Polymorphisms in the glucocorticoid receptor gene and in the glucocorticoid-induced transcript 1 gene are associated with disease activity and response to glucocorticoid bridging therapy in rheumatoid arthritis.

Glucocorticoids (GC) are widely used in rheumatoid arthritis (RA). Ongoing active disease due to GC resistance may unfavorably influence long-term disease outcome in RA. We studied the association between the presence of glucocorticoid receptor (GR) and glucocorticoid-induced transcript 1 (GLCCI1) gene polymorphisms, which modulate GC sensitivity, and baseline disease activity score (DAS) and efficacy of GC bridging therapy in RA. We prospectively studied in vivo GC sensitivity in 138 patients with recent-onset or longstanding RA. In vivo GC sensitivity was expressed as the relative decrease in DAS following 2 weeks of standardized GC therapy. All patients were genotyped for the GR polymorphisms BclI (rs41423247), N363S (rs6195), 9ß (rs6198), ER22/23EK (rs6189 + rs6190), and the GLCCI1 variant rs37972 and subsequently divided in groups carrying a polymorphism associated with increased GC sensitivity (BclI-G allele, N363S-G allele, GLCCI1-C allele) or decreased GC sensitivity (9ß-G allele, ER22/23EK-A/A allele, GLCCI1-T allele). Differences in baseline DAS and relative decrease in DAS in the different genotype groups were analyzed using analysis of covariance and linear regression. Baseline DAS was higher in patients who carried polymorphisms of the GR and GLCCI1 genes associated with decreased GC sensitivity. GLCCI1 genotype, but not GR genotypes, was associated with improvement in DAS in male patients with RA. The GLCCI1 gene minor allele (rs37972) may be associated with less efficient GC bridging therapy in male RA patients. Carriers of the BclI-G, N363S-G, or GLCCI1-C alleles had lower levels of baseline disease activity, suggesting a role for the GLCCI1 and GR gene in regulation of GC sensitivity to endogenously produced cortisol.

Optimizing fracture prevention: the fracture liaison service, an observational study.

UNLABELLED: The response rate to the invitation to the fracture liaison service and reasons for non-response were evaluated in 2,207 fragility fracture patients. Fifty-one percent responded; non-responders were most often not interested (38 %) or were hip fracture patients. After 1 year of treatment, 88 % was still persistent and 2 % had a new fracture. INTRODUCTION: To increase the percentage of elderly fracture patients undergoing a dual energy x-ray absorptiometry (DXA) measurement, and to investigate why some patients did not respond to invitation to our fracture liaison service (FLS). METHODS: In four Dutch hospitals, fracture patients ≥ 50 years were invited through a written or personal invitation at the surgical outpatient department, for a DXA measurement and visit to our FLS. Patients who did not respond were contacted by telephone. In patients diagnosed with osteoporosis, treatment was started. Patients were contacted every 3 months during 1 year to assess drug persistence and the occurrence of subsequent fractures. RESULTS: Of the 2,207 patients who were invited, 50.6 % responded. Most frequent reasons for not responding included: not interested (38 %), already screened/under treatment for osteoporosis (15.7 %), physically unable to attend the clinic (11.5 %), and death (5.2 %). Hip fracture patients responded less frequently (29 %) while patients with a wrist (60 %) or ankle fracture (65.2 %) were more likely to visit the clinic. In 337 responding patients, osteoporosis was diagnosed and treatment was initiated. After 12 months of follow-up, 88 % of the patients were still persistent with anti-osteoporosis therapy and only 2 % suffered a subsequent clinical fracture. CONCLUSION: In elderly fracture patients, the use of a FLS leads to an increased response rate, a high persistence to drug treatment, and a low rate of subsequent clinical fractures. Additional programs for hip fracture patients are required, as these patients have a low response rate.

Skin pentosidine in very early hip/knee osteoarthritis (CHECK) is not a strong independent predictor of radiographic progression over 5 years follow-up.

