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author:("rhazes, J")
1.  Glucocorticoid sensitivity in Behçet's disease 
Endocrine Connections  2012;1(2):103-111.
Glucocorticoid (GC) sensitivity is highly variable among individuals and has been associated with susceptibility to develop (auto-)inflammatory disorders. The purpose of the study was to assess GC sensitivity in Behçet's disease (BD) by studying the distribution of four GC receptor (GR) gene polymorphisms and by measuring in vitro cellular GC sensitivity.
Healthy controls and patients with BD in three independent cohorts were genotyped for four functional GR gene polymorphisms. To gain insight into functional differences in in vitro GC sensitivity, 19 patients with BD were studied using two bioassays and a whole-cell dexamethasone-binding assay. Finally, mRNA expression levels of GR splice variants (GR-α and GR-β) were measured.
Healthy controls and BD patients in the three separate cohorts had similar distributions of the four GR polymorphisms. The Bcll and 9β minor alleles frequency differed significantly between Caucasians and Mideast and Turkish individuals.
At the functional level, a decreased in vitro cellular GC sensitivity was observed. GR number in peripheral blood mononuclear cells was higher in BD compared with controls. The ratio of GR-α/GR-β mRNA expression levels was significantly lower in BD.
Polymorphisms in the GR gene are not associated with susceptibility to BD. However, in vitro cellular GC sensitivity is decreased in BD, possibly mediated by a relative higher expression of the dominant negative GR-β splice variant. This decreased in vitro GC sensitivity might play an as yet unidentified role in the pathophysiology of BD.
PMCID: PMC3681319  PMID: 23781311
Behçet's syndrome; single nucleotide polymorphism; glucocorticoid sensitivity
2.  The H63D variant in the HFE gene predisposes to arthralgia, chondrocalcinosis and osteoarthritis 
Annals of the Rheumatic Diseases  2007;66(11):1436-1442.
To investigate the relation between the HFE C282Y and H63D variants with arthralgia and joint pathology in the population‐based Rotterdam Study.
From a cohort of 7983 people aged 55 years and over, 2095 randomly drawn subjects were genotyped for C282Y and H63D variants. We compared the frequency of arthralgia, and the presence of chondrocalcinosis, osteophytes, joint space narrowing and radiographic osteoarthritis in hand, hip and knee joints, and Heberden's nodes in carriers of HFE variants with that in non‐carriers.
Overall, there was a significantly higher frequency of arthralgia (odds ratio 1.6; 95% CI 1.0 to 2.6), oligoarthralgia (2.3; 1.2 to 4.4) and Heberden's nodes (2.0; 1.1 to 3.8) in H63D homozygotes compared with non‐carriers. In subjects aged 65 years or younger, H63D homozygotes had significantly more often polyarthralgia (3.1; 1.3 to 7.4), chondrocalcinosis in hip or knee joints (4.7; 1.2 to 18.5), and more hand joints with osteophytes (6.1±1.0 vs 4.4±0.3), space narrowing (2.8±0.5 vs 1.0±0.1), radiographic osteoarthritis (4.4±0.7 vs 2.0±0.2) and Heberden's nodes (3.1; 1.3 to 12.8) than non‐carriers. We found no relation of arthralgia or joint pathology to C282Y, but compound heterozygotes had a significantly higher frequency of arthralgia (2.9; 1.0 to 9.3), chondrocalcinosis in hip joints (6.5; 1.8 to 22.3), and an increased number of osteophytes in knee (6.9±1.2, n = 5 vs 2.4±0.1) joints at a later age (>65 years).
The HFE H63D variant may explain, at least in part, the prevalence of arthralgia in multiple joints sites, chondrocalcinosis, and hand osteoarthritis in the general population.
PMCID: PMC2111641  PMID: 17284543
3.  Do metabolic factors add to the effect of overweight on hand osteoarthritis? The Rotterdam Study 
Annals of the Rheumatic Diseases  2007;66(7):916-920.
As hand joints are non‐weight bearing, the association between overweight and hand osteoarthritis (HOA) is critical to understanding how overweight may associate with osteoarthritis (OA) apart from axial load. Overweight might be associated with the occurrence of OA through other metabolic factors.
To evaluate the role of overweight in HOA, cross‐sectional data of a population‐based study were used (⩾55 years, n = 3585). The role of diabetes, hypertension and total cholesterol:high‐density lipoprotein (HDL)‐cholesterol ratio on HOA, and whether they play an intermediate role in the association of overweight/HOA was investigated. Furthermore, the prevalence of HOA in the concurrent presence of overweight and other metabolic factors was evaluated.
Independently of other metabolic factors, overweight (body mass index (BMI) >27.4 kg/m2) showed a significant association with HOA (OR 1.4, 95% CI 1.2 to 1.7). The association between diabetes and HOA was only present in people aged 55–62 years (OR 1.9, 95% CI 1.0 to 3.8), but was absent in the total population or in other age groups. The association of hypertension with HOA was weak, and disappeared after adjustment for BMI. The total/HDL cholesterol ratio showed no significant association with HOA. The concurrent presence of overweight, diabetes and hypertension resulted in an even higher prevalence of HOA (OR 2.3, 95% CI 1.3 to 3.9) compared with subjects with none of these characteristics; this prevalence increased further in the younger age group (OR 3.2, 95% CI 1.1 to 8.8).
