Anticitrullinated protein antibodies and rheumatoid factor are associated with increased mortality but with different causes of death in patients with rheumatoid arthritis: a longitudinal study in three European cohorts.

OBJECTIVE: Patients with rheumatoid arthritis (RA)-related autoantibodies have an increased mortality rate. Different autoantibodies are frequently co-occurring and it is unclear which autoantibodies associate with increased mortality. In addition, association with different causes of death is thus far unexplored. Both questions were addressed in three early RA populations. METHODS: 2331 patients with early RA included in Better Anti-Rheumatic Farmaco-Therapy cohort (BARFOT) (n=805), Norfolk Arthritis Register (NOAR) (n=678) and Leiden Early Arthritis Clinic cohort (EAC) (n=848) were studied. The presence of anticitrullinated protein antibodies (ACPA), rheumatoid factor (RF) and anticarbamylated protein (anti-CarP) antibodies was studied in relation to all-cause and cause-specific mortality, obtained from national death registers. Cox proportional hazards regression models (adjusted for age, sex, smoking and inclusion year) were constructed per cohort; data were combined in inverse-weighted meta-analyses. RESULTS: During 26 300 person-years of observation, 29% of BARFOT patients, 30% of NOAR and 18% of EAC patients died, corresponding to mortality rates of 24.9, 21.0 and 20.8 per 1000 person-years. The HR for all-cause mortality (95% CI) was 1.48 (1.22 to 1.79) for ACPA, 1.47 (1.22 to 1.78) for RF and 1.33 (1.11 to 1.60) for anti-CarP. When including all three antibodies in one model, RF was associated with all-cause mortality independent of other autoantibodies, HR 1.30 (1.04 to 1.63). When subsequently stratifying for death cause, ACPA positivity associated with increased cardiovascular death, HR 1.52 (1.04 to 2.21), and RF with increased neoplasm-related death, HR 1.64 (1.02 to 2.62), and respiratory disease-related death, HR 1.71 (1.01 to 2.88). CONCLUSIONS: The presence of RF in patients with RA associates with an increased overall mortality rate. Cause-specific mortality rates differed between autoantibodies: ACPA associates with increased cardiovascular death and RF with death related to neoplasm and respiratory disease.

A HPLC-SRM-MS based method for the detection and quantification of methotrexate in urine at doses used in clinical practice for patients with rheumatological disease: a potential measure of adherence.

Rheumatoid arthritis (RA) is a common autoimmune disease that causes significant disability and reduced life expectancy. The folate antagonist methotrexate (MTX) is first-line therapy for RA when used weekly at low doses (5-25 mg). However, the true rate of adherence to MTX is uncertain. This is in part due to the different methods of measurement of adherence employed with no biochemical test currently available to determine adherence to low dose MTX. Common methods of MTX measurement include immunoassays in patients with high dose therapy, but these assays cross-react with MTX metabolites and lack the sensitivity required to measure adherence to low dose MTX. HPLC-SRM-MS (selected reaction monitoring-mass spectrometry) has several theoretical advantages over immunoassays with improved specificity, minimal cross-reaction and higher sensitivity. The aim of this study was to develop an assay to measure MTX and its major metabolite 7-OH-MTX in urine as a tool to monitor adherence to low dose MTX in clinic. As a proof of concept, urine samples from 4 participants with RA were measured after directly observed therapy. The assay showed improved sensitivity compared to that reported by immunoassays, with low carryover and high within-run precision. In participant samples, MTX was measurable in the urine for up to 105 hours after administration and 7-OH-MTX was detectable up to 98 hours after administration, suggesting that this assay is suitable for the measurement of adherence to therapy. The assay requires minimal sample preparation and can be adopted by other laboratories with minimal study set up.

Multiple adverse pregnancy outcomes before symptom onset are associated with a worse disease outcome in women with recent-onset inflammatory polyarthritis.