OBJECTIVES: Age-related changes in articular cartilage are likely to play a role in the etiology of osteoarthritis (OA). One of the major age-related changes in cartilage is the accumulation of advanced glycation end products (AGEs). The present study evaluates whether pentosidine can predict radiographic progression and/or burden over 5 years follow-up in a cohort of early knee and/or hip OA. DESIGN: The 5 years follow-up data of 300 patients from cohort hip & cohort knee (CHECK) were used. Radiographic progression and burden were assessed by X-rays of both knees and hips (Kellgren and Lawrence (K&L) and Altman scores). Baseline pentosidine levels (and urinary CTXII as a comparator) were measured by high-performance-liquid-chromatography (HPLC) and enzyme linked immunosorbent assay (ELISA). Univariable and multivariable associations including baseline radiographic damage, age, gender, body mass index (BMI) and kidney function were performed. RESULTS: Both pentosidine and urinary C-terminal telopeptide of type II collagen (uCTXII) correlated with radiographic progression and burden. In general pentosidine did not have an added predictive value to uCTXII for progression nor burden of the disease. The best prediction was obtained for burden of radiographic damage (R(2) = 0.60-0.88), bus this was predominantly determined by baseline radiographic damage (without this parameter R(2) = 0.07-0.17). Interestingly, pentosidine significantly added to prediction of osteophyte formation, whereas uCTXII significantly added to prediction of JSN in multivariable analysis. CONCLUSION: Pentosidine adds to prediction of radiographic progression and burden of osteophyte formation and uCTXII to radiographic progression and burden of JSN, but overall skin pentosidine did not perform better that uCTXII in predicting radiographic progression or burden. Burden of damage over 5 years is mainly determined by radiographic joint damage at baseline.

Brief Report: to squeeze or not to squeeze, that is the question! Optimizing the disease activity score in 28 joints by adding the squeeze test of metatarsophalangeal joints in early rheumatoid arthritis.

OBJECTIVE: To optimize use of the Disease Activity Score in 28 joints (DAS28) in early rheumatoid arthritis (RA) by adding the "squeeze test" of forefeet. METHODS: The squeeze test is used to examine bilateral compression pain (BCP) across the metatarsophalangeal (MTP) joints. For this study, data for patients participating in the Treatment in the Rotterdam Early Arthritis Cohort study, an ongoing clinical trial that evaluates different induction therapies in patients with early RA, were randomly divided into 2 subsets. In subset 1 (149 patients and 819 disease activity assessments), the mathematical function of the DAS28-squeeze was constructed using a linear regression model with the DAS as the dependent variable and the DAS28 and squeeze test as the independent variables. A DAS28-BCP disease state was also constructed, in which DAS28 disease state categorizations were upgraded one state if the result of the squeeze test was positive. In subset 2 (153 patients and 754 assessments), concordance in disease states between the DAS28, DAS28-squeeze, and DAS28-BCP disease states was compared, using both the DAS and Boolean-defined remission criteria as reference. RESULTS: Agreement between the DAS and the DAS28-squeeze (82%) was significantly higher than agreement between the DAS and the DAS28 (76%). When we assessed the group of patients who had arthritis of the forefeet only (22 patients and 46 assessments), overall agreement between the DAS and the DAS28 was 40%, while agreement between the DAS and the DAS28-squeeze was 59% and that between the DAS and the DAS28-BCP disease state was 65%. Furthermore, the specificities of the DAS28-squeeze and the DAS28-BCP (80% and 81%, respectively) were higher than that of the DAS28 (76%), while the sensitivities of the DAS28, DAS28-squeeze, and DAS28-BCP to identify true remission according to the Boolean criteria were 88%, 87%, and 81%, respectively. CONCLUSION: Adding the squeeze test of forefeet to the DAS28 has value for dependably classifying the disease state in patients with early RA.

Serum adipokines in osteoarthritis; comparison with controls and relationship with local parameters of synovial inflammation and cartilage damage.