No intermediate effect of metabolic factors on the association of overweight with HOA was found. An increase in the prevalence of HOA, however, seems to be present when overweight occurs together with hypertension and diabetes especially at a relatively young age.
PMCID: PMC1955104  PMID: 17314121
4.  Body mass index associated with onset and progression of osteoarthritis of the knee but not of the hip: The Rotterdam Study 
Annals of the Rheumatic Diseases  2006;66(2):158-162.
To investigate the relationship between body mass index (BMI) and the incidence and progression of radiological knee as well as of radiological hip osteoarthritis.
Cohort study.
Population based.
3585 people aged ⩾55 years were selected from the Rotterdam Study, on the basis of the availability of radiographs of baseline and follow‐up.
Main outcome measures
Incidence of knee or hip osteoarthritis was defined as minimally grade 2 at follow‐up and grade 0 or 1 at baseline. The progression of osteoarthritis was defined as a decrease in joint space width.
x Rays of the knee and hip at baseline and follow‐up (mean follow‐up of 6.6 years) were evaluated. BMI was measured at baseline.
A high BMI (>27 kg/m2) at baseline was associated with incident knee osteoarthritis (odds ratio (OR) 3.3), but not with incident hip osteoarthritis. A high BMI was also associated with progression of knee osteoarthritis (OR 3.2). For the hip, a significant association between progression of osteoarthritis and BMI was not found.
On the basis of these results, we conclude that BMI is associated with the incidence and progression of knee osteoarthritis. Furthermore, it seems that BMI is not associated with the incidence and progression of hip osteoarthritis.
PMCID: PMC1798486  PMID: 16837490
5.  EULAR recommendations for the management of early arthritis: report of a task force of the European Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT) 
To formulate EULAR recommendations for the management of early arthritis.
In accordance with EULAR's “standardised operating procedures”, the task force pursued an evidence based approach and an approach based on expert opinion. A steering group comprised of 14 rheumatologists representing 10 European countries. The group defined the focus of the process, the target population, and formulated an operational definition of “management”. Each participant was invited to propose issues of interest regarding the management of early arthritis or early rheumatoid arthritis. Fifteen issues for further research were selected by use of a modified Delphi technique. A systematic literature search was carried out. Evidence was categorised according to usual guidelines. A set of draft recommendations was proposed on the basis of the research questions and the results of the literature search.. The strength of the recommendations was based on the category of evidence and expert opinion.
15 research questions, covering the entire spectrum of “management of early arthritis”, were formulated for further research; and 284 studies were identified and evaluated. Twelve recommendations for the management of early arthritis were selected and presented with short sentences. The selected statements included recognition of arthritis, referral, diagnosis, prognosis, classification, and treatment of early arthritis (information, education, non‐pharmacological interventions, pharmacological treatments, and monitoring of the disease process). On the basis of expert opinion, 11 items were identified as being important for future research.
12 key recommendations for the management of early arthritis or early rheumatoid arthritis were developed, based on evidence in the literature and expert consensus.
PMCID: PMC1798412  PMID: 16396980
early arthritis; rheumatoid arthritis; management; diagnosis
6.  Prevalence and pattern of radiographic hand osteoarthritis and association with pain and disability (the Rotterdam study) 
Annals of the Rheumatic Diseases  2004;64(5):682-687.
Objective: To investigate the prevalence and pattern of radiographic osteoarthritis (ROA) of the hand joints and its association with self reported hand pain and disability.
Methods: Baseline data on a population based study (age ⩾55 years) were used (n = 3906). Hand ROA was defined as the presence of Kellgren–Lawrence grade ⩾2 radiological changes in two of three groups of hand joints in each hand. The presence of hand pain during the previous month was defined as hand pain. The health assessment questionnaire was used to measure hand disability.
Results: 67% of the women and 54.8% of the men had ROA in at least one hand joint. DIP joints were affected in 47.3% of participants, thumb base in 35.8%, PIP joints in 18.2%, and MCP joints in 8.2% (right or left hand). ROA of other joint groups (right hand) co-occurred in 56% of DIP involvement, 88% of PIP involvement, 86% of MCP involvement, and 65% of thumb base involvement. Hand pain showed an odds ratio of 1.9 (1.5 to 2.4) with the ROA of the hand (right). Hand disability showed an odds ratio of 1.5 (1.1 to 2.1) with ROA of the hand (right or left).
Conclusions: Hand ROA is common in the elderly, especially in women. Co-occurrence of ROA in different joint groups of the hand is more common than single joint disease. There is a modest to weak association between ROA of the hand and hand pain/disability, varying with the site of involvement.