OBJECTIVE: Previous evidence suggests that women with a history of adverse pregnancy outcomes (APOs) may be at greater risk of developing rheumatoid arthritis. Additionally, one study reported that female patients with rheumatoid arthritis with a history of preonset APOs showed a worse 2-year radiographic outcome than did patients with no APOs. The authors' aim was to investigate the relationship between preonset APOs (spontaneous abortion or stillbirth) and disease outcome in women with inflammatory polyarthritis (IP). METHODS: The Norfolk Arthritis Register (NOAR) is a primary-care-based cohort of patients with recent-onset IP; 1586 gravid women who joined NOAR during 1990-2004 were included in this analysis. The authors examined the relationship between patient-reported preonset APOs and disease outcome, measured using the Health Assessment Questionnaire (HAQ) and disease activity score in 28 joints (DAS28(CRP)) (for a subgroup of patients), using linear random effects analysis, adjusted for age and other factors. RESULTS: In a predominantly parous cohort (99%), 397 (25%) women reported ≥1 APO before symptom onset. The rates of APOs in NOAR were comparable to the general population. On average, women with a history of ≥2 APOs had significantly higher HAQ and DAS28 scores over time than women with no APOs (mean difference in HAQ 0.13 (95% CI 0.002 to 0.26); DAS28, 0.56 (95% CI 0.01 to 1.11)). This relationship was more pronounced in women with ≥3 APOs (mean difference in HAQ 0.23 (95% CI 0.02 to 0.43); DAS28, 0.98 (95% CI 0.23 to 1.74)). CONCLUSION: Women with two or more APOs before IP onset had a worse disease outcome than women with no APOs.

The relationship between oral contraceptive use and functional outcome in women with recent-onset inflammatory polyarthritis: results from the Norfolk Arthritis Register.

OBJECTIVE: Use of oral contraceptives (OCs) may prevent the development of rheumatoid arthritis, but the influence of OC use on disease outcome is unresolved. The purpose of this study was to examine functional outcome and OC use in women with inflammatory polyarthritis (IP). METHODS: The Norfolk Arthritis Register (NOAR) is an inception cohort of patients with recent-onset IP. We studied patient-reported history of OC use in 663 women who were born after 1945 and who had not used OCs during followup. OC use during followup was additionally investigated in 265 women who were <50 years old and had not undergone menopause or hysterectomy during followup. All patients were recruited to the NOAR between 1990 and 2004. Functional ability was assessed using the Health Assessment Questionnaire (HAQ), with adjustment for age at symptom onset. RESULTS: The median followup was 4.9 years. In the investigation analyzing OC use before symptom onset, patients who had used OCs before symptom onset had lower HAQ scores throughout followup than patients who had not taken OCs before symptom onset (difference in score at 5-year followup -0.35; 95% confidence interval [95% CI] -0.51, -0.19). Patients who were taking OCs at baseline had lower HAQ scores over time than women who were not taking OCs at baseline but had previously done so (mean difference -0.21; 95% CI -0.40, -0.02). In the investigation analyzing OC use during followup, OC use during followup was associated with lower HAQ scores over time than no OC use during followup (mean difference -0.06; 95% CI -0.16, 0.03); however, this was only significant for women with moderate or severe functional disability at the previous assessment (mean difference -0.23; 95% CI -0.40, -0.07). Further adjustment for potential confounders and exclusion of hormone replacement therapy users had little impact. CONCLUSION: OC use is generally associated with a beneficial functional outcome in IP, and use before and at symptom onset appeared to have the most consistent benefit.

Parity, time since last live birth and long-term functional outcome: a study of women participating in the Norfolk Arthritis Register.

OBJECTIVE: To investigate the relationship between pre-symptom onset live births and functional outcome in women with inflammatory polyarthritis (IP). METHODS: 1872 women with no subsequent pregnancies were registered with the Norfolk Arthritis Register between 1990 and 2004 and followed-up for a median of 5 years. Functional disability over time was assessed by Health Assessment Questionnaire (HAQ). The number and calendar year of past live births were recorded. Differences in HAQ score over time by parity and time since last live birth (latency), adjusted for age and symptom duration, were examined using linear random effects models. The results were then adjusted for a number of potential confounders. RESULTS: 1553 women (83%) had ≥1 live births before symptom onset. The median latency was 26 years (IQR 16-35). Parous women had significantly lower HAQ scores over time than nulliparous women (-0.19, 95% CI -0.32 to -0.06). Increasing latency was associated with increasing HAQ score; the mean HAQ score of women with a latency of approximately 32 years was the same as for nulliparous women. This was independent of autoantibody status, socioeconomic status, smoking history and comorbidity. CONCLUSION: Parous women who develop IP have better functional outcome over time than nulliparous women who develop IP. The beneficial effect of parity diminishes with time.

