Frequency and effectiveness of dose increase of adalimumab, etanercept, and infliximab in daily clinical practice.

OBJECTIVE: To describe the frequency and effectiveness of dose increase of adalimumab, etanercept, and infliximab in the treatment of rheumatoid arthritis (RA) in daily clinical practice. METHODS: All RA patients with a dose increase of tumor necrosis factor (TNF)-blocking therapy between January 1997 and January 2008 were selected from a register including data from RA patients starting a first TNF-blocking agent (the Dutch Rheumatoid Arthritis Monitoring registry). The primary outcome was change in Disease Activity Score in 28 joints (DAS28) at 3 months after dose increase. Secondary outcomes were the change in DAS28 at 6 months after dose increase, the European League Against Rheumatism response rates, and the percentages of patients reaching a DAS28 of ≤3.2 at 3 and at 6 months after dose increase. Furthermore, the effectiveness of dose increase was assessed for the different reasons for dose increase: nonresponse, loss of response, and partial response. RESULTS: During the study period, the dose was increased in 44 (12%) of the 368 adalimumab patients, 32 (8%) of the 420 etanercept patients, and 115 (36%) of the 323 infliximab patients. The change in DAS28 at 3 months and 6 months after dose increase was limited and only significant in etanercept patients at 3 months (-0.51; P = 0.035). Disease activity decreased significantly at 3 months from dose increase in the nonresponders and patients with loss of response (-0.66 and -0.99, respectively; both P = 0.001), but not in the partial responders. CONCLUSION: Although dose increase was applied in all 3 TNF-blocking agents in daily clinical practice, these results suggest that the effectiveness of dose increase is limited.

Evaluating guidelines on continuation of anti-tumour necrosis factor treatment after 3 months: clinical effectiveness and costs of observed care and different alternative strategies.

OBJECTIVE: To study the adherence of rheumatologists to the Dutch guidelines for anti-tumour necrosis factor alpha (TNF-alpha) treatment. The secondary objective was to evaluate alternatives to the present guidelines with regard to the percentage of responders and costs. METHODS: The response (>1.2 DAS28 decrease) in patients who started on anti-TNF-alpha treatment for the first time was evaluated at 3 and 6 months after initiation. How many patients continued or discontinued their initial anti-TNF-alpha treatment was evaluated. Possible alternative guidelines were evaluated by means of a decision tree, with regard to the expected percentage of successfully (responders) and unsuccessfully treated patients and expected costs. RESULTS: At 3 months 56% (N = 306) and 44% (N = 233) of all 539 evaluable patients were classified as responders or non-responders, respectively. Despite the guidelines, most (81%) (N = 189) of the non-responders continued treatment. 37% of the non-responders who continued anti-TNF-alpha treatment were eventually classified as responders at 6 months. Decision analytical modelling showed that with equal expected costs all alternative strategies would result in more responders than according to theoretical full adherence with the guidelines. "Continuation in case of partial response" had the best trade-off between successfully treated patients (64%) and unsuccessfully treated patients (17%). CONCLUSION: There was suboptimal adherence to the Dutch guidelines for treatment with anti-TNF-alpha for rheumatoid arthritis patients. This seemed to be justified by the fact that a delayed response up to 6 months was shown. If treatment is continued despite a non-response at 3 months, this is only recommended in patients with at least a partial response (at least 0.6 DAS28 improvement).

The effectiveness and medication costs of three anti-tumour necrosis factor alpha agents in the treatment of rheumatoid arthritis from prospective clinical practice data.

AIM: to evaluate the effects of adalimumab, etanercept and infliximab on disease activity, functional ability and quality of life and the medication costs in a naturalistic design. METHODS: All patients from the Dutch Rheumatoid Arthritis Monitoring (DREAM) register starting on tumour necrosis factor (TNF)alpha-blocking agents for the first time were monitored and assessed by trained research nurses every 3 months. The primary outcome was the Disease Activity Score (DAS28) course over the 12 months follow-up, analysed by linear mixed models. Secondary outcomes were the Health Assessment Questionnaire (HAQ), EuroQol five dimensions (EQ-5D) and the Short-Form 36 items (SF36) scores, and medication-related total costs. RESULTS: The DAS28 and SF-36 physical component scale decreased in all three medication groups over 12 months, but the decrease was larger for adalimumab and etanercept in comparison to infliximab (p<0.001). The analyses of the HAQ and the EQ-5D scores showed the same (non-significant) trend, namely that at 12 months, the functionality and quality of life was better for adalimumab and etanercept patients. With regard to the medication costs, infliximab treatment resulted in significantly higher costs over the follow-up period than treatments with either adalimumab or etanercept. The comparison between adalimumab and etanercept showed a significant difference in the 12-month DAS28 course (p = 0.031). There were no additional indications for differences in effectiveness or costs between adalimumab and etanercept. CONCLUSION: The evaluation of the effectiveness and costs showed that adalimumab and etanercept are more or less equal and favourable compared to infliximab in the first year of treatment.