PMCID: PMC1755481  PMID: 15374852
7.  Prevalence and determinants of one month hand pain and hand related disability in the elderly (Rotterdam study) 
Annals of the Rheumatic Diseases  2005;64(1):99-104.
Objective: To study the prevalence of hand pain and hand disability in an open population, and the contribution of their potential determinants.
Methods: Baseline data were used from 7983 participants in the Rotterdam study (a population based study in people aged ⩾55 years). A home interview was used to determine the presence of hand pain during the previous month, rheumatoid arthritis, osteoarthritis in any joint, diabetes, stroke, thyroid disease, neck/shoulder pain, gout, history of fracture in the past five years, and Parkinson's disease, as well as age, sex, and occupation. Hand disability was defined as the mean score of eight questions related to hand function. Body mass index was measured and hand x rays were taken.
Results: The one month period prevalence of hand pain was 16.9%. The prevalence of hand disability was 13.6%. In univariate analysis for hand pain, rheumatoid arthritis had the highest explained variance (R2) and odds ratio. For hand disability, aging showed the highest explained variance and Parkinson's disease had the highest odds ratio. All determinants together showed an explained variance of 19.8% for hand pain and 25.2% for hand disability. In multivariate analysis, positive radiographic hand osteoarthritis was a poor explanation for hand pain (R2 = 0.5%) or hand disability (R2 = 0).
Conclusions: The contribution of available potential determinants in this study was about 20% for hand pain and 25% for hand disability in an unselected population of elderly people. Thus a greater part of hand pain/hand disability remains unexplained.
PMCID: PMC1755169  PMID: 15608306
8.  Bone mineral density in patients with rheumatoid arthritis: relation between disease severity and low bone mineral density 
Annals of the Rheumatic Diseases  2004;63(12):1576-1580.
Objective: To examine variables associated with bone mineral density (BMD) in patients with rheumatoid arthritis (RA).
Methods: We investigated 373 patients with low to moderately active RA. Patients with low disease activity were recruited from a cohort of patients in clinical remission. Patients with moderately active disease were included in a trial comparing the effects of long term high intensity exercise programme and conventional physical therapy. Demographic and clinical data were collected. Bone mineral density (BMD) was measured by means of dual x ray absorptiometry (DXA). Associations between demographic and clinical measurements on the one hand and BMD on the other were investigated in regression analyses.
Results: The patient group consisted of middle aged, mainly female, patients. The median (interquartile range) disease duration was 7 (4 to 13) years, the mean disease activity score (standard deviation) was 3.2 (1.4). Of the group, 66% was rheumatoid factor positive, and 83% (n = 304) had never used corticosteroids. The median Larsen score of hands and feet was 27 (5 to 61). Greater age and low body mass index were related to low BMD at the hip and spine. High Larsen score for hands and feet was significantly associated with low BMD at the hip. The use of corticosteroids was not independently associated with BMD. The results of the multiple regression analyses also applied to the subgroup of corticosteroid naive patients.
Conclusion: BMD data of patients with low to moderately active RA demonstrated an association between high radiological RA damage and low BMD at the hip, which suggests an association between the severity of RA and the risk of generalised bone loss, which also occurred in corticosteroid naive patients.
PMCID: PMC1754831  PMID: 15547081
9.  Validity and reliability of three definitions of hip osteoarthritis: cross sectional and longitudinal approach 
Annals of the Rheumatic Diseases  2004;63(11):1427-1433.
Objectives: To compare the reliability and validity in a large open population of three frequently used radiological definitions of hip osteoarthritis (OA): Kellgren and Lawrence grade, minimal joint space (MJS), and Croft grade; and to investigate whether the validity of the three definitions of hip OA is sex dependent.
Methods: Subjects from the Rotterdam study (aged ⩾55 years, n = 3585) were evaluated. The inter-rater reliability was tested in a random set of 148 x rays. The validity was expressed as the ability to identify patients who show clinical symptoms of hip OA (construct validity) and as the ability to predict total hip replacement (THR) at follow up (predictive validity).
Results: Inter-rater reliability was similar for the Kellgren and Lawrence grade and MJS (κ statistics 0.68 and 0.62, respectively) but lower for Croft's grade (κ statistic, 0.51). The Kellgren and Lawrence grade and MJS showed the strongest associations with clinical symptoms of hip OA. Sex appeared to be an effect modifier for Kellgren and Lawrence and MJS definitions, women showing a stronger association between grading and symptoms than men. However, the sex dependency was attributed to differences in height between women and men. The Kellgren and Lawrence grade showed the highest predictive value for THR at follow up.
Conclusions: Based on these findings, Kellgren and Lawrence still appears to be a useful OA definition for epidemiological studies focusing on the presence of hip OA.
PMCID: PMC1754809  PMID: 15479891
10.  Long term high intensity exercise and damage of small joints in rheumatoid arthritis 
Annals of the Rheumatic Diseases  2004;63(11):1399-1405.
Objective: To investigate the effect of long term high intensity weightbearing exercises on radiological damage of the joints of the hands and feet in patients with rheumatoid arthritis (RA).
