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OBJECTIVE: Anti-tumour necrosis factor alpha (TNF-alpha) therapy yields high response rates shortly after institution of therapy in patients with rheumatoid arthritis (RA), and on theoretical grounds large differences in the effective dose between patients can be expected. Together with the high costs, these differences warrant new approaches to the way patients are dosed. METHODS: We used the Disease Activity Score (DAS28), a composite disease activity index, to titrate the dose of anti-TNF-alpha (adalimumab, D2E7; Knoll) in 21 patients with low disease activity in an open extension study lasting 40 weeks. The dose of anti-TNF-alpha was reduced stepwise and dosing intervals were kept stable. Disease activity and flares were assessed using the DAS28. Patients who flared received the previous effective dose. RESULTS: Dose reduction was accomplished in 15 patients. The total amount of anti-TNF-alpha given to the patients was reduced by 67%. At the end of the study the mean DAS28 had not changed and no patients dropped out because of persistent worsening of the RA. CONCLUSION: Dose titration of anti-TNF-alpha treatment using the DAS28 is feasible and leads to overall dose reduction while maintaining clinical efficacy. This approach will save costs and possibly prevent long-term side-effects.

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OBJECTIVE: To investigate the relationship between functional capacity, disease activity, and joint destruction over the course of rheumatoid arthritis (RA). METHODS: The followup data on 378 patients with early RA (duration <1 year), included in an open, prospective study since 1985 at the Department of Rheumatology of the University Medical Center Nijmegen, were used. Functional capacity, disease activity, and joint destruction were assessed using the Health Assessment Questionnaire disability index (HAQ DI), the Disease Activity Score (DAS), and a modification of the sharp radiographic damage score, respectively. Multiple linear regression was used to model the data collected at 0, 3, 6, and 9 years after study start, to investigate which variables influenced functional capacity during the disease course. A general linear mixed model for longitudinal data, which included the variables identified as significant in the multiple linear regression models and several interaction terms between the variables, was run. RESULTS: On average, the functional capacity of the patients, as measured by the HAQ DI, worsened over the course of the disease after an initial improvement. After an initial reduction in the extent of disease activity, the mean DAS remained more or less stable over the course of the disease. The mean modified sharp joint damage score worsened over the course of the disease, with a slower progression rate later in the disease. In the multiple linear regression at 0, 3, and 6 years after study start, disease activity was found to be an important factor influencing functional capacity, and at 6 and 9 years, joint damage had an important effect on functional capacity. Furthermore, at 6 and 9 years, there was an interaction effect of joint destruction with disease activity. In the general linear mixed model, disease activity, joint damage, and an interaction effect of disease activity and joint damage were the main factors explaining functional capacity. CONCLUSION: The effect of disease activity and joint destruction on functional capacity changes over the course of the disease. In early RA, functional capacity is most associated with disease activity, and in late disease, with joint damage.

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OBJECTIVE: To investigate the influences of the menopausal state, sex, and age on the course and outcome of rheumatoid arthritis (RA). METHODS: A cohort of patients with early RA (209 female, 123 male) was studied. Sex, age, and menopausal state at baseline, and disease activity, radiographic joint destruction, and physical disability during 6 years of followup were assessed. RESULTS: The Disease Activity Score (DAS) was significantly higher in female compared to male patients at any time point except at the time of inclusion. This was mainly due to postmenopausal patients. Radiographic joint destruction (RJD) was significantly worse in female patients compared to males at the time of inclusion. Postmenopausal patients had significantly higher RJD than premenopausal patients at the time of inclusion and 3 years thereafter. Older male patients showed worse RJD than younger male patients at all time points measured. Physical disability was significantly worse in female compared to male patients, as well as in postmenopausal compared to premenopausal patients, and older male compared to younger male patients. Stepwise regression analysis revealed that at 3 years higher age and female sex were the best predictors for a worse DAS. Higher age and the interaction term between menopausal state and age best predicted higher RJD. Higher age and the interaction term between menopausal state and age best predicted Health Assessment Questionnaire (HAQ) score. CONCLUSION: Higher age at presentation of RA leads to a more severe disease course in terms of DAS, RJD, and HAQ. Although female sex has a deteriorating effect on the DAS, the menopausal state is responsible for the major part of the differences in outcome between men and women. Postmenopausal state in early RA influences future disability and damage, especially in older patients.