OBJECTIVE: Adipose tissue is an endocrine tissue releasing adipokines suggested to be involved in the pathogenesis of osteoarthritis (OA). Nevertheless, their relative contribution and exact mechanisms are still ambiguous. The aim of this study is to compare serum adipokine levels between end-stage knee OA patients and controls and to relate these serum levels to local parameters of cartilage damage and synovial inflammation. METHODS: Serum was collected from 172 severe knee OA patients, shortly before total knee replacement (TKR) surgery and from 132 controls without radiographic knee OA [Kellgren & Lawrence (K&L) = 0]. Serum adiponectin, leptin, and resistin levels were measured by enzyme-linked immunosorbent assay (ELISA). Cartilage and synovial tissue were collected at TKR surgery and assessed for cartilage degeneration and synovial inflammation by histochemistry and biochemical analyses. RESULTS: The adipokine levels were all distinctly higher in OA patients as compared to controls. Especially adiponectin and leptin were associated with female gender (stand beta = 0.239 and 0.467, respectively, P < 0.001) and body mass index (BMI) (stand beta = -0.189 and 0.396, respectively, P < 0.001). No associations between serum levels of adipokines and cartilage damage (histochemistry, proteoglycan content) were found whereas weak but positive associations with synovial inflammation were found [adiponectin and interleukin-1ß (IL-1ß), stand beta = 0.172, P = 0.02; resistin and histology, stand beta = 0.183, P = 0.034, adjusted for demographics]. CONCLUSION: This study suggests an important involvement of adipokines in OA patients considering their high serum levels compared to controls. Associations of systemic adipokines with local synovial tissue inflammation were found, although not represented by similar relations with cartilage damage, suggesting that adipokines are of relevance in the inflammatory component of OA.

In end stage osteoarthritis, cartilage tissue pentosidine levels are inversely related to parameters of cartilage damage.

OBJECTIVES: Age is the most prominent predisposition for development of osteoarthritis (OA). Age-related changes of articular cartilage are likely to play a role. Advanced glycation endproducts (AGEs) accumulate in cartilage matrix with increasing age and adversely affect the biomechanical properties of the cartilage matrix and influence chondrocyte activity. In clinical studies AGEing of cartilage and its relation to actual cartilage damage can only be measured by surrogate markers (e.g., serum, skin or urine AGE levels and imaging or biochemical markers of cartilage damage). In this study actual cartilage AGE levels were directly related to actual cartilage damage by use of cartilage obtained at joint replacement surgery. METHODS: Cartilage and urine samples were obtained from 69 patients undergoing total knee replacement. Samples were analyzed for pentosidine as marker of AGE. Cartilage damage was evaluated macroscopically, histologically, and biochemically. RESULTS: Cartilage and urine pentosidine both increased with increasing age. The higher the macroscopic, histological, and biochemical cartilage damage the lower the cartilage pentosidine levels were. In multiple regression analysis age is not found to be a confounder. CONCLUSION: There is an inverse relation between cartilage AGEs and actual cartilage damage in end-stage OA. This is likely due to ongoing (ineffective) increased turnover of cartilage matrix proteins even in end stage disease.

Efficacy of serology driven "test and treat strategy" for eradication of H. pylori in patients with rheumatic disease in the Netherlands.

The treatment of choice of H. pylori infections is a 7-day triple-therapy with a proton pump inhibitor (PPI) plus amoxicillin and either clarithromycin or metronidazole, depending on local antibiotic resistance rates. The data on efficacy of eradication therapy in a group of rheumatology patients on long-term NSAID therapy are reported here. This study was part of a nationwide, multicenter RCT that took place in 2000-2002 in the Netherlands. Patients who tested positive for H. pylori IgG antibodies were included and randomly assigned to either eradication PPI-triple therapy or placebo. After completion, follow-up at 3 months was done by endoscopy and biopsies were sent for culture and histology. In the eradication group 13% (20/152, 95% CI 9-20%) and in the placebo group 79% (123/155, 95% CI 72-85%) of the patients were H. pylori positive by histology or culture. H. pylori was successfully eradicated in 91% of the patients who were fully compliant to therapy, compared to 50% of those who were not (difference of 41%; 95% CI 18-63%). Resistance percentages found in isolates of the placebo group were: 4% to clarithromycin, 19% to metronidazole, 1% to amoxicillin and 2% to tetracycline.

Skin and urine pentosidine weakly correlate with joint damage in a cohort of patients with early signs of osteoarthritis (CHECK).