Methods: Data of the 281 completers of a 2 year randomised controlled trial comparing the effects of usual care physical therapy (UC) with high intensity weightbearing exercises were analysed for the rate of radiological joint damage (Larsen score) of the hands and feet. Potential determinants of outcome were defined: disease activity, use of drugs, change in physical capacity and in bone mineral density, and attendance rate at exercise sessions.
Results: After 2 years, the 136 participants in high intensity weightbearing exercises developed significantly less radiological damage than the 145 participants in UC. The mean (SD) increase in damage was 3.5 (7.9) in the exercise group and 5.7 (10.2) in the UC group, p = 0.045. Separate analysis of the damage to the hands and feet suggests that this difference in rate of increase of damage is more pronounced in the joints of the feet than in the hands. The rate of damage was independently associated with less disease activity, less frequent use of glucocorticoids, and with an improvement in aerobic fitness.
Conclusion: The progression of radiological joint damage of the hands and feet in patients with RA is not increased by long term high intensity weightbearing exercises. These exercises may have a protective effect on the joints of the feet.
PMCID: PMC1754798  PMID: 15479889
11.  High intensity exercise or conventional exercise for patients with rheumatoid arthritis? Outcome expectations of patients, rheumatologists, and physiotherapists 
Annals of the Rheumatic Diseases  2004;63(7):804-808.
Objective: To examine the outcome expectations of RA patients, rheumatologists, and physiotherapists regarding high intensity exercise programmes compared with conventional exercise programmes.
Methods: An exercise outcome expectations questionnaire was administered to 807 RA patients, 153 rheumatologists, and 624 physiotherapists. The questionnaire consisted of four statements regarding positive and negative outcomes of high intensity exercise programmes and four similar statements for conventional exercise programmes. A total expectation score for both conventional and high intensity exercise was calculated, ranging from –2 (very negative expectation) to 2 (very positive expectation).
Results: The questionnaire was returned by 662 RA patients (82%), 132 rheumatologists (86%), and 467 physiotherapists (75%). The mean (95% confidence interval) scores for high intensity exercise programmes were 0.30 (0.25 to 0.34), 0.68 (0.62 to 0.74), and –0.06 (–0.15 to 0.02), and for conventional exercise programmes were 0.99 (0.96 to 1.02), 1.13 (1.09 to 1.17), and 1.27 (1.21 to 1.34) for RA patients, rheumatologists, and physiotherapists, respectively. In all three respondent groups, the outcome expectations of high intensity exercise were significantly less positive than those of conventional exercise programme.
Conclusions: Despite the existing evidence regarding the effectiveness and safety of high intensity exercise programmes, RA patients, rheumatologists, and physiotherapists have more positive expectations of conventional exercise programmes than of high intensity exercise programmes. Physiotherapists were the least positive about outcomes of high intensity exercise programmes while rheumatologists were the most positive. To help the implementation of new insights in the effectiveness of physical therapy modalities in rheumatology, the need for continuous education of patients, rheumatologists and physiotherapists is emphasised.
PMCID: PMC1755060  PMID: 15194575
12.  Radiological outcome after four years of early versus delayed treatment strategy in patients with recent onset rheumatoid arthritis 
Annals of the Rheumatic Diseases  2004;63(3):274-279.
Objective: To determine the effect of different treatment strategies (early versus delayed) on the radiological progression of joint damage during 4 years. Additionally, to determine the effect of treatment strategy on the association of HLA class II alleles and joint damage.
Methods: Progression of radiographic damage and association of radiographic damage and genetic predisposition were compared in two cohorts, one treated according to the delayed treatment strategy (initial treatment with analgesics), the other treated according to the early treatment strategy (treatment with disease modifying antirheumatic drugs (DMARDs) chloroquine or sulfasalazine). Radiographic damage was measured by the modified Sharp-van der Heijde method. Genetic predisposition was determined by high resolution HLA-DR and DQ typing.
Results: A completers-only analysis of 153 patients (originally 206 patients) in a non-randomised design showed less radiographic progression from 0 to 4 years in the early treatment group (median Sharp progression rate 1.3 points/year, n = 75) than in the delayed treatment group (2.5 points/year, n = 78) (p = 0.03). The progression from 1 to 4 years did not differ significantly between the groups. At 4 years, joint destruction in both groups was positively correlated with the presence of the shared epitope.
Conclusions: The beneficial effect of early DMARD treatment on the radiological progression of joint damage is still present at 4 years. However, the rate of joint destruction from 1 to 4 years did not differ between the delayed and early treatment group. Neither the radiographic nor the immunogenetic data suggest that longlasting disease modification has been induced by early treatment.
PMCID: PMC1754928  PMID: 14962962
13.  Validity, reliability, and applicability of seven definitions of hip osteoarthritis used in epidemiological studies: a systematic appraisal 
Annals of the Rheumatic Diseases  2004;63(3):226-232.
Methods: Medline and Embase were searched and articles studying the validity, reliability, or applicability of the definitions of hip OA were selected. Two reviewers independently extracted data on the quality of the seven definitions.