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BACKGROUND: Physical disability is part of the end point measures in rheumatoid arthritis clinical trials. The Stanford Health Assessment Questionnaire Disability Index (HAQ DI) is often used for this purpose but lacks international uniformity owing to variations in the translated and adapted questionnaires and variations in its calculation. To study the consequences of these variations the previous Dutch HAQ (HAQ90) was revised, resulting in a new Dutch HAQ (HAQ99). OBJECTIVE: To compare DI scores from the two versions, and to study the consequences of applying different calculation methods for the DI score. METHODS: 78 patients completed both the HAQ99 and the HAQ90. To compare the use of different category score calculation methods a post hoc analysis on prospectively collected data obtained in clinical trials was performed. RESULTS: No statistically significant differences were observed between the DI scores of the HAQ90 and the HAQ99 using the alternative method (that is, without correcting for aid and devices). However, correcting for the use of aid or devices or not did result in statistically significant different DI scores. The systematic shift when using the maximum or mean item score for calculation of the category score resulted in non-comparable absolute DI scores. CONCLUSION: The use of HAQ DI questionnaires with different numbers of items and/or categories does not hinder international comparability, except when these variations interfere with the calculation method of the DI (as in the case of questionnaires without a section correcting for devices). For the sake of international uniformity the HAQ or any validated translation should be used and calculated in a standard way, including correcting for the use of aid and devices, and taking the maximum within each category as the category score.

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OBJECTIVE: To study the presence of chronic coexisting diseases in patients with rheumatoid arthritis (RA) and its effect on RA treatment, disease course, and outcome during the first years of the disease. METHODS: From January 1985 to December 1990, 186 patients with recent onset RA were enrolled in a prospective longitudinal study. Between January 1991 and November 1992 patients were interviewed on the basis of a comorbidity questionnaire. For analysis the diseases were coded according to the International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) medical diagnoses. Disease activity during the period of followup was measured by the Disease Activity Score. Outcome in terms of physical disability (Health Assessment Questionnaire) and radiological damage (Sharp's modified version) over 3 and 6 year periods was determined. RESULTS: In the group of 186 patients, with mean disease duration of 4.3 years at January 1991, 50 patients (27%) reported at least one chronic coexisting disease. The most frequently reported coexisting diseases were of cardiovascular (29%), respiratory (18%), or dermatological (11%) origin. For the major part (66%) chronic coexisting diseases were already present before onset of RA. No statistically significant differences in use of disease modifying antirheumatic drugs or corticosteroids were observed between RA patients with and without chronic coexisting diseases. No statistically significant differences were found in disease activity or in outcome in terms of physical disability and radiological damage over 3 and 6 year periods between the 2 groups with RA. CONCLUSION: The results showed that about 27% of patients with RA in this inception cohort had at least one chronic coexisting disease. Treatment, disease course, and outcome did not differ between patients with and without chronic coexisting diseases during the first years of the disease.

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OBJECTIVE: Few data have been presented to document the impact of rheumatoid arthritis (RA) on socio-economic well-being. In this study, exact figures on socio-economic consequences were assessed. METHODS: The socio-economic consequences were studied in an inception cohort (186 early RA patients, mean disease duration 3 yr) by measuring the change in work capability, income, rest during the daytime, leisure time activity, transport mobility, housing and social support occurring in the first years of the disease. RESULTS: For 89% of the patients, RA had an impact on one of the socio-economic items; for 58%, at least three of these items were affected simultaneously. Work disability appeared to be 4-15 times higher than in the general population. After 3 yr, 42% of the patients were registered as work disabled. Nearly a quarter of the patients experienced income reduction. Over 40% of the patients claimed extra rest during the daytime. Leisure activity changed towards activities with a lower joint load. There was a decline in transport mobility for 52% of the patients. Social support increased strongly. CONCLUSIONS: Socio-economic change already presents in the first years of RA and appears to be influenced by age, gender, marital status and work disability. Furthermore, physical limitation appeared to be predictive for work-related income reduction, reduced transport mobility and development of social dependency.