Beneficial effects of a 3-week course of intramuscular glucocorticoid injections in patients with very early inflammatory polyarthritis: results of the STIVEA trial.

OBJECTIVE: To evaluate whether treating patients with very early inflammatory polyarthritis (IP) with a 3-week course of intramuscular (IM) methylprednisolone acetate may postpone the need for disease-modifying antirheumatic drugs (DMARDs) and prevent IP from evolving into rheumatoid arthritis (RA). METHODS: Patients with very early IP (4-10 weeks' duration) were randomised to receive three injections of either 80 mg IM methylprednisolone acetate or placebo, given at weekly intervals. Assessments were monthly until 6 months after the first injection, and then concluded at 12 months. The primary outcome was the need to start DMARDs by the 6-month assessment. Secondary outcomes included disease activity and final clinical diagnosis by the rheumatologist at 12 months. RESULTS: Patients in the placebo group (76%) were more likely to need DMARDs during the first 6 months of the trial than patients in the glucocorticoid group (61%) (adjusted OR = 2.11, 95% CI 1.16 to 3.85, p = 0.015). Disease activity did not differ between the two groups at 12 months, probably because many patients in the placebo group started DMARDs early in the study. After 12 months, the arthritis had resolved without the need for DMARDs in 9.9% (11/111) of the patients in the placebo group and in 19.8% (22/111) in the glucocorticoid-treated group (adjusted OR = 0.42, 95% CI 0.18 to 0.99, p = 0.048). CONCLUSION: Treatment of patients with very early IP with IM methylprednisolone acetate appears to postpone the prescription of DMARDs and prevent one in 10 patients from progressing into RA.

The relationship between post-onset pregnancy and functional outcome in women with recent onset inflammatory polyarthritis: results from the Norfolk Arthritis Register.

OBJECTIVE: To examine the influence of post-symptom-onset pregnancy on disease outcome in women with inflammatory polyarthritis (IP). METHODS: A total of 631 women, aged <48 years at symptom onset, were registered with the Norfolk Arthritis Register (NOAR) between 1990 and 2004. Functional disability was assessed using the Stanford Health Assessment Questionnaire (HAQ). Blood was tested for rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA). The date and outcome of all pregnancies were reported during a median follow-up of 7 years. Linear random effects models were used to examine HAQ score over time, by pregnancy status. RESULTS: were then stratified for RF and ACPA status. Results In all, 72 women had a post-onset pregnancy (Po-P) including 45 women who were pregnant at a follow-up assessment. Pregnancy was generally associated with lower HAQ scores over time than non-pregnancy. The 10 ACPA-positive women who had a Po-P had significantly worse subsequent HAQ scores. CONCLUSION: Overall, Po-P is associated with lower HAQ scores, compared to no Po-P. This may reflect a beneficial effect of pregnancy on disease outcome, or that predominantly women with milder disease become pregnant. In women with the worst predicted outcome (APCA positive), Po-P is associated with a worse outcome than no pregnancy.

Adverse events and factors associated with toxicity in patients with early rheumatoid arthritis treated with methotrexate tight control therapy: the CAMERA study.

OBJECTIVE: To evaluate toxicity profiles in patients with rheumatoid arthritis (RA) treated either according to an intensive or a conventional treatment strategy approach with methotrexate (MTX) and to study factors associated with MTX-related toxicity. METHODS: Data were used from the Computer-Assisted Management in Early Rheumatoid Arthritis (CAMERA) study, in which clinical efficacy of an intensive treatment strategy with MTX was more beneficial than a conventional treatment strategy approach. In this study, data on adverse events (AEs) were compared between the two strategy groups. Logistic regression analyses were used to identify possible associations between factors assessed at baseline and withdrawal due to MTX-related AEs or liver toxicity at follow-up. RESULTS: Although significantly more patients in the intensive strategy group experienced MTX-related AEs than in the conventional strategy group, all recorded AEs were relatively mild. A higher body mass index (BMI) was significantly associated with withdrawal due to MTX-related AEs in the multiple regression analyses (odds ratio=1.207, 95% confidence interval 1.02 to 1.44, p=0.033). There was a trend towards an association between diminished creatinine clearance and MTX withdrawal. For liver toxicity, increased serum liver enzymes at baseline were associated with liver toxicity during follow-up. CONCLUSION: Although the occurrence of AEs in the intensive strategy group was higher than in the conventional strategy group, the previously observed clinical efficacy of an intensive treatment strategy seems to outweigh the observed toxicity profiles. When starting MTX, attention should be given to patients with a high BMI and those with increased levels of liver enzymes and decreased renal function.