Results: Review of the literature showed the validity of the various definitions of hip OA, in particular, has barely been investigated. Minimal joint space (MJS) demonstrated the highest (intra- and interrater) reliability, and showed the highest association with hip pain and restricted internal rotation compared with the other definitions of hip OA. The reliability of the Kellgren and Lawrence grade and the index according to Lane is comparable with that of the MJS, but the construct validity should be investigated more thoroughly. The reliability and validity according to the Croft grade were inferior to the MJS, the Kellgren and Lawrence grade, and the index according to Lane. Despite precise and extensive development, the ACR criteria showed poor reliability and poor cross-validity (agreement between three ACR criteria sets) in a primary care setting.
Conclusions: The reliabilities of MJS, Kellgren and Lawrence, and the index according to Lane were comparable, but the MJS had the highest relationship with hip pain in a male population. Considering how often definitions of hip OA are used, it is surprising that the validity has been so poorly investigated, and the validity needs to be studied more thoroughly.
PMCID: PMC1754907  PMID: 14962953
14.  Prevalence of self reported musculoskeletal diseases is high 
Annals of the Rheumatic Diseases  2003;62(7):644-650.
Objectives: To present the prevalence of self reported musculoskeletal diseases, the coexistence of these diseases, the test-retest reliability with six months in between, and the association with musculoskeletal pain symptoms.
Methods: Twelve layman descriptions of common musculoskeletal diseases were part of the questionnaires of a prospective cohort study of a random sample in the general Dutch population aged 25 years or more (baseline: n=3664, follow up after six months: n=2338). Data collection also included information about pain relating to five different anatomical areas.
Results: Osteoarthritis of the knee (men 10.1%, women 13.6%) was amongst the most reported musculoskeletal diseases, whereas the figures for self reported rheumatoid arthritis (RA) were 1.6% and 4.6% for men and women, respectively. The coexistence of these diseases is high: 47 of the 66 combinations were reported more often than would be expected if they were independent of each other (p<0.05). For most diseases the test-retest reliability was good (κ between 0.6 and 0.8), but for repetitive strain injury (κ=0.37) and chronic arthritis other than RA (κ=0.44) the agreement was fair to moderate. All complaints of pain were more often reported by those with musculoskeletal diseases than those without those diseases, and the pain pattern was disease-specific.
Conclusions: Self reported musculoskeletal diseases are highly prevalent, with a fair to good reliability and a disease-specific pain pattern. Health surveys are a limited but valuable source of information for this group of health problems, which is not available from most other sources of information.
PMCID: PMC1754612  PMID: 12810427
15.  Diagnostic strategy for the assessment of rheumatoid vasculitis 
Annals of the Rheumatic Diseases  2003;62(5):407-413.
Objective: To determine the clinical features associated with histologically proven rheumatoid vasculitis (HRV) and the additional diagnostic value of serological markers in an inception cohort of 81 patients with rheumatoid arthritis (RA) suspected of RV.
Methods: The presence and number of recently developed extra-articular manifestations (EAMs) and a weighted EAM score, as well as the levels of serological markers, were compared between 31 patients with RA with histologically proven vasculitis and 50 patients with RA in whom vasculitis could not be documented histologically. The following markers were evaluated: circulating immune complexes, complement components C3 and C4, class-specific rheumatoid factors (IgM RF, IgG RF, IgA RF), antineutrophil cytoplasmic antibodies, antinuclear antibodies, antiendothelial antibodies, circulating intercellular adhesion molecule-1 and -3, circulating vascular cell adhesion molecule and E-selectin, cellular fibronectin, von Willebrand factor antigen, and C reactive protein. The diagnostic value of these markers, in addition to the clinical features, was evaluated with logistic regression analysis.
Results: Peripheral neuropathy or purpura/petechiae, or both, were the most important clinical features to discriminate patients with RA with and without histologically proven RV. The presence of a high number of EAMs and a higher weighted EAM score in patients with RA suspected of vasculitis were also associated with an increased probability of histologically proven RV. After adjustment for EAMs, only the combination of an increased serum IgA RF level and a decreased serum C3 level appeared to make an additional contribution to the diagnosis histologically proven RV. Evidence of systemic vasculitis was found in a muscle biopsy of the rectus femoris in 9/14 (64%) patients with vasculitis with neuropathy and in 3/11 (27%) patients with purpura/petechiae and vasculitis of the skin.
Conclusions: In the diagnostic process of RV the presence of peripheral neuropathy and/or purpura/petechiae or a high weighted EAM score will increase the probability of histologically proven RV. Of the circulating factors previously suggested to be markers for RV only IgA RF and C3 further increase the probability of histologically proven RV and may be useful to guide diagnostic decisions.
PMCID: PMC1754537  PMID: 12695150
16.  Cost effectiveness and cost utility analysis of multidisciplinary care in patients with rheumatoid arthritis: a randomised comparison of clinical nurse specialist care, inpatient team care, and day patient team care 
Annals of the Rheumatic Diseases  2003;62(4):308-315.