The efficacy of anti-TNF in rheumatoid arthritis, a comparison between randomised controlled trials and clinical practice.

BACKGROUND: Randomised controlled trials (RCTs) evaluating the efficacy of antagonists to tumour necrosis factor alpha (TNFalpha) showed high response percentages in the groups treated with active drugs. OBJECTIVE: To compare the efficacy of anti-TNF treatments for rheumatoid arthritis (RA) patients in RCTs and in daily clinical practice, with an emphasis on the efficacy for patients eligible and not eligible for RCTs of anti-TNF treatments. METHODS: First, randomised placebo-controlled trials written in English for etanercept, infliximab and adalimumab for patients with RA were selected by a systematic review. Second, the DREAM (Dutch Rheumatoid Arthritis Monitoring) register with patients starting for the first time on one of the TNF-blocking agents was used. Patient characteristics, doses of medication and co-medication as well as the ACR20 response percentages were compared between RCTs and DREAM data, stratified for trial eligibility. RESULTS: In 10 of 11 comparisons, the ACR20 response percentages were lower in daily clinical practice than in the RCT active drug group, which was significant in five of 11 comparisons. Only 34-79% of DREAM patients fulfilled the selection criteria for disease activity in the several RCTs examined. DREAM patients eligible for RCTs had higher response percentages than ineligible DREAM patients. ACR20 response percentages of eligible DREAM patients were comparable with the ACR20 response percentages of the RCT active drug group in 10 of 11 comparisons. CONCLUSION: The efficacy of TNF-blocking agents in RCTs exceeded the efficacy of these drugs in clinical practice. However, in clinical practice more patients with lower disease activity were treated with TNF-blocking agents compared with those treated in RCTs. For daily practice patients who were eligible for RCTs, responses were more similar to responses reached in RCTs.

Aggressive treatment in early rheumatoid arthritis: a randomised controlled trial. On behalf of the Rheumatic Research Foundation Utrecht, The Netherlands.

OBJECTIVES: To compare three therapeutic strategies using slow acting antirheumatic drugs (SAARDs) in early rheumatoid arthritis (RA), for their disease modifying properties, toxicity, and lag time until treatment effect. METHODS: Patients with recent onset RA from six hospitals were randomly assigned to immediate initiation of one of three treatment strategies: (I) a "mild SAARD with a long lag time" (hydroxychloroquine, if necessary replaced by auranofin); (II) a "potent SAARD with a long lag time" (intramuscular gold, if necessary replaced by D-penicillamine); (III) a "potent SAARD with a short lag time" (methotrexate, if necessary replaced by sulfasalazine). Comparisons included two years of follow up. RESULTS: All SAARD strategies reduced mean disease activity. A greater percentage of patients improved clinically with strategies II and III than with strategy I: percentages of patients improved on joint score with strategies II and III (79% and 82%, respectively), which was statistically different from strategy I (66%). The same was true for remission percentages: 31% and 24% v 16%, respectively). Longitudinal analysis showed significantly less disability with strategy III, and a lower erythrocyte sedimentation rate with strategy II than with strategy I. In addition, radiological damage after one and two years, was significantly lower in strategies II and III (at two years median scores were 11 and 10 v 14 in strategy I, p<0.05). Toxicity was increased in strategy II compared with the other strategies. CONCLUSION: Strategy III, comprising methotrexate or sulfasalazine, produced the best results weighing effectiveness and toxicity. Strategy I (hydroxychloroquine or auranofin) was slightly less effective, and strategy II (intramuscular gold or D-penicillamine) was associated with increased toxicity.

Toxicity of anti-rheumatic drugs in a randomized clinical trial of early rheumatoid arthritis.

OBJECTIVE: To evaluate the toxicity of slow-acting anti-rheumatic drugs (SAARDs) and non-steroidal anti-inflammatory drugs (NSAIDs) in early rheumatoid arthritis. METHODS: Patients were randomized to receive a SAARD-hydroxychloroquine (HCQ; n=120), i.m. gold (n=114) or methotrexate (MTX; n=118)-or a NSAID only (n=67). Patients in the three SAARD groups were allowed to take NSAIDs. Follow-up included 545 patient-years (p-yr). Adverse effects were attributed to specific medications using the Naranjo scoring method. RESULTS: Fifty-five per cent of the patients suffered from adverse effect(s). Adverse effects were most common during i.m. gold therapy (87 per 100 p-yr), which led to permanent discontinuation of this treatment in 31 cases. The incidences of adverse effects that were probably attributable to NSAIDs in patients treated simultaneously with a SAARD were similar for the three SAARD groups. The mean period until the first adverse effect was longer in the MTX group (39 weeks) than in the HCQ group (27 weeks). Baseline clinical and sociodemographic parameters were not predictive of the occurrence of adverse effects. CONCLUSION: No adverse effect could be classified as definitely related to either SAARDs or NSAIDs by the Naranjo scoring method. The incidence of possible adverse effects of NSAIDs and SAARDs was 72 per 100 p-yr, and adverse effects led to permanent discontinuation of the therapy in 56 cases (13%) (31 patients receiving i.m. gold, 12 receiving MTX, 10 receiving HCQ and three receiving NSAID only).