Gender, body mass index and rheumatoid arthritis disease activity: results from the QUEST-RA Study.

OBJECTIVES: To investigate whether body mass index (BMI), as a proxy for body fat, influences rheumatoid arthritis (RA) disease activity in a gender-specific manner. METHODS: Consecutive patients with RA were enrolled from 25 countries into the QUEST-RA program between 2005 and 2008. Clinical and demographic data were collected by treating rheumatologists and by patient self-report. Distributions of Disease Activity Scores (DAS28), BMI, age, and disease duration were assessed for each country and for the entire dataset; mean values between genders were compared using Student's t-tests. An association between BMI and DAS28 was investigated using linear regression, adjusting for age, disease duration and country. RESULTS: A total of 5,161 RA patients (4,082 women and 1,079 men) were included in the analyses. Overall, women were younger, had longer disease duration, and higher DAS28 scores than men, but BMI was similar between genders. The mean DAS28 scores increased with increasing BMI from normal to overweight and obese, among women, whereas the opposite trend was observed among men. Regression results showed BMI (continuous or categorical) to be associated with DAS28. Compared to the normal BMI range, being obese was associated with a larger difference in mean DAS28 (0.23, 95% CI: 0.11, 0.34) than being overweight (0.12, 95% CI: 0.03, 0.21); being underweight was not associated with disease activity. These associations were more pronounced among women, and were not explained by any single component of the DAS28. CONCLUSIONS: BMI appears to be associated with RA disease activity in women, but not in men.

Adverse events of low- to medium-dose oral glucocorticoids in inflammatory diseases: a meta-analysis.

OBJECTIVES: To systematically analyse the literature on reported adverse events of low- to medium-dose glucocorticoids during >or=1 month for inflammatory diseases. METHODS: Data were systematically retrieved and selected from PUBMED, EMBASE and CINAHL databases (6097 hits). RESULTS: A total of 28 studies (2382 patients) met the inclusion criteria. The risk of adverse events over all studies was 150 per 100 patient-years (95% confidence interval (CI) 132 to 169). Psychological and behavioural adverse events (eg, minor mood disturbances) were most frequently reported, followed by gastrointestinal events (eg, dyspepsia, dysphagia). In 14 studies comprising 796 patients with rheumatoid arthritis the risk of adverse events was 43/100 patient-years (95% CI 30 to 55), in 4 studies of 167 patients with polymyalgia rheumatica the risk of adverse events was 80/100 patient-years (95% CI 15 to 146), and in 10 studies of 1419 patients with inflammatory bowel disease the risk of adverse events was 555/100 patient-years (95% CI 391 to 718). High rates of adverse events were reported in high-quality studies with short follow-up, notably in studies of patients with inflammatory bowel disease. CONCLUSIONS: The risk of adverse events depends on study design and disease. Studies on inflammatory bowel disease were often of short duration with frequent documentation of adverse events which resulted in higher adverse event rates whereas, in studies of rheumatoid arthritis, the longer follow-up may have resulted in lower adverse event rates. In most studies aimed at efficacy of glucocorticoids or other drugs, adverse events were not systematically assessed. Clear guidelines on assessment of adverse events are lacking.

The comparative responsiveness of the EQ-5D and SF-6D to change in patients with inflammatory arthritis.

PURPOSE: Comparative evidence regarding the responsiveness of the EQ-5D and SF-6D in arthritis patients is conflicting and insufficient across the range of disease severity. We examined the comparative responsiveness of the EQ-5D and SF-6D in cohorts of patients with early inflammatory disease through to severe rheumatoid arthritis (RA). METHODS: Responsiveness was tested using the effect size (ES) and standardised response mean (SRM). Correlation of change in EQ-5D and SF-6D with disease specific measures was tested using Pearson correlations and the Steiger's Z test. Treatment response and self-reported change were used as anchors of important change. RESULTS: The EQ-5D was more responsive to deterioration (ES ratio (EQ-5D/SF-6D): 1.6-3.0) and the SF-6D more responsive to improvement (ES ratio (SF-6D/EQ-5D): 1.1-1.8) in health. The SF-6D did not respond well to deterioration in patients with established severe RA (ES and SRM 0.08). The EQ-5D provided larger absolute mean change estimates but with greater variance compared to the SF-6D. CONCLUSIONS: The comparative responsiveness of the EQ-5D and SF-6D differs according to the direction of change. The level of mean change of the EQ-5D relative to the SF-6D has implications for cost-effectiveness analysis. Use of the SF-6D in patients with severe progressive disease may be inappropriate.