Objective: To assess the relative cost effectiveness of clinical nurse specialist care, inpatient team care, and day patient team care.
Methods: Incremental cost effectiveness analysis and cost utility analysis, alongside a prospective randomised controlled trial with two year follow up. Included were patients with rheumatoid arthritis (RA) with increasing difficulty in performing activities of daily living over the previous six weeks. Quality of life and utility were assessed by the Rheumatoid Arthritis Quality of Life questionnaire, the Short Form-6D, a transformed rating scale, and the time tradeoff. A cost-price analysis was conducted to estimate the costs of inpatient and day patient hospitalisations. Other healthcare and non-healthcare costs were estimated from cost questionnaires.
Results: 210 patients with RA (75% female, median age 59 years) were included. Aggregated over the two year follow up period, no significant differences were found on the quality of life and utility instruments. The costs of the initial treatment were estimated at €200 for clinical nurse specialist care, €5000 for inpatient team care, and €4100 for day patient team care. Other healthcare costs and non-healthcare costs were not significantly different. The total societal costs did not differ significantly between inpatients and day patients, but were significantly lower for the clinical nurse specialist patients by at least €5400.
Conclusions: Compared with inpatient and day patient team care, clinical nurse specialist care was shown to provide equivalent quality of life and utility, at lower costs. Therefore, for patients with health conditions that allow for any of the three types of care, the preferred treatment from a health-economic perspective is the care provided by the clinical nurse specialist.
PMCID: PMC1754484  PMID: 12634227
17.  Sarcoid arthritis: clinical characteristics, diagnostic aspects, and risk factors 
Annals of the Rheumatic Diseases  2002;61(6):499-504.
Objectives: (a) To describe the clinical characteristics of acute sarcoid arthritis and the diagnostic value of its presenting clinical features; (b) to evaluate whether disease onset is seasonal; and (c) to evaluate whether smoking behaviour or the presence of HLA class II alleles is a risk factor for the disease.
Methods: 579 consecutive patients with recent onset arthritis who had been newly referred to a rheumatology outpatient clinic were included in a prospective cohort study. The presenting clinical features, the smoking behaviour, and the results of HLA-DQ and HLA-DR DNA typing of 55 patients with sarcoid arthritis, 524 patients with other arthritides of recent onset, and samples of the normal population were compared.
Results: In all cases the disease showed a self limiting arthritis and overall good prognosis. The diagnostic ability of a combination of four clinical features—symmetrical ankle arthritis, symptoms of less than two months, age below 40 years, and erythema nodosum—was exceptionally high. When test positivity is defined as the presence of at least three of four criteria the set rendered a sensitivity of 93%, a specificity of 99%, a positive predictive value of 75%, and a negative predictive value of 99.7%. The disease clustered in the months March–July. The disease was negatively associated with smoking (odds ratio (OR) 0.09; 95% confidence interval (95% CI) 0.02 to 0.37) and positively associated with the presence of the DQ2 (DQB1*0201)-DR3 (DRB1*0301) haplotype (OR 12.33; 95% CI 5.97 to 25.48).
Conclusion: The disease entity acute sarcoid arthritis has highly diagnostic clinical features. The seasonal clustering, the protective effect of smoking, and the association with specific HLA class II antigens support the hypothesis that it results from exposure of susceptible hosts to environmental agents through the lungs.
PMCID: PMC1754119  PMID: 12006321
18.  Role of radiography in predicting progression of osteoarthritis of the hip: prospective cohort study 
BMJ : British Medical Journal  2005;330(7501):1183.
Objectives To investigate which variables identify people at high risk of progression of osteoarthritis of the hip.
Design Population based cohort study.
Setting Ommoord district in Rotterdam, Netherlands.
Participants 1904 men and women aged 55 years and older from the Rotterdam study were selected on the basis of the presence of osteoarthritic signs on radiography at baseline, as defined by a Kellgren and Lawrence score ≥ grade 1.
Main outcome measures Radiological progression of osteoarthritis of the hip, defined as a decrease of joint space width (≥ 1.0 mm) at follow-up or the presence of a total hip replacement.
Methods Potential determinants of progression of hip osteoarthritis were collected at baseline. x Ray films of the hip at baseline and follow-up (mean follow-up time 6.6 years) were evaluated. Multivariate logistic regression models were used to assess the association between potential risk factors and progression of hip osteoarthritis.
Results In 13.1% (1904 subjects) of the study population (mean age 66.2 years), progression of hip osteoarthritis was evident on the radiograph. Starting with a simple model of only directly obtainable variables, the Kellgren and Lawrence score at baseline, when added to the model, was a strong predictor (odds ratio 5.8, 95% confidence interval 4.0 to 8.4), increasing to 24.3 (11.3 to 52.1) in subjects with hip pain at baseline.
Conclusions The Kellgren and Lawrence score at baseline was by far the strongest predictor for progression of hip osteoarthritis, especially in patients with existing hip pain at baseline. In patients with hip pain, a radiograph has strong additional value in identifying those at high risk of progression of hip osteoarthritis.