OBJECTIVES: Age-related changes in articular cartilage are likely to play a role in the aetiology of osteoarthritis (OA). One of the major age-related changes in cartilage is the accumulation of advanced-glycation-endproducts (AGEs). Since, cartilage tissue is not readily available from patients for studying AGE levels, alternative approaches such as analyzing skin and urine are needed to study the role of cartilage AGE levels in OA. METHODS: Paired human skin and cartilage samples were obtained post mortem. Paired skin and urine samples were obtained from the CHECK cohort (early OA patients). Pentosidine levels were measured by high-performance liquid chromatography (HPLC). As marker of cumulative cartilage damage X-rays of both knees and hips were scored. Urinary CTXII (uCTXII) levels were measured, to assess current cartilage breakdown. RESULTS: Cartilage and skin pentosidine correlate well (R=0.473, P=0.05). Skin pentosidine was higher in mild (summed (Kellgren & Lawrence K&L) over four large joints ≥4) compared to no (summed K&L≤3) radiographic OA (P=0.007). Urinary pentosidine was not different between these two groups. Skin pentosidine levels were not related to cartilage breakdown (highest vs lowest tertile of uCTXII). Urinary pentosidine, however, was higher in the highest compared to the lowest uCTXII tertile (P=0.009). Multiple regression analysis showed age to be the only predictor of the summed K&L score and age, creatinine clearance and urinary pentosidine as predictors of uCTXII. CONCLUSION: The higher skin and urinary pentosidine levels in those with mild compared to no radiographic joint damage and low vs high cartilage breakdown respectively suggest that AGEs may contribute to disease susceptibility and/or progression. However, relations are weak and cannot be used as surrogate markers of severity of OA.

The chondroprotective effect of selective COX-2 inhibition in osteoarthritis: ex vivo evaluation of human cartilage tissue after in vivo treatment.

OBJECTIVE: Recent in vitro studies showed that celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, protects human osteoarthritic cartilage tissue from degeneration. The objective was to substantiate these beneficial effects in an in vivo (clinical) study with celecoxib treatment of patients with severe knee osteoarthritis (OA) and subsequent evaluation of cartilage tissue ex vivo. METHODS: Patients with knee OA were treated 4 weeks prior to total knee replacement surgery with either celecoxib 200mg b.d., indomethacin 50mg b.d., or received no treatment. During surgery cartilage and synovium were collected and analyzed in detail ex vivo. RESULTS: When compared to non-treated patients, patients treated with celecoxib showed significant beneficial effects on proteoglycan synthesis, -release, and -content, confirming the in vitro data. In the indomethacin group, no significant differences were found compared to the control group. On the contrary, a tendency towards a lower content and lower synthesis rate was found. In the treated groups prostaglandin-E(2) levels were lower than in the control group, indicating COX-2 inhibition. Ex vivo release of interleukin-1 beta (IL-1 beta) and tumour necrosis factor-alpha by synovial tissue was decreased by treatment with celecoxib, whereas in the indomethacin group only IL-1 beta release was decreased. CONCLUSION: Using this novel approach we were able to demonstrate an in vivo generated chondrobeneficial effect of celecoxib in patients with end stage knee OA.

[Alendronate more effective than alfacalcidol in the prevention of osteoporosis in patients with rheumatic disease who are starting glucocorticoid therapy]. / Alendroninezuur effectiever dan alfacalcidol voor preventie van osteoporose bij patiënten met een reumatische ziekte die starten met glucocorticoïdtherapie.

