrointestinal events are an important threat to patients with arthritis who are treated with non-steroidal anti-inflammatory drugs (NSAIDs). In this study risk factors for serious upper gastrointestinal events are identified in patients with possible or definite rheumatoid arthritis (RA). METHODS: A retrospective analysis of factors that might contribute to the risk of serious upper gastrointestinal events was performed in a cohort of 2315 consecutive patients with possible or definite RA. The relative influences of disease severity, drug treatment, particularly with corticosteroids, and history of peptic ulceration were analysed with a conditional logistic regression model for the 106 patients with serious upper gastrointestinal intestinal events and for an equal number of control patients who were matched for age, gender, number of criteria for RA, and disease duration. RESULTS: The incidence rate for serious upper gastrointestinal events was 4.0/1000 patients in each year. The study reconfirmed that age over 60 years, history of peptic ulceration, and use of corticosteroids are risk factors. The presence of extra-articular manifestations of RA was associated with a two to 11-fold increase in the risk for serious upper gastrointestinal events. This risk was independent of the use of corticosteroids. CONCLUSION: Disease severity, in particular the presence of extra-articular features, may be an important factor in the pathogenesis of upper gastrointestinal ulceration in patients with RA who are treated with NSAIDs.

Components of health: an analysis in rheumatoid arthritis using quality of life questionnaires and clinical and laboratory variables.

OBJECTIVE: To gain insight into the overlap between additional information supplied by recently developed health status instruments for rheumatoid arthritis (RA) and traditional clinical and laboratory tests. METHODS: A cross sectional study of 282 outpatients with RA was made. From each patient, variables of clinical and laboratory measurements were obtained and the modified health assessment questionnaire (MHAQ) and a Dutch quality of life questionnaire, the IRGL, were completed. These variables were analysed for their interrelationship. RESULTS: Clinical and laboratory variables correlated significantly with the scales of the physical dimension and the disease impact scale of the IRGL. Their significant correlations with the IRGL psychological scales were weak. There were no significant correlations between any of the traditional variables and the IRGL social scales. Factor analysis yielded five factors: functionality, pain, depressive mood, social support, and laboratory. The laboratory factor is a measure of the disease process. The other four factors provide a health model. CONCLUSION: The results suggest that the IRGL questionnaire that was studied covers a complete health model that incorporates aspects of health that are not measured by clinical and laboratory tests. A simple questionnaire for the psychological and social dimension of health status, however, would probably be more cost effective and easier to use in clinical practice.

Proteoglycan depletion of intact articular cartilage by retinoic acid is irreversible and involves loss of hyaluronate.

Intact sesamoid bones from bovine metacarpophalangeal joints were cultured with retinoic acid for 9 days and allowed to recover in control medium for up to 17 days. Retinoic acid (300 ng/ml) induced 91.8% inhibition of glycosaminoglycan (GAG) synthesis and 50.6% loss of sulfated GAGs from the cartilage. Retinoic acid also induced 38.2% loss of hyaluronate from the matrix. The synthesis and content of the large aggregating proteoglycan (aggrecan) were preferentially decreased compared with that of the small nonaggregating species. The aggrecan synthesized was similar to control aggrecan in size, aggregation capacity, and composition of its GAGs. GAG synthesis was almost completely restored in control medium within the next 6 days. The GAGs synthesized during recovery were slightly shorter than control GAGs and showed a higher ratio of chondroitin-6-sulfate over chondroitin-4-sulfate. Neither the proteoglycan content nor the hyaluronate content recovered within 17 days. The aggregation capacity of newly synthesized aggrecan was normal. However, the retention of proteoglycans synthesized in the recovery period was much lower in treated cartilage than in control cartilage (T1/2 of 17 and 38 days, respectively). In conclusion, the retinoic-acid-induced proteoglycan depletion was irreversible in spite of the restored synthesis of aggrecan with a normal aggregation capacity. The reduced retention of newly synthesized aggrecan during recovery might be caused by a lack of hyaluronate. This model seems suitable to study aspects of cartilage destruction and repair.

Kinetics of proteoglycan turnover in bovine articular cartilage explants.