PMCID: PMC558014  PMID: 15894555
19.  Pregnancy and oral contraceptive use do not significantly influence outcome in long term rheumatoid arthritis 
Annals of the Rheumatic Diseases  2002;61(5):405-408.
Background: Oral contraceptives (OC) and pregnancy are known to have an influence on the risk of onset of rheumatoid arthritis (RA). Pregnancy itself has beneficial effects on the activity of the disease, with relapses post partum. It is not known, however, whether OC and pregnancies influence the ultimate outcome of RA.
Objectives: To explore whether OC use and pregnancies influence the 12 year outcome in RA as measured by radiological damage and disability.
Methods: In a prospective inception cohort of 132 female patients with recent RA according to the 1987 American College of Rheumatology criteria—a cohort initially gathered to study the association between hormonal factors and the onset of RA—outcome was assessed in a follow up after 12 years. The outcome was evaluated in 112 (85%) women by the radiological damage of hands and feet as measured with the Sharp score modification van der Heijde (SHS), the damage of the large joints measured with the Larsen score (LS) of large joints (0–60), and the disability measured with the Health Assessment Questionnaire (HAQ). The median values of each outcome variable were calculated for several subgroups of patients stratified for OC use and pregnancies before and after onset of the disease and the tertiles of the total number of months of OC use and of pregnancies. The association of OC use and pregnancies before and after onset of the disease with the outcome variables was calculated using Spearman's rank correlation (rs). The combined influence of OC use and pregnancies on the SHS, LS, and HAQ at 12 years was estimated using ordinal polytomous logistic regression.
Results: The median values of the SHS, LS, and HAQ showed a trend towards less radiological joint damage and less disability in women with long term OC use and multiple pregnancies. This difference, however, was not significant, except for the HAQ score in women with three or more pregnancies in life. There was no association between pregnancies, however defined, and any parameter of RA outcome after 12 years (maximum rs=-0.10). The only significant correlation was found between OC use before symptom onset and the LS (rs=-0.22, p<0.05). The combination of hormonal variables explained no more than a maximum of 3% of the variance of the 12 year outcome as measured by the SHS.
Conclusion: OC use and pregnancy do not significantly influence outcome in long term RA. There is, however, a trend for patients with multiple pregnancies and long term OC use to have less radiographic joint damage and a better functional level.
PMCID: PMC1754092  PMID: 11959763
20.  Communication between Dutch rheumatologists and occupational physicians in the occupational rehabilitation of patients with rheumatic diseases 
Objective: To assess the quality and quantity of communication and cooperation between Dutch rheumatologists and occupational physicians.
Methods: A postal survey among 187 Dutch rheumatologists.
Results: 153/187 rheumatologists (82%) returned the questionnaire. They considered reducing pain and fatigue to be their major responsibility in the process of occupational rehabilitation, followed by improving work participation (68/153 (44%)) and quality of work (55/153 (36%)). Although 112/153 (73%) of the rheumatologists judged the communication and cooperation with occupational physicians as reasonable to good, 119/153 (78%) of them were willing to improve the collaboration. Perceived bottlenecks mentioned were a lack of clarity about the occupational physician's position and activities, and the absence of practice guidelines. The most important prerequisites for improvement were found to be guarantees about the occupational physician's professional independence and more clarity about the competence of the occupational physicians and how they used the information provided.
Conclusion: Dutch rheumatologists are willing to improve cooperation and communication with occupational physicians. The perceived lack of clarity about their mutual tasks appears to be a major obstacle. Thus the development of a joint education programme and a guideline for occupational rehabilitation in rheumatic diseases may be appropriate first steps towards improvement.
PMCID: PMC1753888  PMID: 11779762
21.  Effect of intensive exercise on patients with active RA 
PMCID: PMC1753612  PMID: 11284455
22.  Value of the time trade off method for measuring utilities in patients with rheumatoid arthritis 
Annals of the Rheumatic Diseases  2000;59(11):892-897.
OBJECTIVE—To assess the feasibility, reliability, and validity of the time trade off (TTO) in patients with rheumatoid arthritis (RA).
METHODS—The TTO was applied in 194 patients with RA with increasing difficulty in performing activities of daily living. The test-retest reliability was determined in 35 of these patients and was calculated by the intraclass correlation coefficient (ICC). Construct validity was evaluated with the following sets of variables: measures of utility (rating scale), quality of life (RAND 36 item Health Status Survey (RAND-36) and RAQoL), functional status (Health Assessment Questionnaire, grip strength, and walk test), and disease activity (doctor's global assessment, disease activity score, pain, and morning stiffness).
RESULTS—Ten patients (5%) did not complete the TTO. The median value of the TTO was 0.77 (range 0.03-1.0). The test-retest ICC of the TTO was 0.85 (p<0.001). Construct validity testing of the TTO showed poor to moderate correlations (Spearman's rs between 0.19 and 0.36, p<0.01) with all outcome measures except for the subscale role limitation (physical problem) of the RAND-36, the walk test, the doctor's global assessment of disease activity, and morning stiffness. Multiple regression analysis showed that only 17% of the variance of the TTO scores could be explained.