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We compared the validity of the American College of Rheumatology (ACR) and the European League of Associations for Rheumatology (EULAR) definitions of response in rheumatoid arthritis (RA) clinical trials. US: ACR and EULAR improvement criteria were calculated in 7 large randomized RA clinical trials. The discriminant validity of the response criteria between treatment groups was studied using the Mantel-Haenszel chi-squared value. To compare both sets of criteria the chi-squared ratio was determined for each trial. Europe: In 2 large randomized RA clinical trials, ACR and EULAR criteria were calculated, once with extensive and once with 28 joint counts. The classification of patients with these 4 criteria were compared with each other using cross tables. We further studied the difference in response between treatment groups per trial, the association of response with patient and investigator assessment of improvement, and the association of response with radiological progression. US: The chi-squared ratio for most trials was close to 1. There was no clear pattern suggesting that the discriminant validity of the ACR criteria was stronger than the discriminant validity of the EULAR definition of response or vice versa. Europe: Conflicting results between ACR and EULAR were present in only 3% of patients in both trials. The discriminant validity of all 4 criteria (ACR and EULAR with reduced and extensive joint counts) was comparable. All criteria were related with the overall assessment of improvement by both investigator and patient. The association with radiographic progression was comparable for EULAR and ACR improvement criteria. There is a high level of agreement between ACR and EULAR improvement classification, and their validity is equivalent. The discriminating potential of the criteria between treatment groups is comparable, as is the association with patient's and investigator's overall assessment and with radiographic progression.

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There are two major aspects to evaluate in patients with established RA, namely (i) the state or progress of the disease, and (ii) the effects of specific interventions. The evaluation should include reliable, valid and sensitive measures of disease activity, tissue damage and health status. It is important to recognise that measures of disease activity can be influenced by tissue damage as well. Also, in established RA, health status is likely to be influenced by both disease activity and tissue damage. Whether current rules concerning improvement or remission, which were developed in the context of early RA, can be applied to established disease has to be investigated. While use of radiographs is the current standard method of assessing damage in established RA, range-of-motion measures and muscle strength indices may be a more practical and an equally valid alternative. When selecting health status instruments one should carefully explore and pretest possible health status measures for specific clinical or study settings.

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OBJECTIVE: To study the validity of response criteria for rheumatoid arthritis (RA) that included 28-joint counts instead of more comprehensive joint counts. METHODS: In a double-blind, placebo-controlled trial of 105 patients treated with methotrexate, sulfasalazine, or both, response was evaluated at week 52. Both European League Against Rheumatism and American College of Rheumatology definitions of response, with comprehensive as well as simplified joint counts, were calculated. We studied the differences between the criteria with and without simplified joint counts, the discriminating capacity between treatment groups, and the association with change in functional capacity and joint damage. RESULTS: Response criteria that included 28-joint counts classified patients' responses more conservatively. No differences between treatment groups were found with either set of response criteria. The association with change in functional capacity was significant in all cases. All response criteria were significantly associated with radiographic progression of RA. CONCLUSION: Improvement criteria that include 28-joint counts are as valid as the original improvement criteria that included more comprehensive joint counts.

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In rheumatoid arthritis nowadays a more aggressive treatment strategy is followed based on early consistent use of second-line agents frequently given in combination. This approach requires an accurate monitoring of the disease activity to follow the course of the disease and to evaluate therapeutic interventions. International consensus is reached over a core set of disease activity variables, including: a 28-joint count for tenderness and swelling, an acute phase reactant, patient's pain and global disease activity, physician's global disease activity, functional disability and radiographs. Guidelines for measurement techniques need to be further specified. Indices of disease activity are developed to improve the unambiguous interpretation of disease activity and comparability of trial results. These measures can be divided in measures for current disease activity and improvement criteria. Further validation will be necessary to adapt finally a uniform measurement technique. The usefulness of self-administered joint counts needs to be studied further.

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Treatment with slow-acting anti-rheumatic drugs (SAARDs) is nowadays initiated earlier in the disease course, preferably before any radiographic damage has occurred. SAARDs have the ability to decrease inflammatory synovitis as measured by clinical and laboratory variables, and there is some evidence that they improve physical function and decrease the progression rate of joint damage in patients with early rheumatoid arthritis. There is a clear difference in survival time between the various SAARDs. The efficacy/toxicity profiles of the SAARDs show equal variation. Rank order of prescription or disease duration may have an effect on drug survival, but different treatment strategies are also important sources of variation. Efficacy might be improved by combining different SAARDs (starting with a multiple drug regimen, or adding a drug to the first one), but further research is necessary to prove this hypothesis.