The turnover of proteoglycans was studied in explant cultures of mature bovine articular cartilage. The aim of the study was to compare the in vitro turnover rates of newly synthesized proteoglycans and endogenous proteoglycans. Cartilage was maintained in the presence of various serum concentrations in order to determine the conditions of steady-state proteoglycan metabolism. The steady state was achieved in medium containing 20% fetal calf serum. The proteoglycan synthesis rate and the half-life of labeled proteoglycans in steady-state cultures were used to calculate the size of the metabolic pool of newly synthesized proteoglycans in steady state. This metabolic pool was shown to be equal to the total amount of proteoglycans in the matrix. It is concluded that all of the proteoglycans in the matrix have the same half-life in vitro. Taking another approach, aggrecan was isolated from the cartilage and the medium of steady-state cultures prelabeled with [35S]sulfate. The specific activity of the glycosaminoglycans from cartilage aggrecan were compared with that of glycosaminoglycans from medium aggrecan. These proved to be the same throughout the culture period. This shows that newly synthesized aggrecan and endogenous aggrecan have the same turnover rate in vitro. The significance of explant culture systems for the study of proteoglycan turnover is discussed.

['Anatomia actuosa et apta'. The mechanist 'proto'-physiology of B.S. Albinus]. / Anatomia actuosa et apta. De mechanicistische 'proto'-fysiologie van B.S. Albinus.

Already during his tenure as professor of anatomy and surgery (1721-1746) and before he became a professor of physiology and medicine at the University of Leiden, Bernard Siegfried Albinus held private lecture courses on physiology. In these lectures he pleaded for a separation of physiology from theoretical medicine, which was still its customary place in the medical curriculum of the first half of the eighteenth century. According to Albinus, physiology was a science in its own right and should be solely based on the careful observation of forms and structures of the human body. From the 'fabrica', the function ('aptitudo') could be derived by careful reasoning. As shown by a set of lecture notes, which recently came to light, Albinus adhered, initially, to a strictly mechanistic explanatory model, which was almost completely based on the physiological concepts of Herman Boerhaave. However, in contrast to the latter, he even rejected the involvement of chemical processes in digestion. Although his lectures were highly acclaimed as demonstrations of minute anatomy, Albinus met with little or no direct response in regard to his concept of physiology.

Effects of loading on the synthesis of proteoglycans in different layers of anatomically intact articular cartilage in vitro.

The anatomically intact articular cartilage (approximately equal to 2.5 cm2) of whole bovine sesamoid bones was cultured on its bone support. A load of 5 kg was applied intermittently at 0.3 Hz by a specially designed loading apparatus for 7 days. [35S]-sulfate was added during the last 17 h of the experiment. Loading induced a 40% increase in [35S]-sulfate incorporation into aggrecans and an almost 3-fold increase in the synthesis of small proteoglycans. The loading effects occurred mainly in the upper half of the articular cartilage. Samples left unloaded for 7 days and then loaded for 7 days likewise showed an increase in [35S]-sulfate incorporation compared with unloaded controls.

Food intolerance in rheumatoid arthritis. I. A double blind, controlled trial of the clinical effects of elimination of milk allergens and azo dyes.

The hypothetically negative influence of food on the clinical activity of seropositive rheumatoid arthritis was studied using two types of artificial elementary food. One diet was allergen free, the other allergen restricted, containing only lactoproteins and yellow dyes. Ninety four patients entered the study, which lasted 12 weeks. During the second four week period they were randomly assigned to one of the two artificial foods. Comparison between baseline and subsequent periods showed only subjective improvements. No differences were seen between the clinical effects of the two tested diets. Nine patients (three in the allergen restricted group, six in the allergen free group) showed favourable responses, followed by marked disease exacerbation during rechallenge. Dietary manipulation also brought about changes in objective disease activity parameters in these patients. The existence of a subgroup of patients in whom food intolerance influences the activity of rheumatoid factor seropositive rheumatoid arthritis deserves serious consideration.

Food intolerance in rheumatoid arthritis. II. Clinical and histological aspects.

Six patients with rheumatoid factor positive rheumatoid arthritis who had shown a marked symptomatic improvement during four weeks of hypoallergic, artificial diet were studied in greater detail. Placebo controlled rechallenges showed intolerance for specific foodstuffs in four patients. In three of these patients biopsies of both the synovial membrane and of the proximal small intestine were carried out before and during allergen free feeding. In two patients, both with raised serum IgE concentrations and specific IgE antibodies to certain foods, a marked reduction of mast cells in the synovial membrane and proximal small intestine was demonstrated. Although the number of food intolerant patients with RA remains limited and markers of allergic activity are scanty, our observations suggest an underlying immunoallergological mechanism.