Mortality trends in patients with early rheumatoid arthritis over 20 years: results from the Norfolk Arthritis Register.

OBJECTIVE: To examine mortality rates in UK patients with early rheumatoid arthritis (RA) from 1990-2011 and compare with population trends. METHODS: The Norfolk Arthritis Register (NOAR) recruited adults with ≥2 swollen joints for ≥4 weeks: cohort 1 (1990-1994), cohort 2 (1995-1999), and cohort 3 (2000-2004). At baseline, serum rheumatoid factor and anti-citrullinated protein antibody were measured and the 2010 American College of Rheumatology/European League Against Rheumatism RA classification criteria were applied. Patients were followed for 7 years, until emigration or death. The UK Office for National Statistics notified the NOAR of the date and cause of deaths, and provided mortality rates for the Norfolk population. All-cause and cardiovascular-specific standardized mortality ratios (SMRs) were calculated. Poisson regression was used to compare mortality rate ratios (MRRs) between cohorts and then, with cubic splines, to model rates by calendar year. Analyses were performed in patients 1) with early inflammatory arthritis, 2) classified as having RA, and 3) autoantibody positive. RESULTS: A total of 2,517 patients were included, with 1,639 women (65%) and median age 55 years, and 1,419 (56%) fulfilled the 2010 RA criteria. All-cause and cardiovascular-specific SMRs were significantly elevated in the antibody-positive groups. There was no change in mortality rates over time after accounting for changes in the population rates. In RA patients, all-cause MRRs, compared to cohort 1, were 1.13 (95% confidence interval [95% CI] 0.84-1.52) and 1.00 (95% CI 0.70-1.43) in cohorts 2 and 3, respectively. CONCLUSION: Mortality rates were increased in patients with RA and SMRs were particularly elevated in those who were autoantibody positive. Compared to the general population, mortality rates have not improved over the past 20 years.

Association of morbid obesity with disability in early inflammatory polyarthritis: results from the Norfolk Arthritis Register.

OBJECTIVE: Obesity has been associated with disease outcomes in inflammatory arthritis. This study aimed to investigate cross-sectionally the relationship between body mass index (BMI) and functional disability in a large inception cohort of patients with early inflammatory polyarthritis (IP). METHODS: Patients age ≥16 years with ≥2 swollen joints for ≥4 weeks were recruited into the Norfolk Arthritis Register. At the initial assessment, clinical and demographic data were obtained, joints were examined, and height and weight were measured. Blood samples were taken to measure inflammatory markers and autoantibodies, and patients completed the Health Assessment Questionnaire (HAQ) to assess functional disability. Univariate and multivariate ordinal regression were used to examine the cross-sectional association between BMI and the HAQ. Multiple imputation using chained equations allowed inclusion of patients with missing variables. RESULTS: A total of 1,246 patients were studied (median age 57 years). Of those patients, 782 patients (63%) were female and 303 (25%) were obese (BMI ≥30 kg/m(2) ). Morbid obesity (BMI ≥35 kg/m(2) ) was significantly associated with worse functional disability in the univariate and multivariate analysis with missing data imputed, adjusting for age, sex, symptom duration, smoking status, disease activity, autoantibodies, comorbidities, and treatment (multivariate odds ratio 1.87, 95% confidence interval 1.14-3.07). CONCLUSION: Morbid obesity in patients with early IP is associated with worse HAQ scores. This should be taken into account in patient management and when interpreting the HAQ in clinical practice.

Association between socioeconomic status, learned helplessness, and disease outcome in patients with inflammatory polyarthritis.