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In a prospective follow-up study of patients with early-onset rheumatoid arthritis, the prevalence of remission according to the 1981 American Rheumatism Association (ARA) preliminary criteria was evaluated. A total of 227 patients with a median follow-up of 3.9 yr and a total of 2832 follow-up visits were studied. The ARA remission criteria were fulfilled in 9.5% of these visits. The percentage of patients with at least one visit fulfilling the ARA criteria was for years 2-6 approximately 25%. Each year, approximately 15% of the patients were in remission for at least two consecutive visits. A comparison was made between the ARA remission criteria and the Disease Activity Score (DAS). DAS < 1.6 corresponded with being in remission according to the ARA criteria. The DAS is being proposed as a tool to define remission because absence of disease activity should be measured using the same method as for higher levels of disease activity, preferably on a continuous scale.

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The course of rheumatoid arthritis (RA) is highly variable, ranging from a mild self-limiting to a very aggressive form. To follow and predict the course of the disease in an individual patient, several recognized and proposed prognostic markers, including markers for disease activity, have been considered. However, no individual marker for disease activity has shown satisfactory specificity and sensitivity. Thus an index of disease activity combining several variables is needed. Response criteria based on the Disease Activity Score (DAS) were developed in an open study of 227 patients with RA of recent onset. Response was defined as a combination of a significant change from baseline and the level of disease activity attained. Good response was defined as a significant decrease in DAS (> 1.2) and a low level of disease activity ( < or = 2.4). Non-response was defined as a decrease < or = 0.6, or a decrease > 0.6 and < or = 1.2 with an attained DAS > 3.7. Any other scores were regarded as moderate responses. These response criteria were adopted as the EULAR response criteria and were validated, together with the WHO/ILAR and ACR response criteria, in a 48 week, double-blind trial comparing hydroxychloroquine and sulphasalazine in 60 patients. Response was evaluated against radiographic damage (construct validity) and functional disability (criterion validity); discriminating capacity was also assessed. EULAR response criteria showed significant association with X-ray progression and functional disability, and differentiated between sulphasalazine and hydroxychloroquine. ACR and WHO/ILAR response criteria performed less well, only showing good criterion validity. Several groups are working on the prognosis of early RA and have agreed to collaborate to test DAS and other prognostic markers to better recognize severe, progressive RA, before joint damage takes place.

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OBJECTIVE: To validate the European League Against Rheumatism (EULAR), the American College of Rheumatology (ACR), and the World Health Organization (WHO)/International League Against Rheumatism (ILAR) response criteria for rheumatoid arthritis (RA). METHODS: EULAR response criteria were developed combining change from baseline and level of disease activity attained during follow up. In a trial comparing hydroxychloroquine and sulfasalazine, we studied construct (radiographic progression), criterion (functional capacity), and discriminant validity. RESULTS: EULAR response criteria had good construct, criterion, and discriminant validity, ACR and WHO/ILAR criteria showed only good criterion validity. CONCLUSION: EULAR response criteria showed better construct and discriminant validity than did the ACR and the WHO/ILAR response criteria for RA.

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In a cohort of patients with early rheumatoid arthritis, sulphasalazine (SASP) was mainly given as a first-choice second-line agent. SASP resulted in a significantly better survival rate compared with hydroxychloroquine, which is also given as a first-choice agent. When the survival rate of SASP was compared with that of aurothioglucose, both given as second-choice agents, again, a statistically significant better survival rate was found for SASP. In 9% of the patients, SASP could be withdrawn as a complete remission was obtained. Adverse reactions occurred mainly during the first 3 months of treatment, and in 20% of patients these were severe enough to stop treatment. Gastrointestinal adverse reactions were most frequently observed, and all adverse reactions were completely reversible after treatment withdrawal. Treatment was started with a standard dose of 2000 mg/day. However, in approximately 30% of the patients, this dose was increased up to 3000 mg/day and, in another 30%, the dose was decreased to 1,500 or 1,000 mg/day.

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The herd health approach for dairy herds with a high bulk milk somatic cell count, in which Streptococcus agalactiae plays a major role, was evaluated. After introduction of the standard mastitis prevention programme, all quarters of infected cows were treated during lactation. In three of the four herds investigated, the bulk milk somatic cell count dropped below the limit of 400,000 cells/ml for a long period of time. The herd in which there were many infections with Staphylococcus aureus and Streptococcus agalactiae was an exception. The management, somatic cell count, and prevalence of subclinical mastitis in the different herds is discussed. It is concluded that for infection with Streptococcus agalactiae at the herd level, treatment during lactation can be an effective method to lower the bulk milk somatic cell count. In essence, however, the approach to the problem lies in the standard mastitis prevention programme.

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