CONCLUSIONS—The TTO method appeared to be feasible and reliable in patients with RA. The poor to moderate correlations of the TTO with measures of quality of life, functional ability, and disease activity suggest that the TTO considers additional attributes of health status. This may have implications for the application of the TTO in clinical trials in patients with RA.

PMCID: PMC1753018  PMID: 11053068
23.  Effect of intensive exercise on patients with active rheumatoid arthritis: a randomised clinical trial 
Annals of the Rheumatic Diseases  2000;59(8):615-621.
OBJECTIVE—To investigate the effects of a dynamic, intensive exercise regimen on pain, disease activity, and physical functioning in active rheumatoid arthritis (RA).
METHODS—64 patients with RA with a mean age of 60 (13) years and mean disease duration of 8 (8) years, admitted to hospital because of active disease, were randomly assigned to an intensive exercise programme or to a conservative exercise programme during their period in hospital with a mean length of 30 (14) days. The intensive exercise programme consisted of knee and shoulder dynamic and isometric muscle strengthening exercises against resistance five times a week and conditioning bicycle training three times a week and was supplemental to the conservative exercise programme of range of motion and isometric exercises. Indices of disease activity, pain, muscle strength, and functional ability were assessed at 0, 3, 6, 12, and 24 weeks by a blinded observer.
RESULTS—The medical treatment during the study was the same in both groups. Both groups improved in measures of disease activity, differences between groups were not statistically significant. The mean improvement in disease activity score at 24 weeks in the intensive and conservative exercise group was −1.4 (1.5) and −0.7 (1.4), respectively. Measures of physical functioning improved significantly for patients in the intensive exercise group, and differences between groups were statistically significant for measures of muscle strength.
CONCLUSION—A short term intensive exercise programme in active RA is more effective in improving muscle strength than a conservative exercise programme and does not have deleterious effects on disease activity.

PMCID: PMC1753212  PMID: 10913058
24.  Influence of non-inherited maternal HLA-DR antigens on susceptibility to rheumatoid arthritis 
Annals of the Rheumatic Diseases  1998;57(11):672-675.
OBJECTIVE—It has recently been observed that non-inherited maternal DR4 antigens (NIMAs) of DR4 negative rheumatoid arthritis (RA) patients were increased compared with non-inherited paternal DR4 antigens (NIPAs). The aim of this study was to determine the prevalence of non-inherited DR4 antigens and DRB1 alleles in parents of RA patients. 
METHODS—HLA-DR serology and DRB1 typing was performed in 97 RA patients and their parents. NIMA and NIPA frequencies were compared, stratified according to the presence of DR4 and/or the shared epitope (SE).
RESULTS—In DR4 negative patients, NIMA DR4 was increased compared with NIPA DR4 (OR 3.10, 95% CI 0.76, 12.70). When combined with results from a previous study this increase was significant (OR 3.65, 95% CI 1.29, 10.31). The NIMA effect of SE positive DR4 subtypes in this study (OR 4.73, 95% CI 0.94, 23.8) was stronger than the NIMA effect of combined SE positive DRB1 alleles (OR 2.19 95% CI 0.36, 13.22).
CONCLUSIONS—The association between non-inherited maternal HLA-DR4 alleles and the susceptibility to RA was observed in two independent populations.

 Keywords: rheumatoid arthritis; non-inherited maternal DR4 antigens; HLA; genetics
PMCID: PMC1752500  PMID: 9924209
25.  Influence of HLA-class II incompatibility between mother and fetus on the development and course of rheumatoid arthritis of the mother 
Annals of the Rheumatic Diseases  1998;57(5):286-290.
OBJECTIVE—To assess the relation between the course of rheumatoid arthritis (RA) during pregnancy or the onset of RA postpartum and DRB1, DQA1, and DQB1 incompatibilities between mother and child.
METHODS—In 45 pregnancies of 33 RA patients the course of RA was related to the number of class II incompatibilities. Furthermore class II incompatibilities in 16 pregnancies followed by RA onset were compared with those in 87 control pregnancies.
RESULTS—The risk of a favourable compared with an unfavourable course was 0.95, 2.67, and 2.38 in case of DRB1, DQA1, and DQB1 incompatibility respectively. DQA1 and DQB1 incompatibilities were seen more often in the 10 pregnancies followed by RA onset within three months than in control pregnancies (OR 8.02, 95% CI 0.97, 66.06 and OR 8.79 95% CI 1.07, 72.46 respectively).
CONCLUSIONS—DQA1 and DQB1 incompatibility between mother and child seems to have a favourable effect on the course of RA and may postpone the risk of RA onset during pregnancy.

 Keywords: pregnancy; rheumatoid arthritis; HLA; incompatibility
PMCID: PMC1752598  PMID: 9741312

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