OBJECTIVE: To compare the effects of alendronate and alfacalcidol in the prevention ofglucocorticoid-related osteoporosis in patients with a rheumatic disease. DESIGN: Randomised, double-blind, double-placebo clinical trial (www. clinicaltrials.gov; number: NCT00138983). METHODS: A total of 201 patients with rheumatic disease who were starting glucocorticoid treatment at a daily dose that was equivalent to at least 7.5 mg of prednisone were randomised to alendronate (10 mg) and a placebo capsule ofalfacalcidol daily (n = 100) or alfacalcidol (1 microg) and a placebo tablet ofalendronate daily (n = 101) for 18 months. Primary outcome was change in lumbar spine bone mineral density at 18 months. The main secondary outcome was the incidence of morphometrically confirmed vertebral deformities. RESULTS: Overall, 163 patients completed the study. The bone mineral density of the lumbar spine increased by 2.1% (95% CI: 1.1-3.1) in the alendronate group and decreased by 1.9% (95% CI: -3.I--0.7) in the alfacalcidol group. At 18 months the mean difference in change in bone mineral density between the two groups was 4.0% (95% CI: 2.4-5-5). Three patients in the alendronate group had a new vertebral deformity, compared with 8 patients in the alfacalcidol group, including 5 symptomatic vertebral fractures in 3 patients; the hazard ratio was 0.4 (95% CI: 0.1-1.4). CONCLUSION: Alendronate was more effective than alfacalcidol in preventing glucocorticoid-induced bone loss during this 18-month trial in patients with rheumatic diseases who were starting glucocorticoid treatment.

[New developments in glucocorticoid therapy: selective glucocorticoid receptor agonists, nitrosteroids and liposomal glucocorticoids]. / Nieuwe ontwikkelingen in glucocorticoïdtherapie: selectieve glucocorticoïdreceptoragonisten, nitrosteroïden en liposomale glucocorticoïden.

Two mechanisms of the genomic action ofglucocorticoids (GCs) can be distinguished: transrepression, yielding mainly an anti-inflammatory effect, and transactivation, resulting mainly in metabolic-endocrine side effects. Selective glucocorticoid receptor agonists (SEGRAs) cause selective transrepression, yielding the same anti-inflammatory effect as GCs, but with fewer side effects. NO is bound to several drugs to increase their effect; in nitrosteroids, NO is coupled to GC, resulting in a synergistic anti-inflammatory effect. Drug targeting can be achieved with GCs by incorporation of GC into polyethyleneglycol(PEG)-liposomes, resulting in very high concentrations ofGCs at the site of inflammation. Well-designed studies are needed to determine the place of SEGRAs, nitrosteroids and liposomal GCs in clinical practice.

[Arthritis as a consequence of diabetes mellitus or haemochromatosis]. / Artritis ten gevolge van diabetes mellitus of hemochromatose.

Four patients with arthritis appeared to have this as a consequence of an internal disorder: a 60-year-old woman and a 20-year-old man with diabetes mellitus and arthritis of an ankle had Charcot arthropathy, whilst a 53-year-old woman and a 60-year-old man with polyarthritis had previously undiagnosed haemochromatosis. Patients were then adequately treated. Charcot arthropathy and haemochromatosis are not uncommon. Early diagnosis is important with respect to preventive and therapeutic measures. In patients with Charcot arthropathy immobilisation allows healing of the fractures. Bisphosphonates may be given in order to decrease bone resorption. In patients with haemochromatosis therapeutic bleeding may limit further damage to the joints and to the internal organs.

Retrograde double labeling of neurons: the combined use of horseradish peroxidase and diamidino yellow dihydrochloride (DY X 2HCl) compared with true blue and DY X 2HCl in rat descending brainstem pathways.

Three series of double-labeling experiments were carried out in a study of the collateralization of brainstem nuclei which project to the spinal cord in the rat. The fluorescent tracer Diamidino Yellow Dihydrochloride (DY X 2HCl) was injected in one half of the spinal gray and white matter at T7-T8 or T13-L1. Subsequently, either True Blue (TB), wheat germ agglutinin-conjugated horseradish peroxidase (WGA-HRP) or free HRP were injected ipsilaterally in the gray matter at C5-C8. The distributions of single and double retrogradely labeled neurons were studied in the following cell groups: red nucleus, interstitial nucleus of Cajal, ventrolateral pontine tegmentum, nuclei coeruleus and subcoeruleus and nuclei raphe magnus and raphe pallidus including the adjoining ventral reticular formation. The numbers of TB- or HRP-labeled neurons present in those nuclei were counted and the percentages of double-labeled neurons were calculated when TB or HRP had been used in combination with DY X 2HCl. The results indicate: The HRP-TMB reaction product and the DY X 2HCl fluorescence can be visualized simultaneously in retrogradely single- or double-labeled neurons. The distributions of single- and double-labeled neurons in the various brainstem nuclei were entirely comparable when using TB with DY X 2HCl or HRP with DY X 2HCl. The percentages of double-labeled neurons obtained with HRP and DY X 2HCl were consistent over a series of cases, and were comparable to those obtained with TB and DY X 2HCl in several structures. However, in the red nucleus slightly lower percentages of double-labeled neurons were obtained using HRP and DY X 2HCl as compared with the percentages obtained using TB and DY X 2HCl.