Development and validation of a computer program using Bayes's theorem to support diagnosis of rheumatic disorders.

A computer program has been developed to support the differential diagnosis of major rheumatic disease categories. Knowledge for the program was derived from the sensitivity and specificity of findings in a group of 1052 consecutive patients of a rheumatological outpatient clinic. Computer predictions based on two variations of Bayes's theorem were compared with 'gold standard' diagnoses in 570 test cases from the same clinic. The results demonstrate the feasibility of this approach, but also that refinements of both the method of calculation and the knowledge are required.

Comparison of the sensitivity and specificity of the 1958 and 1987 criteria for rheumatoid arthritis.

The 2 variations of the new criteria for rheumatoid arthritis (RA) proposed by a subcommittee of the American College of Rheumatology (ACR) in 1987 were evaluated and compared with the earlier (1958) criteria in 2 patients data collections from a Dutch rheumatological outpatient clinic. One group comprised 1,570 newly referred, consecutive patients, including 93 patients with RA. The other consisted of 1,338 patients with a clinical diagnosis of RA, whose charts were reviewed retrospectively. The sensitivities of the 2 variations of the 1987 criteria in the prospective and retrospective subgroups varied from 66 to 89%; those of the 1958 set, from 71 to 86%. Specificity was 98% for both criteria sets. Comparison in subgroups with different disease durations showed reduction in sensitivity for early RA for either variation of the new criteria. However, the differences between the results of the 1958 and 1987 criteria sets are small enough to conclude that they perform equally well.

Computer-assisted diagnosis of rheumatic disorders.

A review of the literature regarding computer-assisted diagnosis of rheumatic diseases is presented. After a general outline of the history and goals of computer programs intended to support physicians in the diagnostic process, 14 systems or projects are described. The scope of seven of these is general internal medicine, and the other seven are intended exclusively for rheumatic problems. The majority of these systems are prototypes. To date, none of them is widely used by physicians. Preliminary evaluation studies and/or independent reviews have been reported for all of the systems. The need for further evaluation studies is recognized, and strategies to carry these out are outlined. Furthermore, the potential usefulness for patient care and education is discussed. It is concluded that a new and interesting field is being developed that deserves more attention among rheumatologists.

Assessment of inflammatory joint activity in rheumatoid arthritis and changes in atmospheric conditions.

Seventy-nine patients suffering from rheumatoid factor positive rheumatoid arthritis (RA) were included in this study. In each patient disease activity was assessed three times at two-week intervals during a four-week period. All factors that might possibly influence RA, except atmospheric conditions (AC) were held constant as far as possible. Current AC parameters were obtained from the local observatory of the Royal Dutch Meteorological Institute. There were no relevant correlations between AC and RA variables. Also relations between changes in AC variables preceding the disease activity assessment or between changes in AC variables and RA variables were not seen. By means of factor analysis, uncorrelated factors pertaining to RA or to weather were extracted. No clear association between any of the AC variables and any of the RA variables was noted. Our results do not support the widely accepted, but insufficiently documented, influence of weather on RA.

Comparison of rheumatological diagnoses by a Bayesian program and by physicians.

A Bayesian decision support system was developed for the diagnosis of rheumatic disorders. Knowledge in this system is represented as evidential weights of findings. Simple weights were calculated as the logarithm of likelihood ratios on the basis of 1,000 consecutive patients from a rheumatological clinic. The effect of various methods to improve performance of the system by modification of the weights was studied. Three methods had a mathematical basis; a fourth consisted of weights adapted by a human expert, which allowed inclusion of diagnostic rules such as defined in widely accepted criteria sets. The system's performance was measured in a test population of 570 different cases from the same clinic and compared with predictions of diagnostic outcome made by rheumatologists. The weights from a human expert gave optimal results (sensitivity 65% and specificity 96%), that were close to the physicians' predictions (sensitivity 64% and specificity 98%). The methods to measure the performance of the various models used in this study emphasize sensitivity, specificity and the use of receiver operating characteristics.