Is there an indication for HLA-DR typing for individual patients with rheumatoid arthritis?

The clinical expression of rheumatoid arthritis (RA) varies considerably among individual patients. Genetic variations in human leucocyte antigen (HLA) may influence susceptibility to RA and the severity of the disease. The literature concerning the association of HLA-DR with the susceptibility to and the clinical expression of RA is reviewed here, taking into account the different populations studied and different typing techniques. An association between the 'shared epitope' and RA susceptibility is present on a group level and may be of some pathophysiological interest. However HLA-DR typing is not useful as a diagnostic test for individuals. The reported associations between HLA-DR and RA severity are various, which might be due to the different typing techniques used. Results from most studies using genomic techniques for HLA-DR typing show an association between HLA-DR4+, DR1+ and a more severe disease course in patient groups. However, this association is too weak to be relevant for individual patients. Therefore, with our current typing techniques, HLA-DR typing is not a useful prognostic test for individual RA patients.

Association of HLA-DR with susceptibility to and clinical expression of rheumatoid arthritis: re-evaluation by means of genomic tissue typing.

The clinical expression of rheumatoid arthritis (RA) varies considerably among individual patients. Genetic variations in human leucocyte antigen (HLA) may influence clinical expression. We re-examined the association of HLA-DR with susceptibility to and clinical expression of RA using genomic tissue typing, since most studies were based on (less reliable) serological techniques. Seventy-eight patients with recent-onset RA, all participating in a clinical trial on therapeutic strategies, were HLA-DR typed by means of low-resolution genomic typing. Cumulative disease activity within the first 3 yr of disease was measured. Of the RA patients, 54% expressed DR4 (DR4+) vs 26% of healthy controls. Rheumatoid factor (RF)-positive patients had a higher cumulative disease activity than RF-negative patients. Patients who were either DR1+ or DR4+ had a higher cumulative disease activity than those who expressed neither DR1 nor DR4. This association was less obvious after correction for RF status. The association of DR52+ (DR3, 5, 6) and a lower cumulative disease activity could also not be demonstrated after correction for RF status. Among RF-negative patients, DR51+ (or DR2+) was associated with a higher cumulative disease activity. Other HLA-DR types (including DR1 and DR4 separately) were not associated with the severity of RA. DR4 was associated with susceptibility to RA in our patients; HLA-DR low-resolution genomic tissue typing did not yield additional information to RF status for the clinical identification of individual patients with a poor prognosis.

Effects of patient education on compliance with basic treatment regimens and health in recent onset active rheumatoid arthritis.

OBJECTIVES: To determine the effects of patient education on compliance and on health in patients with active, recent onset rheumatoid arthritis (RA). METHODS: A randomised, controlled, assessor blinded, one year trial. The experimental group followed an education programme. All patients started on sulphasalazine therapy. Compliance with sulphasalazine was measured by pill counting. Compliance rates with regimens of physical exercise, endurance activities, and energy conservation were measured by questionnaires. Compliance with prescriptions of joint protection was scored using a test for joint protection performance. Health was measured by a Disease Activity Score (function of erythrocyte sedimentation rate, Ritchie score, and number of swollen joints), C reactive protein, Dutch-AIMS scores, and M-HAQ scores, range of motion of shoulder, elbow, and knee joints. Parameters were scored at baseline and after three, six, and 12 months. RESULTS: Sixty of 65 patients gave informed consent, five of them withdrew from follow up. Compliance with sulphasalazine exceeded 80% with no differences between groups. Compliance with physical exercise (at three months), energy conservation (at three and at 12 months), and joint protection (at three months) improved significantly more in the experimental group. The improvements of health were not different in the groups. CONCLUSION: Compliance with sulphasalazine among patients with active, recent onset RA is high, whether formal patient education is followed or not. Compliance with physical exercise, energy conservation, and joint protection was increased by patient education. Formal patient education did not improve health status.

Patient education and disease activity: a study among rheumatoid arthritis patients.