OBJECTIVE: Independent investigations have shown that socioeconomic status (SES) and learned helplessness (LH) are associated with poor disease outcome in patients with rheumatoid arthritis (RA). Our aim was to investigate the cross-sectional relationship between SES, LH, and disease outcome in patients with recent-onset inflammatory polyarthritis (IP), the broader group of conditions of which RA is the major constituent. METHODS: SES was measured using the Index of Multiple Deprivation 2007 for 553 patients consecutively recruited to the Norfolk Arthritis Register. Patients also completed the Rheumatology Attitudes Index, a measure of LH. SES and LH were investigated as predictors of disease outcome (functional disability [Health Assessment Questionnaire (HAQ)] and disease activity [Disease Activity Score in 28 joints]) in a regression analysis, adjusted for age, sex, and symptom duration. The role of LH in the relationship between SES and disease outcome was then investigated. RESULTS: Compared to patients of the highest SES, those of the lowest SES had a significantly worse outcome (median difference in HAQ score 0.42; 95% confidence interval [95% CI] 0.08, 0.75). Compared to patients with normal LH, patients with low LH had a significantly better outcome and patients with high LH had a significantly worse outcome (median difference in HAQ score 1.12; 95% CI 0.82, 1.41). There was a significant likelihood that LH mediated the association between SES and disease outcome (P = 0.04). CONCLUSION: LH is robustly associated with cross-sectional disease outcome in patients with IP, and appears to mediate the relationship between SES and disease outcome. As LH is potentially modifiable, these findings have potential clinical implications.

Tight control in the treatment of rheumatoid arthritis: efficacy and feasibility.

OBJECTIVE: To evaluate the available evidence on the efficacy and feasibility of the new concept of tight control in randomised trials in patients with rheumatoid arthritis (RA). Tight control is a treatment strategy tailored to the individual patient with RA, which aims to achieve a predefined level of low disease activity or remission within a certain period of time. METHODS: The literature database PubMed was searched and yielded four trials: the FIN-RACo trial, the TICORA study, the BeSt study and the CAMERA study. RESULTS: Tight control resulted in greater improvement and a higher percentage of patients meeting the preset aim of low disease activity or remission when compared to the control intervention. In the FIN-RACo trial, analysing the subset of patients completing the study, 68% in the tight control group achieved remission (DAS28<2.6) verus 41% in the contrast group [corrected] In the TICORA study, 65% of patients in the tight control group versus 16% of the contrast group achieved remission, based on DAS<1.6 (p<0.0001). In the CAMERA study, 50% of patients in the tight control group using a computer decision model achieved remission, versus 37% in the contrast group (p = 0.029). The BeSt study consisted of only tight control groups aimed at a DAS<1.6; remission was achieved in 38-46% of patients. This is higher than the range of remission in earlier trials of 13-36%. CONCLUSION: Tight control aiming for low disease activity or even better still, remission, seems a promising option in treating patients with RA in clinical trials and probably also in daily practice.

Trends in economic consequences of rheumatoid arthritis over two subsequent years.

OBJECTIVE: To examine changes in direct costs and in working status over 2 yrs in patients with rheumatoid arthritis (RA). PATIENTS AND METHODS: In both 1999 and 2000, RA patients (n = 461) filled out a questionnaire retrospectively regarding utilization of health care, other RA-related direct costs and working status. Patients were categorized into four disease duration groups: 0-2 yrs, 2-6 yrs, 6-10 yrs and >10 yrs. At the same time points, disease activity was assessed. Logistic regression analyses were performed to identify a possible association between disease activity (high >66th percentile) measured at start of the second year and high direct costs (high >66th percentile) in the second year. RESULTS: Compared with the first year, a significant decrease in the costs for contacts with health care workers and for costs for laboratory tests was observed in the second year for the <2 yrs group. In the 2-6 yrs group and the >10 yrs group, we found a significant decrease in costs for devices and adaptations, but medication costs increased in the <2 yrs and the >10 yrs group in the second year. In the >10 yrs group, this was mainly due to an increasing number of patients who started to use biological agents during the second year. In all four disease duration groups, worse Visual Analogue Scale (VAS) disease activity and VAS general well-being were significantly associated with high direct costs. Of 97 patients working without disability at time of the first assessment, 12 (12%) patients became (partial) work disabled during follow-up. CONCLUSION: In particular, costs for devices/adaptations and for medication changed during follow-up. The latter was probably due to an increase in the use of biological agents. Hopefully a decrease in direct costs and a reduced percentage of patients getting work disabled by better disease control will outweigh the high costs of biological drugs in the future.

Safety and efficacy of leflunomide in primary Sjögren's syndrome: a phase II pilot study.