Retrograde neuronal labeling of cells of origin of descending brainstem pathways in rat using SITS as a retrograde tracer.

Recently, the retrograde tracer SITS has been introduced, a cytoplasmic label, which seems to be taken up by terminals only. In order to test the transport of SITS from terminals of brainstem pathways to he spinal cord SITS was injected in different rats at different spinal levels. It could be concluded that SITS is taken up primarily from axon terminals.

Quantitative differences in collateralization of the descending spinal pathways from red nucleus and other brain stem cell groups in rat as demonstrated with the multiple fluorescent retrograde tracer technique.

In 8 rats 'True Blue' was injected into dorsal half of C5-C8 spinal grey, 5 days later 'Nuclear Yellow' was injected in midthoracic, upper lumbar, lumbosacral and sacral cord respectively. The animals were sacrificed about 43 hours after NY injections. The distribution of retrogradely labeled neurons was studied in Red Nucleus, in Ventrolateral Pontine Tegmentum and in Nucleus Raphe Magnus, all of which project to spinal dorsal grey. In Red Nucleus large populations of single TB-labeled neurons and single NY-labeled ones occurred in the dorsomedial and ventrolateral part, respectively. In addition, about 8% of the neurons labeled with TB from C5-C8 were double labeled with NY from L5-S1, and 35% from T7-8, which percentages resemble those of electrophysiological studies. However, in ipsilateral Nucleus Raphe Magnus about 40% of the TB-labeled neurons were double labeled from L5-S1. This percentage resembles the 66% obtained in electrophysiological studies of reticulospinal collaterals. These findings in rat support electrophysiological findings in cat and show, that rubrospinal neurons distribute their fibers primarily to the grey matter of specific groups of spinal segments, while many of the raphe spinal neurons distribute fibers throughout the spinal cord.

Collateralization of brainstem pathways in the spinal ventral horn in rat as demonstrated with the retrograde fluorescent double-labeling technique.

The collateralization of brainstem pathways to the spinal ventral horn was studied in rat by means of injections of True Blue (TB) and Diamidino Yellow Dihydrochloride (DY .2HCl) at different levels in the spinal cord. TB (or DY .2HCl) was injected in the cervical gray and DY .2HCl (or TB) was injected ipsilaterally either at mid-thoracic or at lumbar levels. The retrogradely single- and double-labeled neurons were studied in the interstitial nucleus of Cajal, the lateral vestibular nucleus of Deiters, the nucleus (sub) coeruleus and the nucleus raphe pallidus, including the adjoining ventral medullary reticular formation. In all those brainstem nuclei many double-labeled neurons were present after both mid-thoracic and lumbar injections. This indicates that these brainstem spinal pathways to the ventral horn probably give off many collaterals along their trajectory in the spinal cord.

Collaterals of rubrospinal neurons to the cerebellum in rat. A retrograde fluorescent double labeling study.

In a previous study the collateralization of the rubrospinal tract in the spinal cord of rat, cat and monkey was studied by means of the fluorescent retrograde double labeling technique. In the present study the existence of rubrospinal collaterals to the cerebellar interpositus nucleus (NI) has been studied using the same technique. In rat 'True Blue' (TB) was injected in the cerebellar NI and 'Nuclear Yellow' (NY) was injected ipsilaterally in white and gray matter of C5-C8 spinal segments. In some cases a new fluorescent retrograde tracer was used instead of NY, i.e. 'Diamidino Yellow' (DY), which produces retrograde labeling similar to NY but which migrates only very slowly out of the retrogradely labeled neurons. In these experiments only very few single TB-labeled rubrocerebellar neurons occurred, but many (+/- 90%) of the TB-fluorescent rubrocerebellar neurons were TB-NY or TB-DY double-labeled from the spinal cord. At least 37% of the NY and DY-fluorescent rubrospinal neurons were NY-TB and DY-TB double-labeled from the cerebellum. These findings indicate that, in rat, almost all rubrocerebellar fibers represent collaterals of rubrospinal neurons, and that at least 37% of the rubrospinal neurons give rise to such cerebellar collaterals.