OBJECTIVE: To determine whether patients experiencing high disease activity derive more benefit from patient education than those experiencing low disease activity. METHODS: Data from a randomized study on the effects of a program of patient education were analyzed retrospectively. Four subgroups were studied: the high disease activity subgroup of patients who had participated in the educational program, the complementary low disease activity subgroup, the high disease activity subgroup of controls, and its low disease activity complement. Patients with erythrocyte sedimentation rate > 28 mm/first hour were classified as having high disease activity. Effects on frequency of physical exercises, endurance exercises, and relaxation exercises and effects on health status (Modified Health Assessment Questionnaire, Dutch Arthritis Impact Measurement Scales [AIMS]) were measured. RESULTS: There were no significant differences between the adherence parameters of the various pairs of groups. Four months after the educational program began, anxiety and depression scores on the Dutch-AIMS had increased among participating patients who were experiencing high disease activity and decreased among those who were experiencing low disease activity. CONCLUSIONS: Patients experiencing high disease activity did not derive more benefit from patient education than those experiencing low disease activity. On the contrary, an increase of anxiety and depression is found in these patients. Further study is needed to confirm our findings.

Coordinated individual education with an arthritis passport for patients with rheumatoid arthritis.

OBJECTIVE: To evaluate the effects of a program for individual education in combination with the use of an arthritis passport. METHODS: We studied 3 groups of patients with rheumatoid arthritis. The first experimental group received educational materials and followed the program under the guidance of their regular providers of health care whose activities were coordinated through arthritis passports. The second experimental group only received education materials; the control group received only usual care. RESULTS: There were no effects on self-efficacy expectations, knowledge, health status, or behavior in either experimental group. Opinions of general practitioners, physiotherapists, and visiting nurses concerning the arthritis passport were very positive, but rheumatologists' opinions were not. Opinions on coordination of care were more positive among the physiotherapists of the experimental group. CONCLUSIONS: Individual education for patients with rheumatoid arthritis by health care providers during routine consultations, as implemented in this program, had no effect on self-efficacy expectations, knowledge, health status, or health behavior. Likewise, the distribution of educational materials by itself without the involvement of health care providers had no effect. The use of the arthritis passport improved coordination of care, especially for physiotherapists.

The effectiveness of early treatment with "second-line" antirheumatic drugs. A randomized, controlled trial.

OBJECTIVE: To compare two therapeutic strategies for patients with recent-onset rheumatoid arthritis. DESIGN: Open, randomized clinical trial. SETTING: Outpatient clinics of six clinical centers. PATIENTS: 238 consecutive patients with recently diagnosed rheumatoid arthritis. INTERVENTIONS: Delayed or immediate introduction of treatment with slow-acting antirheumatic drugs (SAARDs). MEASUREMENTS: Primary end points were functional disability, pain, joint score, and erythrocyte sedimentation rate at 6 and 12 months and progression of radiologic abnormalities at 12 months. RESULTS: Statistically significant advantages at 12 months for patients receiving the SAARD strategy (immediate treatment with SAARDs) with regard to all primary end points that may be clinically important are indicated by the differences in improvements from baseline and their 95% CIs. These differences were 0.3 (95% CI, 0.2 to 0.6) for disability (range, 0 to 3), 10 mm (CI, 1 to 19 mm) for pain (range, 0 to 100 mm), 39 (CI, 4 to 74) for joint score (range, 0 to 534), and 11 mm/h (CI, 3 to 19 mm/h) for erythrocyte sedimentation rate (range, 1 to 140 mm/h), all in favor of SAARD treatment. The SAARD strategy also appears to be advantageous at 6 months. Radiologic abnormalities progressed at an equal rate in the SAARD and the non-SAARD groups; the difference in progression (range, 0 to 448) was 1 (CI, -3 to 5). Analyses were based on the intention-to-treat principle and thus included 29% of patients in the non-SAARD group who discontinued the non-SAARD treatment strategy; treatment was usually discontinued because of insufficient effectiveness. The SAARD strategy including two alternative SAARDs could not be continued by 8% of patients, usually because of adverse reactions. CONCLUSIONS: Early introduction of SAARDs may be more beneficial than delayed introduction for patients with recently diagnosed rheumatoid arthritis.

Group education for patients with rheumatoid arthritis.

Patients with rheumatoid arthritis must learn to adjust their exercise, rest and medication to the varying activity of the disease. Patient education can help patients in making the right decisions about adjustments in their treatment regimen and in attaining "self-management" behaviors. We developed a group education program based on social learning theory and the 'Arthritis Self-Management Course' developed in the USA by Lorig. Goal of the program is the strengthening of self-efficacy, outcome expectations and self-management behaviors of RA patients which may lead to better health status. The program has been evaluated in an experimental design. We established significant positive effects of the group training on functional disability, joint tenderness, practice of relaxation and physical exercises, self-management behavior, outcome expectations, self-efficacy function and knowledge. After 14 months we still found effects on practice of physical exercises, self-efficacy function and knowledge.