BACKGROUND: For invalidating symptoms in primary Sjögren's syndrome (pSS), there is still a need for easy-to-administer, cost-effective and well-tolerated systemic treatment. Leflunomide (LEF) is structurally unrelated to other immunomodulatory drugs and might be efficacious in pSS, given its characteristic immunoregulatory modes of action. OBJECTIVE: To investigate the safety and efficacy of LEF in pSS in a phase II open-label pilot study. METHODS: 15 patients with pSS with early and active disease received LEF 20 mg once daily for 24 weeks. Tolerability, safety and efficacy of LEF were evaluated every 8 weeks. Additional safety visits were performed every fortnight. RESULTS: Mild gastrointestinal discomfort (including diarrhoea) and hair loss were mainly reported. Five patients developed lupus-like skin lesions on the face, arms or trunk, responding well to topical corticosteroids, nevertheless causing the withdrawal of one patient. Two patients with pre-existing hypertension had to increase dosages of anti-hypertensive drugs. Increased levels of alanine aminotransferase normalised after dose reduction in two patients. A decrease in general fatigue and an increase in physical functioning were observed after 24 weeks. Serum IgG levels decreased from 8 weeks onwards. Schirmer test values increased, not reaching statistical significance, whereas sialometry values did not change. In four of five repeated biopsies, the lymphocytic focus score decreased at the rate of 1 focus/4 mm(2). A remarkable amelioration of leucocytoclastic vasculitis was observed in three patients. CONCLUSIONS: Although the safety profile seems fairly acceptable, the observed indications for efficacy were modest and may be doubtful in justifying a randomised controlled trial of LEF in pSS.

Utility and direct costs: ankylosing spondylitis compared with rheumatoid arthritis.

OBJECTIVES: To compare utility and disease-specific direct costs between patients with ankylosing spondylitis (AS) and patients with rheumatoid arthritis (RA) in the Netherlands. METHODS: Patients with AS and those with RA completed questions on disease characteristics, the EuroQol-5D (EQ-5D) to assess utility, and questionnaire resource utilisation. Resource utilisation was assessed prospectively in AS, but retrospectively in RA. True cost estimates (2003) were used to calculate the costs. Differences in disease characteristics between AS and RA were described, and determinants of EQ-5D utility and costs were explored by Cox proportional hazard regressions. RESULTS: 576 patients with RA and 132 with AS completed the questionnaires. EQ-5D utility (0.63 vs 0.7) was lower, and annual direct costs higher in RA (euro5167 vs euro2574). In multivariate Cox proportional hazard regressions, there was no difference in utility between the diagnostic groups, but patients with RA incurred higher direct costs after controlling for age, gender and disease duration. CONCLUSIONS: In patients with RA and patients with AS, who are under the care of a rheumatologist, utility is equally reduced, but healthcare costs are higher in RA after controlling for age, gender and disease duration. These data can be helpful to provide insights into the differences and similarities between the healthcare needs of both patient groups and to identify issues for further research and for policy in healthcare organisations.

Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA, an open-label strategy trial).

BACKGROUND: To investigate whether intensive treatment with methotrexate (MTX) according to a strict protocol and a computerised decision program is more beneficial compared to conventional treatment with MTX in early rheumatoid arthritis. METHODS: In a two-year multicentre open label strategy trial, 299 patients with early rheumatoid arthritis were randomly assigned to the intensive strategy group or the conventional strategy group. Patients in both groups received MTX, the aim of treatment being remission. Patients in the intensive treatment group came to the outpatient clinic once every month; adjustment of the MTX dosage was tailored to the individual patient on the basis of predefined response criteria, using a computerised decision program. Patients of the conventional strategy group came to the outpatient clinic once every three months; they were treated according to common practice. Cyclosporine was added if patients had an inadequate response to maximal tolerated MTX doses. RESULTS: Seventy six (50%) patients in the intensive strategy group achieved at least one period of remission during the two year trial, versus 55 patients (37%) in the conventional strategy group (p = 0.03). Areas under the curve for nearly all clinical variables were significantly lower-that is, there was a better clinical effect for the intensive treatment group compared with the conventional treatment group. CONCLUSION: The results of this study show that it is possible to substantially enhance the clinical efficacy early in the course of the disease by intensifying treatment with MTX, aiming for remission, tailored to the individual patient. Furthermore, participating rheumatologists indicated that the computerised decision program could be a helpful tool in their daily clinical practice.