Down regulation of glucocorticoid receptors in early-diagnosed rheumatoid arthritis.

OBJECTIVE: In patients with rheumatoid arthritis (RA) of longer duration, glucocorticoid receptor (GR) down-regulation has been reported without any change in cortisol levels. This phenomenon might play a role in the aetio-pathogenesis of RA. Therefore we studied GR expression, as well as the serum cortisol levels, in patients with recently diagnosed RA. METHODS: In 81 early diagnosed RA patients with disease duration < 1 year (52F/29M; mean (SD) age 63 (13) years) and in 39 age and sex matched controls (23F/16M; mean age 63 (15) years) blood samples were taken between 8-10 h AM. GR expression (GR-number and GR-affinity), serum cortisol levels, ESR, CRP, painful and swollen joints were measured. RESULTS: A significantly lower GR-number was found in the female patients compared with female controls: 7.0 versus 9.8fmol/million cells, respectively (difference: 2.8, 95% CI 1.1 - 4.6). Interestingly, also serum cortisol levels were significantly lower in the female patients compared with the female controls: 0.21 versus 0.41 micromol/l, respectively (difference: 0.20, 95% CI 0.12 - 0.28). However, between the male patients and male controls no difference was found in GR expression nor in serum cortisol levels. Neither in female nor in male patients were correlations found between GR expression and parameters of disease activity nor was there a relation between GR expression and serum cortisol levels. CONCLUSIONS: Changes in GR expression as well as serum cortisol were not a general phenomenon in early diagnosed RA patients, being present only in females and not related to disease activity. Therefore it seems unlikely that GR expression per se is causally involved in the pathogenesis of RA. We cannot preclude that it may be involved in the incidence, severity and course of RA, as this may be differentially regulated in males and females.

Glucocorticoid receptor up-regulation in early rheumatoid arthritis treated with low dose prednisone or placebo.

OBJECTIVE: Low or medium dose prednisone in early rheumatoid arthritis (RA), albeit with significant variation in clinical efficacy, reduces the progression of joint damage. The glucocorticoid receptor (GR) number in peripheral mononuclear cells (PBMC) might be helpful to predict which patients will respond to low or medium dose prednisone and therefore do not or will not need higher doses. With this in mind we determined in a double blind, placebo controlled study at baseline and yearly the GR number in PBMC. METHODS: Eighty-one early RA patients (disease duration less than one year) were included. All patients fulfilled the ACR criteria and were disease modifying antirheumatic drugs (DMARD) and glucocorticoid-naive. They were randomly assigned to treatment with 10 mg prednisone daily or placebo. From all patients disease activity (CRP, number of tender and swollen joints), the radiological joint score, bone mineral density, and the GR number in PBMC were measured annually. RESULTS: In females the GR number was up-regulated over time in both the prednisone and the placebo group. The same trend was observed in males. No correlations were found between the GR number in the prednisone users at the start of their treatment and changes in radiological scores or bone density after 2 years of treatment. No correlations were found between the GR number at the start and the clinical characteristics after a follow-up of 2 years. CONCLUSION: The GR number in the PBMC of early RA patients did not predict which patients would be prednisone responders based on clinical or radiological parameters. However, the up-regulation of the GR number in PBMC in early RA patients towards the GR number of healthy subjects during the first two years of their disease course seems to reflect a recovery or compensatory mechanism as a response to an ongoing inflammatory process. This recovery may be not enough to efficiently control the inflammatory situation.

Disturbed liver function in heart transplantation candidates: two case reports.

Heart transplantation candidates frequently have a disturbed liver function. Two cases with jaundice are described in whom the cause and prognosis of the associated liver disease were analysed. In the 4-yr period during which heart transplantation patients with a disturbed liver function were investigated, "cirrose cardiaque" was not encountered; liver tests usually normalized after a successful heart transplant.